ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)] Neutropenia [see Warnings and Precautions (5.2)] Left Ventricular Dysfunction [see Warnings and Precautions (5.3)] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)] Neutropenia [see Warnings and Precautions (5.2)] Left Ventricular Dysfunction [see Warnings and Precautions (5.3)] The most common adverse reactions (>=20%), including laboratory abnormalities, in patients with:HER2-Positive, HER2-Low, and HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and HER2-Positive (including IHC 3+) Solid Tumors are decreased white blood cell count, nausea, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, fatigue, decreased platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, increased blood alkaline phosphatase, vomiting, alopecia, constipation, decreased blood potassium, decreased appetite, diarrhea, and musculoskeletal pain. (6.1)HER2-Positive Early Breast Cancer are decreased hemoglobin, increased alanine aminotransferase, increased aspartate aminotransferase, decreased white blood cell count, nausea, peripheral neuropathy, diarrhea, decreased neutrophil count, alopecia, fatigue, decreased lymphocyte count, rash, musculoskeletal pain, decreased blood potassium, constipation, vomiting, stomatitis, and decreased appetite. (6.1) HER2-Positive Metastatic Breast Cancer in Combination with Pertuzumab are decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, nausea, increased alanine aminotransferase, diarrhea, increased aspartate aminotransferase, decreased lymphocyte count, decreased platelet count, increased blood alkaline phosphatase, decreased blood potassium, fatigue, alopecia, vomiting, upper respiratory tract infection, constipation, decreased appetite, decreased weight, COVID-19, musculoskeletal pain, increased blood bilirubin, and abdominal pain. (6.1)HER2-Positive Gastric Cancer are decreased hemoglobin, decreased white blood cell count, decreased neutrophil count, decreased lymphocyte count, decreased platelet count, nausea, decreased appetite, increased aspartate aminotransferase, fatigue, increased blood alkaline phosphatase, increased alanine aminotransferase, diarrhea, decreased blood potassium, vomiting, constipation, increased blood bilirubin, pyrexia, and alopecia. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. HER2-Positive, HER2-Low, and HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and HER2-Positive (including IHC 3+) Solid Tumors are decreased white blood cell count, nausea, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, fatigue, decreased platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, increased blood alkaline phosphatase, vomiting, alopecia, constipation, decreased blood potassium, decreased appetite, diarrhea, and musculoskeletal pain. (6.1). HER2-Positive Early Breast Cancer are decreased hemoglobin, increased alanine aminotransferase, increased aspartate aminotransferase, decreased white blood cell count, nausea, peripheral neuropathy, diarrhea, decreased neutrophil count, alopecia, fatigue, decreased lymphocyte count, rash, musculoskeletal pain, decreased blood potassium, constipation, vomiting, stomatitis, and decreased appetite. (6.1) HER2-Positive Metastatic Breast Cancer in Combination with Pertuzumab are decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, nausea, increased alanine aminotransferase, diarrhea, increased aspartate aminotransferase, decreased lymphocyte count, decreased platelet count, increased blood alkaline phosphatase, decreased blood potassium, fatigue, alopecia, vomiting, upper respiratory tract infection, constipation, decreased appetite, decreased weight, COVID-19, musculoskeletal pain, increased blood bilirubin, and abdominal pain. (6.1). HER2-Positive Gastric Cancer are decreased hemoglobin, decreased white blood cell count, decreased neutrophil count, decreased lymphocyte count, decreased platelet count, nausea, decreased appetite, increased aspartate aminotransferase, fatigue, increased blood alkaline phosphatase, increased alanine aminotransferase, diarrhea, decreased blood potassium, vomiting, constipation, increased blood bilirubin, pyrexia, and alopecia. (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.HER2-Positive, HER2-Low, and HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)ENHERTU as MonotherapyThe pooled safety population described in WARNINGS and PRECAUTIONS reflects exposure to ENHERTU 5.4 mg/kg intravenously every weeks in 2233 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast02, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Breast06, DESTINY-Lung01, DESTINY-Lung02, DESTINY-CRC02, and DESTINY-PanTumor02. Among these patients, 67% were exposed for greater than months and 39% were exposed for greater than 12 months. In this pooled safety population, the most common (>=20%) adverse reactions (including laboratory abnormalities) were decreased white blood cell count (73%), nausea (72%), decreased hemoglobin (67%), decreased neutrophil count (65%), decreased lymphocyte count (60%), fatigue (55%), decreased platelet count (48%), increased aspartate aminotransferase (46%), increased alanine aminotransferase (43%), increased blood alkaline phosphatase (39%), vomiting (38%), alopecia (37%), constipation (32%), decreased blood potassium (32%), decreased appetite (31%), diarrhea (30%), and musculoskeletal pain (24%). ENHERTU in Combination with PertuzumabThe pooled safety population described in WARNINGS and PRECAUTIONS reflects exposure to ENHERTU 5.4 mg/kg in combination with pertuzumab intravenously every weeks in 431 patients in DESTINY-Breast07 (n=50), and DESTINY-Breast09 (n=381). Among these patients, 86% were exposed for greater than months and 73% were exposed for greater than 12 months. In this pooled safety population, the most common (>=20%) adverse reactions (including laboratory abnormalities) were decreased white blood cell count (86%), decreased hemoglobin (80%), decreased neutrophil count (79%), nausea (74%), increased alanine aminotransferase (65%), diarrhea (64%), increased aspartate aminotransferase (63%), decreased lymphocyte count (61%), decreased platelet count (55%), increased blood alkaline phosphatase (54%), decreased blood potassium (54%), fatigue (53%), alopecia (48%), vomiting (46%), upper respiratory tract infection (32%), constipation (31%), decreased appetite (31%), decreased weight (28%), musculoskeletal pain (23%), increased blood bilirubin (23%), and abdominal pain (22%). ENHERTU followed by THPThe data described in the WARNINGS and PRECAUTIONS reflect exposure to ENHERTU 5.4 mg/kg intravenously every weeks for four cycles followed by THP for four cycles in 320 patients in Study DESTINY-Breast11.HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)The data described in WARNINGS and PRECAUTIONS reflect exposure to ENHERTU 6.4 mg/kg intravenously every weeks in 125 patients in DESTINY-Gastric01.HER2-Positive Early Breast CancerDESTINY-Breast11The safety of ENHERTU followed by THP was evaluated in 320 patients with HER2-positive (IHC 3+ or ISH+) early breast cancer who received at least one dose of ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11 [see Clinical Studies (14.1)]. ENHERTU was administered by intravenous infusion once every three weeks for four cycles followed by THP for four cycles. The median duration of treatment was 5.6 months (range: 0.7 to 9.1) for patients who received ENHERTU followed by THP.Serious adverse reactions occurred in 11% of patients receiving ENHERTU followed by THP, including COVID-19 (0.9%) and ILD/pneumonitis (0.6%). Fatal adverse reactions occurred in 0.6% of patients, including ILD/pneumonitis and death not otherwise specified (one patient each).In patients treated with ENHERTU followed by THP, the permanent discontinuation of ENHERTU due to adverse reactions occurred in 1.3%, of which ILD/pneumonitis accounted for 0.6%. Dose interruptions of ENHERTU due to adverse reactions occurred in 11% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count and COVID-19. Dose reductions of ENHERTU occurred in 2.5% of patients treated with ENHERTU. The most common (>=20%) adverse reactions in patients treated with ENHERTU followed by THP, including laboratory abnormalities, were decreased hemoglobin, increased alanine aminotransferase, increased aspartate aminotransferase, decreased white blood cell count, nausea, peripheral neuropathy, diarrhea, decreased neutrophil count, alopecia, fatigue, decreased lymphocyte count, rash, musculoskeletal pain, decreased blood potassium, constipation, vomiting, stomatitis, and decreased appetite.Tables and summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast11.Table 4: Common Adverse Reactions (>=10% All Grades or >=2% Grades or 4) Patients in DESTINY-Breast11Adverse ReactionsENHERTU 5.4 mg/kg followed by THPN 320ddAC followed by THP = 312All Grades%Grade or 4%All Grades%Grade or 4%THP= paclitaxel, trastuzumab, and pertuzumab; ddAC=dose dense doxorubicin and cyclophosphamide; Events were graded using NCI CTCAE version 5.0.Gastrointestinal DisordersNausea651.9520.3Diarrhea596543.2Constipation290.3240Vomiting290.9210.6Stomatitis Including aphthous ulcer, cheilitis, glossitis, mouth ulceration, mucosal inflammation, and stomatitis. 230.3361.0Abdominal painIncluding abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and gastrointestinal pain. 160120Nervous System DisordersPeripheral neuropathyIncluding dysesthesia, hypoesthesia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy. 592.5472.2HeadacheIncluding headache, migraine, and sinus headache. 180160Skin and Subcutaneous Tissue DisordersAlopecia480490RashIncluding dermatitis, dermatitis acneiform, dermatitis bullous, eczema, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, skin exfoliation, and urticarial dermatitis. 310.9251.0General Disorders and Administration Site ConditionsFatigueIncluding asthenia, fatigue, and malaise. 410.6552.2Musculoskeletal and Connective Tissue DisordersMusculoskeletal painIncluding arthralgia, back pain, bone pain, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and pain in extremity. 300280.3Metabolism and Nutrition DisordersDecreased appetite200180.3Respiratory, Thoracic and Mediastinal DisordersEpistaxis150100Cough100140Infections and InfestationsUpper respiratory tract infectionIncluding influenza, influenza-like illness, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection. 130.6200.3COVID-19100.9110.3Other clinically relevant adverse reactions reported in less than 10% of patients in the ENHERTU followed by THP treated group were: General disorders and administration site conditions: peripheral edema (9%), pyrexia (8%), mucosal inflammation (1.9%)Nervous System Disorders: dysgeusia (9%), dizziness (4.7%)Eye Disorders: dry eye (8%), blurred vision (6%) [including vision blurred, visual impairment]Gastrointestinal disorders: dyspepsia (8%), gastritis (3.4%), abdominal distension (2.5%), flatulence (0.9%)Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (7%), ILD (4.4%) [including interstitial lung disease, lung opacity, pneumonia fungal, pneumonitis].Skin and Subcutaneous Tissue Disorders: pruritus (6%) and skin hyperpigmentation (1.6%) [including skin hyperpigmentation and skin discoloration]Injury, Poisoning, and Procedural Complications: infusion-related reactions (4.7%) Investigations: decreased weight (3.4%)Blood and Lymphatic System Disorders: febrile neutropenia (0.9%)Metabolism and Nutrition Disorders: dehydration (0.3%)Table 5: Selected Laboratory Abnormalities in Patients in DESTINY-Breast11Laboratory ParameterENHERTU 5.4 mg/kg followed by THPN=320ddAC followed by THPN 312All Grades%Grades 3-4%All Grades%Grades 3-4%THP= paclitaxel, trastuzumab, and pertuzumab; ddAC= dose dense doxorubicin and cyclophosphamide Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.Hematology Decreased hemoglobin832.29710 Decreased white blood cell count6788731 Decreased neutrophil count58176638 Decreased lymphocyte count403.19339 Decreased platelet count80.9282.9Chemistry Increased alanine aminotransferase795774.2 Increased aspartate aminotransferase742.5681 Decreased blood potassium294.1254.5 Increased blood alkaline phosphatase190240 Decreased sodium191.9232.6 Increased blood creatinine80.681.3 Increased blood bilirubin704.20.6DESTINY-Breast05The safety of ENHERTU was evaluated in 806 patients with HER2-positive breast cancer with residual invasive disease following neoadjuvant HER2-targeted therapy who then received at least one dose of ENHERTU 5.4 mg/kg [see Clinical Studies (14.1)]. ENHERTU was administered by intravenous infusion once every three weeks for 14 cycles. The median duration of treatment was 10 months (range: 0.7 to 16) for patients who received ENHERTU.Serious adverse reactions occurred in 17% of patients receiving ENHERTU. Serious adverse reactions in >=1% of patients who received ENHERTU were ILD/pneumonitis, radiation pneumonitis, pneumonia, and platelet count decreased. Fatal adverse reactions occurred in 0.4% of patients including ILD/pneumonitis (2 patients) and respiratory tract infection (one patient). Permanent discontinuation of ENHERTU due to an adverse reaction occurred in 18% of patients. The adverse reaction which resulted in permanent discontinuation of ENHERTU >2% included ILD/pneumonitis. Dose interruptions of ENHERTU due to an adverse reaction occurred in 50% of patients. Adverse reactions which required dosage interruptions in >2% included radiation pneumonitis, neutrophil count decreased, COVID-19, white blood cell count decreased, ILD/pneumonitis, platelet count decreased, upper respiratory tract infection, fatigue, cough, and pyrexia. Dose reductions of ENHERTU due to an adverse reaction occurred in 26% of patients. Adverse reactions which required dose reductions in >2% of patients included nausea, fatigue, platelet count decreased, ILD/pneumonitis, and neutrophil count decreased.The most common (>=20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count, decreased lymphocyte count, decreased neutrophil count, nausea, decreased hemoglobin, increased aspartate aminotransferase, fatigue, increased alanine aminotransferase, decreased platelet count, increased blood alkaline phosphatase, constipation, vomiting, decreased blood potassium, diarrhea, musculoskeletal pain, and decreased appetite.Tables and summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast05.Table 6: Common Adverse Reactions (>=10% All Grades or >=2% Grades 3-4) in Patients Treated with ENHERTU in DESTINY-Breast05Adverse ReactionsENHERTU 5.4 mg/kgN= 806Ado-Trastuzumab Emtansine (T-DM1) 3.6mg/kgN=801All Grades%Grade or 4%All Grades%Grades or 4%Events were graded using NCI CTCAE version 5.0.Gastrointestinal DisordersNausea714.5290.1Constipation320160.1Vomiting311.190.1Diarrhea231.290.4Abdominal painIncluding abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and gastrointestinal pain. 150.290.1StomatitisIncluding aphthous ulcer, cheilitis, mouth ulceration, mucosal inflammation, pharyngeal inflammation, and stomatitis. 100.260.1General Disorders and Administration Site ConditionsFatigueIncluding asthenia, fatigue, lethargy, and malaise. 546371.0Pyrexia100.1120.2Musculoskeletal and Connective Tissue DisordersMusculoskeletal painIncluding arthralgia, back pain, bone pain, limb discomfort, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and pain in extremity. 230.7320.6Metabolism and Nutrition DisordersDecreased appetite200.9100Infections and InfestationsUpper respiratory tract infectionIncluding influenza, influenza like illness, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection. 180.1170.5COVID-19170.5200.4Respiratory, Thoracic and Mediastinal DisordersInterstitial lung diseaseIncluding COVID-19 pneumonia, interstitial lung disease, lung opacity, organizing pneumonia, pneumocystis jirovecii pneumonia, pneumonia, and pneumonitis which was adjudicated as ILD (irrespective of causality). Adjudicated drug-related ILD for ENHERTU was 10% for all Grades and 0.9% for Grades or and for T-DM1, 1.6% for all Grades and 0% for Grades or 4. 171.13.70.2Cough130110Nervous System DisordersHeadacheIncluding headache, migraine, and sinus headache. 160.2210.1Peripheral neuropathyIncluding dysesthesia, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy. 130.4201.1DizzinessIncluding dizziness, dizziness postural, vertigo, and vertigo positional. 110.470.1Skin and Subcutaneous Tissue DisordersAlopecia1601.20RashIncluding dermatitis, dermatitis acneiform, dermatitis exfoliative generalized, drug eruption, dyshidrotic eczema, eczema, eczema asteatotic, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, skin exfoliation, and Stevens-Johnson syndrome. 100.4140.1InvestigationsDecreased weight120.270.1Other clinically relevant adverse reactions reported in less than 10% of patients in the ENHERTU-treated group were:Gastrointestinal disorders: dyspepsia (8%), gastritis (2.5%), abdominal distension (1.7%), flatulence (1.5%) Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (4.5%), epistaxis (3.8%)Skin and Subcutaneous Tissue Disorders: pruritus (4.2%), skin hyperpigmentation (3.5%) [including pigmentation disorder, skin discoloration, skin hyperpigmentation] Nervous System Disorders: dysgeusia (3.7%) Eye Disorders: dry eye (2.7%), vision blurred (2.7%) [including vision blurred, visual impairment]Metabolism and Nutrition Disorders: dehydration (1%)Injury, Poisoning, and Procedural Complications: infusion related reaction (0.7%) [including hypersensitivity, infusion related reaction]Blood and Lymphatic System Disorders: febrile neutropenia (0.5%)Table 7: Selected Laboratory Abnormalities in Patients in DESTINY-Breast05Laboratory ParameterENHERTU5.4 mg/kgN=806Ado-Trastuzumab Emtansine (T-DM1) 3.6mg/kgN 801All Grades%Grades 3-4%All Grades%Grades 3-4%Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.Hematology Decreased white blood cell count8017462.3 Decreased lymphocyte count72355417 Decreased neutrophil count7223384.9 Decreased hemoglobin612.9362 Decreased platelet count4689333Chemistry Increased aspartate aminotransferase601914.3 Increased alanine aminotransferase531804.2 Increased blood alkaline phosphatase390530.1 Decreased blood potassium271.7442.1 Increased blood creatinine130.290.1 Increased blood bilirubin90200Radiotherapy-Related Pneumonitis and Skin Injury in the Post Neoadjuvant Early Breast Cancer SettingAmong patients receiving sequential or concurrent adjuvant radiotherapy in DESTINY-Breast05, radiation pneumonitis occurred in 31% of patients receiving ENHERTU 5.4 mg/kg (N=757) and 31% of patients receiving ado-trastuzumab emtansine (T-DM1) 3.6 mg/kg (N=750), as reported by the investigator. All cases of patients receiving ENHERTU and adjuvant radiotherapy (ART) were either Grade (27%) or Grade (4.9%). Similarly, all cases of patients receiving T-DM1 and ART were either Grade (24%) or Grade (7%). higher incidence of radiation pneumonitis was reported for patients who received sequential vs. concurrent ART, irrespective of treatment arm: 34% for ENHERTU vs. 37% for T-DM1, respectively, with sequential ART and 29% vs. 27%, respectively, with concurrent ART. For patients treated with ENHERTU, median time to onset of first event of radiation pneumonitis was 4.1 months (range: 1.3 11.6 months).Among patients receiving ART and ENHERTU, radiation skin injury occurred in 20% of all patients, of which 1.6% were Grade and none were Grade 4. Among patients receiving ART and T-DM1, radiation skin injury occurred in 18% of all patients, of which 0.4% were Grade and none were Grade 4. HER2-Positive Metastatic Breast CancerDESTINY-Breast09 The safety of ENHERTU 5.4 mg/kg in combination with pertuzumab was evaluated in DESTINY-Breast09, randomized, three-arm, multicenter study including 763 patients with HER2-positive (IHC 3+ or ISH+) unresectable or metastatic breast cancer [see Clinical Studies (14.2)]. Three hundred eighty-one patients received ENHERTU in combination with pertuzumab and 382 patients received THP (taxane [docetaxel or paclitaxel], trastuzumab, and pertuzumab). Among patients who received ENHERTU in combination with pertuzumab, the median duration of treatment was 22 months (range: 0.3 months to 44.5 months). Serious adverse reactions occurred in 27% of patients receiving ENHERTU in combination with pertuzumab. Serious adverse reactions in >1% of patients were diarrhea, pneumonia, febrile neutropenia, hypokalemia, vomiting, ILD, pulmonary embolism, and sepsis. Fatalities due to adverse reactions occurred in 3.4% of patients including pneumonia (n=3), ILD (n=2), sepsis (n=2), pulmonary embolism, septic shock, acute kidney injury, dyspnea, febrile neutropenia, and intestinal ischemia (one patient each). ENHERTU was discontinued for adverse reactions in 21% of patients. The most frequent adverse reactions (>2%) associated with permanent discontinuation was ILD/pneumonitis (6%).Dose interruptions due to adverse reactions occurred in 69% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were COVID-19, neutropenia, upper respiratory tract infection, fatigue, anemia, hypokalemia, ILD/pneumonitis, thrombocytopenia, pneumonia, diarrhea, transaminase increased, leukopenia, cough, pyrexia, decreased appetite, and blood bilirubin increased. Dose reductions occurred in 46% of patients treated with ENHERTU in combination with pertuzumab. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, neutropenia, nausea, diarrhea, ILD/pneumonitis, thrombocytopenia, vomiting, transaminases increased, decreased weight, febrile neutropenia, and hypokalemia. The most common (>=20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, nausea, increased alanine aminotransferase, diarrhea, increased aspartate aminotransferase decreased lymphocyte count, decreased platelet count, increased blood alkaline phosphatase, decreased blood potassium, fatigue, alopecia, vomiting, upper respiratory tract infection, constipation, decreased appetite, decreased weight, COVID-19, musculoskeletal pain, increased blood bilirubin, and abdominal pain.Tables and summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast09. Table 8: Common Adverse Reactions (>=10% All Grades or >=2% Grades or 4) in Patients Treated with ENHERTU in Combination with Pertuzumab in DESTINY-Breast09Adverse ReactionsENHERTU 5.4 mg/kg PertuzumabN= 381THPTHP=taxane [docetaxel or paclitaxel], trastuzumab, and pertuzumab N=382All Grades%Grade 3-4%All Grades%Grades 3-4%Gastrointestinal DisordersNausea755340.3Diarrhea648626Vomiting462.4180.5Constipation330.3120Abdominal painIncluding abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and gastrointestinal pain. 230.3130StomatitisIncluding aphthous ulcer, mouth ulceration, oral mucosal eruption, and stomatitis. 161.3171.3Dyspepsia12060General Disorders and Administration Site Conditions FatigueIncluding asthenia, fatigue, lethargy, and malaise. 538422.1Pyrexia160181.0Skin and Subcutaneous Tissue DisordersAlopecia480530.5RashIncluding rash, rash macular, rash maculo-papular, rash pruritic, and rash pustular. 170.3220.3Pruritus110110.3Infections and InfestationsUpper respiratory tract infectionIncluding Influenza, Influenza like illness, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection. 331.6300.5COVID-19280.3220.3Metabolism and Nutrition DisordersDecreased appetite322.4180.8Hypoalbuminemia110.380.3InvestigationsDecreased weight303.1110.8Musculoskeletal and Connective Tissue DisordersMusculoskeletal painIncluding back pain, bone pain, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and pain in extremity. 241330.3Nervous System DisordersHeadacheIncluding headache and migraine. 190.3140Dysgeusia13090Dizziness120.3100Respiratory, Thoracic, and Mediastinal DisordersCough170.3130Interstitial lung diseaseInterstitial lung disease includes chronic obstructive pulmonary disease (n=1), interstitial lung disease (n=23), pneumonia (n=3), and pneumonitis (n=22). These events were adjudicated as ILD and related to use of ENHERTU 12010Eye DisordersDry eye11060Other clinically relevant adverse reactions reported in less than 10% of patients treated with ENHERTU in combination with pertuzumab were: Blood and Lymphatic System Disorders: febrile neutropenia (2.9%)Eye Disorders: blurred vision (4.2%)Gastrointestinal Disorders: abdominal distension (6%), gastritis (3.9%), flatulence (2.4%)General Disorders and Administration Site Conditions: mucosal inflammation (9%)Injury, poisoning, and procedural complications: infusion related reactions (2.6%) [including hypersensitivity and infusion-related reactions]Metabolism and Nutrition Disorders: dehydration (2.9%)Respiratory, Thoracic, and Mediastinal Disorders: epistaxis (8%), dyspnea (6%)Skin and Subcutaneous Tissue Disorders: dry skin (7%), skin hyperpigmentation (6%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder]Table 9: Selected Laboratory Abnormalities in Patients in DESTINY-Breast09Laboratory ParameterENHERTU 5.4 mg/kg PertuzumabN= 381THPTHP=taxane [docetaxel or paclitaxel], trastuzumab, and pertuzumab] N=382All Grades%Grade 3-4%All Grades%Grades 3-4%Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.HematologyDecreased white blood cell count87118231Decreased hemoglobin8012866Decreased neutrophil count78296640Decreased lymphocyte count62145811Decreased platelet count568201.9ChemistryIncreased alanine aminotransferase663.2451.9Increased aspartate aminotransferase622.1411.9Increased blood alkaline phosphatase550.3360.3Decreased blood potassium5420296Increased blood bilirubin230.3100.3Increased blood creatinine91.870.3DESTINY-Breast03The safety of ENHERTU was evaluated in 257 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast03 [see Clinical Studies (14.2)]. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 14 months (range: 0.7 to 30) for patients who received ENHERTU and months (range: 0.7 to 25) for patients who received ado-trastuzumab emtansine.Serious adverse reactions occurred in 19% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. Fatalities due to adverse reactions occurred in 0.8% of patients including COVID-19 and sudden death (one patient each).ENHERTU was permanently discontinued in 14% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 44% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis. Dose reductions occurred in 21% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, neutropenia, and fatigue.The most common (>=20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased neutrophil count, increased aspartate aminotransferase, decreased hemoglobin, decreased lymphocyte count, increased alanine aminotransferase, decreased platelet count, fatigue, vomiting, increased blood alkaline phosphatase, alopecia, decreased blood potassium, constipation, musculoskeletal pain, diarrhea, decreased appetite, headache, respiratory infection, abdominal pain, increased blood bilirubin, and stomatitis. Tables 10 and 11 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast03.Table 10: Common Adverse Reactions (>=10% All Grades or >=2% Grades 3-4) in Patients Treated with ENHERTU in DESTINY-Breast03Adverse ReactionsENHERTU5.4 mg/kgN=257Ado-trastuzumab emtansine3.6 mg/kgN=261All Grades%Grades 3-4%All Grades%Grades 3-4%Events were graded using NCI CTCAE version 5.0.Gastrointestinal Disorders Nausea767300.4 Vomiting491.6100.8 Constipation340200 Diarrhea291.270.4 Abdominal painIncluding abdominal pain, abdominal discomfort, lower abdominal pain, and upper abdominal pain. 210.880.4 StomatitisIncluding stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosal eruption. 200.850 Dyspepsia11060General Disorders and Administration Site Conditions FatigueIncluding fatigue, asthenia, malaise, and lethargy. 496350.8Skin and Subcutaneous Tissue Disorders AlopeciaThis Grade event was reported by the investigator. Per NCI CTCAE v.5.0, the highest NCI CTCAE grade for alopecia is Grade 2. 370.43.10Musculoskeletal and Connective Tissue Disorders Musculoskeletal painIncluding back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, and limb discomfort. 311.2250.4Metabolism and Nutrition Disorders Decreased appetite291.6170.4Investigations Decreased weight171.260.4Respiratory, Thoracic, and Mediastinal Disorders Respiratory infectionIncluding respiratory tract infection, lower and upper respiratory tract infection, pneumonia, influenza, influenza-like illness, viral upper respiratory infection, bronchitis, and respiratory syncytial virus infection. 220.8121.1 Epistaxis110160.4 Cough110.4100 Interstitial lung diseaseInterstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU: pneumonitis, interstitial lung disease, organizing pneumonia, pneumonia, and pulmonary mass. For ado-trastuzumab emtansine: pneumonitis, interstitial lung disease, organizing pneumonia, and pulmonary embolism. 110.81.90Nervous System Disorders HeadacheIncluding headache and migraine. 220.4160 Peripheral neuropathyIncluding peripheral neuropathy, peripheral sensory neuropathy, and paresthesia. 130.4140.4 Dizziness130.480Other clinically relevant adverse reactions reported in less than 10% of patients in the ENHERTU-treated group were: Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (8%)Skin and Subcutaneous Tissue Disorders: pruritus (8%) and skin hyperpigmentation (6%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder]Nervous System Disorders: dysgeusia (6%)Metabolism and Nutrition Disorders: dehydration (4.3%)Eye Disorders: blurred vision (3.5%)Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (2.7%) [see Warnings and Precautions (5.3)] Injury, Poisoning, and Procedural Complications: infusion-related reactions (2.3%) [including hypersensitivity and infusion-related reactions]Blood and Lymphatic System Disorders: febrile neutropenia (0.8%)Table 11: Selected Laboratory Abnormalities in Patients in DESTINY-Breast03Laboratory ParameterENHERTU5.4 mg/kg N=257Ado-trastuzumab emtansine 3.6 mg/kgN=261All Grades%Grades 3-4%All Grades%Grades 3-4%Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.Hematology Decreased white blood cell count748240.8 Decreased neutrophil count7018302.3 Decreased hemoglobin647386 Decreased lymphocyte count5514233.9 Decreased platelet count5277924Chemistry Increased aspartate aminotransferase670.8835 Increased alanine aminotransferase531.6676 Increased blood alkaline phosphatase490.8460.8 Decreased blood potassium354.7391.5 Increased blood bilirubin200140 Increased blood creatinine160.880.4DESTINY-Breast02The safety of ENHERTU was evaluated in 404 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast02 [see Clinical Studies (14.2)]. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 11 months (range: 0.7 to 45) for patients who received ENHERTU.Serious adverse reactions occurred in 26% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were COVID-19, ILD, pneumonia, vomiting, fatigue, and nausea. Fatalities due to adverse reactions occurred in 2.5% of patients including pneumonitis (2 patients), acute myeloid leukemia, brain edema, COVID-19, hemorrhage, hepatitis B, malignant pleural effusion, pneumonia, and vasogenic cerebral edema (one patient each).ENHERTU was permanently discontinued in 20% of patients, of which ILD accounted for 9%. Dose interruptions due to adverse reactions occurred in 45% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, COVID-19, anemia, fatigue, leukopenia, upper respiratory tract infection, and thrombocytopenia. Dose reductions occurred in 25% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, neutropenia, and vomiting.The most common (>=20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, fatigue, decreased lymphocyte count, decreased platelet count, increased alanine aminotransferase, vomiting, increased aspartate aminotransferase, alopecia, increased blood alkaline phosphatase, constipation, decreased appetite, decreased blood potassium, diarrhea, musculoskeletal pain, increased blood bilirubin, abdominal pain, and headache. Tables 12 and 13 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast02.Table 12: Common Adverse Reactions (>=10% All Grades or >=2% Grades 3-4) in Patients Treated with ENHERTU in DESTINY-Breast02Adverse ReactionsENHERTU 5.4 mg/kg N=404Treatment of Physicians Choice N=195All Grades %Grades 3-4 %All Grades %Grades 3-4 %Events were graded using NCI CTCAE version 5.0.Gastrointestinal Disorders Nausea737372.6 Vomiting383.7131 Constipation350.3110.5 Diarrhea272.7547 Abdominal painIncluding abdominal discomfort, abdominal pain, upper abdominal pain, lower abdominal pain, and gastrointestinal pain 221202.1 Dyspepsia12090 StomatitisIncluding aphthous ulcer, mouth ulceration, and stomatitis 121211General Disorders and Administration Site Conditions FatigueIncluding asthenia, fatigue, lethargy, and malaise 629371Skin and Subcutaneous Tissue Disorders Alopecia370.34.10Metabolism and Nutrition Disorders Decreased appetite311.7180.5Musculoskeletal and Connective Tissue Disorders Musculoskeletal painIncluding back pain, bone pain, limb discomfort, musculoskeletal chest pain, musculoskeletal pain, muscle spasms, myalgia, neck pain, and pain in extremity 250.7180.5Nervous System Disorders HeadacheIncluding headache and migraine 200.360Investigations Decreased weight180.33.60Respiratory, Thoracic, and Mediastinal Disorders Cough130100 Interstitial lung diseaseInterstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU: pneumonitis, interstitial lung disease, idiopathic interstitial pneumonia, lung disorder, pulmonary toxicity, and pneumonia. 100.70.50.5Other clinically relevant adverse reactions reported in less than 10% of patients in the ENHERTU-treated group were:Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (8%) and epistaxis (8%)Skin and Subcutaneous Tissue Disorders: rash (8%) [including rash, pustular rash, maculo-papular rash, and pruritic rash], pruritus (5%), skin hyperpigmentation (5%) [including skin hyperpigmentation and pigmentation disorder]Nervous System Disorders: dizziness (8%) and dysgeusia (8%)Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (4.2%) [see Warnings and Precautions (5.3)] Eye Disorders: dry eye (6%) and blurred vision [including blurred vision and visual impairment] (3%)Metabolism and Nutrition Disorders: dehydration (2.7%)Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.2%)Blood and Lymphatic System Disorders: febrile neutropenia (0.3%)Table 13: Selected Laboratory Abnormalities in Patients in DESTINY-Breast02Laboratory ParameterENHERTU 5.4 mg/kg N=404Treatment of Physicians Choice N=195All Grades %Grades 3-4 %All Grades %Grades 3-4 %Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.Hematology Decreased white blood cell count7012423.2 Decreased hemoglobin679543.2 Decreased neutrophil count6416344.7 Decreased lymphocyte count5817384.7 Decreased platelet count482.7311.6Chemistry Increased alanine aminotransferase431321.6 Increased aspartate aminotransferase370.7292.1 Increased blood alkaline phosphatase370170 Decreased blood potassium303.7298 Increased blood bilirubin230.3442.1 Increased blood creatinine70.3130DESTINY-Breast01 and Study DS8201-A-J101The safety of ENHERTU was evaluated in pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101 (NCT02564900) [see Clinical Studies (14.2)]. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was months (range: 0.7 to 31).In the pooled 234 patients, the median age was 56 years (range: 28-96), 74% of patients were <65 years, 99.6% of patients were female, and the majority were White (51%) or Asian (42%). Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of (58%) or (42%) at baseline. Ninety-four percent had visceral disease, 31% had bone metastases, and 13% had brain metastases.Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, decreased blood potassium, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.The most common (>=20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, fatigue, vomiting, alopecia, increased aspartate aminotransferase, increased alanine aminotransferase, decreased platelet count, constipation, decreased appetite, diarrhea, decreased blood potassium, and cough.Tables 14 and 15 summarize common adverse reactions and laboratory abnormalities observed in ENHERTU-treated patients in DESTINY-Breast01 and Study DS8201-A-J101.Table 14: Common Adverse Reactions (>=10% All Grades or >=2% Grades or 4) in Patients in DESTINY-Breast01 and Study DS8201-A-J101Adverse ReactionsENHERTU 5.4 mg/kgN=234All Grades%Grades or 4%Events were graded using NCI CTCAE version 4.03. Gastrointestinal Disorders Nausea797 Vomiting473.8 Constipation350.9 Diarrhea291.7 Abdominal painIncluding abdominal discomfort, gastrointestinal pain, abdominal pain, lower abdominal pain, and upper abdominal pain 191.3 StomatitisIncluding stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosa blistering. One Grade event of aphthous ulcer was not included in the summary of grouped term stomatitis (from DESTINY-Breast01). 140.9 Dyspepsia120General Disorders and Administration Site Conditions FatigueIncluding fatigue and asthenia 596Skin and Subcutaneous Tissue Disorders Alopecia460.4This Grade event was reported by the investigator. Per NCI CTCAE v.4.03, the highest NCI CTCAE grade for alopecia is Grade 2. RashIncluding rash, pustular rash, and maculo-papular rash 100Metabolism and Nutrition Disorders Decreased appetite321.3Respiratory, Thoracic, and Mediastinal Disorders Cough200 Dyspnea131.3 Epistaxis130 Interstitial lung diseaseInterstitial lung disease includes events that were adjudicated as drug-induced ILD: pneumonitis, interstitial lung disease, respiratory failure, organizing pneumonia, acute respiratory failure, lung infiltration, lymphangitis, and alveolitis. 92.6All events had fatal outcomes (n=6). Nervous System Disorders HeadacheIncluding headache, sinus headache, and migraine 190 Dizziness100Infections and Infestations Upper respiratory tract infectionIncluding influenza, influenza-like illness, and upper respiratory tract infection 150Eye Disorders Dry eye110.4This Grade event was reported by the investigator. Per NCI CTCAE v.4.03, the highest NCI CTCAE grade for dry eye is Grade 3. Other clinically relevant adverse reactions reported in less than 10% of patients were:Injury, Poisoning, and Procedural Complications: infusion-related reactions (2.6%)Blood and Lymphatic System Disorders: febrile neutropenia (1.7%)Table 15: Selected Laboratory Abnormalities in Patients with Unresectable or Metastatic HER2-positive Breast Cancer Treated with ENHERTU in DESTINY-Breast01 and Study DS8201-A-J101Laboratory ParameterENHERTU 5.4 mg/kgN=234All Grades%Grades or 4%Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.Frequencies were based on NCI CTCAE v.4.03 grade-derived laboratory abnormalities.HematologyDecreased white blood cell count707Decreased hemoglobin707Decreased neutrophil count6216Decreased platelet count373.4ChemistryIncreased aspartate aminotransferase410.9Increased alanine aminotransferase380.4Decreased blood potassium263HER2-Low and HER2-Ultralow Metastatic Breast CancerDESTINY-Breast06The safety of ENHERTU was evaluated in 434 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC with membrane staining) breast cancer who received ENHERTU 5.4 mg/kg in DESTINY-Breast06 [see Clinical Studies (14.3)]. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 11 months (range: 0.4 to 39.6) for patients who received ENHERTU.Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease (ILD)/pneumonitis, COVID-19, febrile neutropenia, and hypokalemia. Fatalities due to adverse reactions occurred in 2.8% of patients including ILD (0.7%); sepsis (0.5%); and COVID-19 pneumonia, bacterial meningoencephalitis, neutropenic sepsis, peritonitis, cerebrovascular accident, general physical health deterioration (0.2% each). ENHERTU was permanently discontinued in 14% of patients. The most frequent adverse reactions (>2%) associated with permanent discontinuation was ILD/pneumonitis. Dose interruptions due to adverse reactions occurred in 48% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were COVID-19, decreased neutrophil count, anemia, pyrexia, pneumonia, decreased white blood cell count, and ILD. Dose reductions occurred in 25% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, fatigue, decreased platelet count, and decreased neutrophil count.The most common (>=20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count, decreased neutrophil count, nausea, decreased hemoglobin, decreased lymphocyte count, fatigue, decreased platelet count, alopecia, increased alanine aminotransferase, increased blood alkaline phosphatase, increased aspartate aminotransferase, decreased blood potassium, diarrhea, vomiting, constipation, decreased appetite, COVID-19, and musculoskeletal pain.Tables 16 and 17 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast06.Table 16: Common Adverse Reactions (>=10% All Grades or >=2% Grades or 4) in Patients Treated with ENHERTU in DESTINY-Breast06Adverse ReactionsENHERTU5.4 mg/kgChemotherapyN=434N=417All Grades%Grades or 4%All Grades%Grades or 4%Events were graded using NCI CTCAE version 5.0. Gastrointestinal Disorders Nausea702.1300.5 Diarrhea342.3272.6 Vomiting341.4120.2 Constipation320.7150.5 Abdominal painIncluding abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, and gastrointestinal pain. 200.5140.2 StomatitisIncluding stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, oral mucosal blistering, and oral mucosal eruption. 150110.5 Dyspepsia1204.80General Disorders and Administration Site Conditions FatigueIncluding fatigue, asthenia, malaise, and lethargy. 534.4402.4 Pyrexia120.270Skin and Subcutaneous Tissue Disorders Alopecia480210.5 RashIncluding dermatitis, dermatitis allergic, dermatitis contact, eczema, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. 120.2438Metabolism and Nutrition Disorders Decreased appetite261.4120.5Infections and Infestations COVID-19Including COVID-19, COVID-19 pneumonia. 260.9131 Upper respiratory tract infectionIncluding influenza, influenza-like illness, upper respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, rhinitis, and laryngitis. 19090Musculoskeletal and Connective Tissue Disorders Musculoskeletal painIncluding back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, and limb discomfort. 240.5231.9Nervous System Disorders HeadacheIncluding migraine, headache, and sinus headache. 180.5100 Dysgeusia120.260Respiratory, Thoracic, and Mediastinal Disorders Cough16090 Interstitial lung diseaseIncluding bronchiectasis, interstitial lung disease, lower respiratory tract infection, pneumonia, pneumonia bacterial, pneumonitis, and pulmonary toxicity. 110.70.20 Epistaxis1003.60.2Other clinically relevant adverse reactions reported in less than 10% of patients in the ENHERTU-treated group were:Nervous System Disorders: dizziness (9%)Investigations: decreased weight (7%)Eye Disorders: dry eye (7%), and blurred vision (5%)Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (6%)Gastrointestinal Disorders: abdominal distension (4.8%), flatulence (2.3%), and gastritis (0.7%)Skin and Subcutaneous Tissue Disorders: pruritus (3.9%), and skin hyperpigmentation (0.9%)Metabolism and Nutrition Disorders: dehydration (1.6%)Blood and lymphatic system disorders: febrile neutropenia (1.2%)Injury, Poisoning, and Procedural Complications: infusion related reaction (1.2%)Table 17: Selected Laboratory Abnormalities in Patients in DESTINY-Breast06Laboratory ParameterENHERTU5.4 mg/kgChemotherapyN=434N=417All Grades%Grades or 4%All Grades%Grades or 4%Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.Hematology Decreased white blood cell count86137111 Decreased neutrophil count75275320 Decreased hemoglobin699585 Decreased lymphocyte count6619468 Decreased platelet count486251Chemistry Increased alanine aminotransferase443.2300.7 Increased blood alkaline phosphatase430.2220.2 Increased aspartate aminotransferase412.6271.2 Decreased blood potassium358152.9 Increased blood bilirubin161.9231.5 Increased blood creatinine101.981DESTINY-Breast04The safety of ENHERTU was evaluated in 371 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who received ENHERTU 5.4 mg/kg in DESTINY-Breast04 [see Clinical Studies (14.3)]. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was months (range: 0.2 to 33) for patients who received ENHERTU.Serious adverse reactions occurred in 28% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to adverse reactions occurred in 4.0% of patients including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each).ENHERTU was permanently discontinued in 16% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 39% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia. Dose reductions occurred in 23% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia.The most common (>=20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, fatigue, decreased platelet count, alopecia, vomiting, increased aspartate aminotransferase, increased alanine aminotransferase, constipation, increased blood alkaline phosphatase, decreased appetite, musculoskeletal pain, diarrhea, and decreased blood potassium.Tables 18 and 19 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast04.Table 18: Common Adverse Reactions (>=10% All Grades or >=2% Grades or 4) in Patients Treated with ENHERTU in DESTINY-Breast04Adverse ReactionsENHERTU5.4 mg/kgChemotherapyN=371N=172All Grades%Grades or 4%All Grades%Grades or 4%Events were graded using NCI CTCAE version 5.0. Gastrointestinal Disorders Nausea764.6300 Vomiting401.6130 Constipation340.8220 Diarrhea271.3221.7 Abdominal painIncluding abdominal pain, abdominal discomfort, lower abdominal pain, and upper abdominal pain 180.5130 StomatitisIncluding stomatitis, aphthous ulcer, mouth ulceration, and pharyngeal inflammation 130.3120.6General Disorders and Administration Site Conditions FatigueIncluding fatigue, asthenia, and malaise 549484.7 Pyrexia120.3130Skin and Subcutaneous Tissue Disorders Alopecia400330 RashIncluding rash, pustular rash, pruritic rash, maculo-papular rash, palmar-plantar erythrodysesthesia syndrome, papular rash, macular rash, eczema, erythema multiforme, dermatitis, urticarial dermatitis, drug eruption, and dermatitis bullous 130234.7Metabolism and Nutrition Disorders Decreased appetite322.4191.2Musculoskeletal and Connective Tissue Disorders Musculoskeletal painIncluding back pain, myalgia, pain in extremity, musculoskeletal pain, bone pain, musculoskeletal chest pain, arthralgia, noncardiac chest pain, musculoskeletal stiffness, arthritis, spinal pain, and neck pain 321.3310.6Investigations Decreased weight160.380Vascular Disorders HemorrhageIncluding esophageal varices, hemorrhage, hemorrhoidal hemorrhage, epistaxis, hematuria, conjunctival hemorrhage, vaginal hemorrhage, gingival bleeding, genital hemorrhage, eye hemorrhage, hemoptysis, hemorrhagic cystitis, pharyngeal hemorrhage, rectal hemorrhage, upper gastrointestinal hemorrhage, and esophageal hemorrhage 1603.50Nervous System Disorders HeadacheIncluding headache and migraine 150.360 Peripheral neuropathyIncluding peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, polyneuropathy, paresthesia, hypoesthesia, dysesthesia, and neuralgia 130295 DizzinessIncluding dizziness, postural dizziness, and vertigo 110.560Infections and Infestations Upper respiratory tract infectionIncluding upper respiratory tract infection, influenza, influenza-like illness, nasopharyngitis, pharyngitis, sinusitis, and rhinitis 140.350Respiratory, Thoracic and Mediastinal Disorders Interstitial lung diseaseInterstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU: interstitial lung disease, pneumonitis, organizing pneumonia, pneumonia, and radiation pneumonitis. 121.30.60 Dyspnea101.391.2Other clinically relevant adverse reactions reported in less than 10% of patients treated with ENHERTU:Nervous System Disorders: dysgeusia (10%)Respiratory, Thoracic and Mediastinal Disorders: cough (10%)Gastrointestinal Disorders: abdominal distension (5%), gastritis (2.7%), flatulence (2.4%)Eye Disorders: blurred vision (4.9%) [including blurred vision and visual impairment]Skin and Subcutaneous Tissue Disorders: pruritus (3.2%) and skin hyperpigmentation (2.7%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder]Metabolism and Nutrition Disorders: dehydration (1.9%)Blood and Lymphatic System Disorders: febrile neutropenia (1.1%)Injury, Poisoning, and Procedural Complications: infusion-related reactions (0.5%) [including injection-site reaction and chills]Table 19: Selected Laboratory Abnormalities in Patients in DESTINY-Breast04Laboratory ParameterENHERTU5.4 mg/kgChemotherapyN=371N=172All Grades%Grades or 4%All Grades%Grades or 4%Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.Hematology Decreased white blood cell count7097825 Decreased hemoglobin648536 Decreased neutrophil count64147338 Decreased lymphocyte count55184011 Decreased platelet count446210.6Chemistry Increased aspartate aminotransferase382.2384.1 Increased alanine aminotransferase360.8384.1 Increased blood alkaline phosphatase340.3240 Decreased blood potassium253.3171.2 Increased blood bilirubin162.7150.6 Increased blood creatinine151.190.6HER2-Mutant Unresectable or Metastatic NSCLCDESTINY-Lung02 evaluated two dose levels (5.4 mg/kg [n=101] and 6.4 mg/kg [n=50]); however, only the results for the recommended dose of 5.4 mg/kg intravenously every weeks are described below due to increased toxicity observed with the higher dose in patients with NSCLC, including ILD/pneumonitis.The safety of ENHERTU was evaluated in 101 patients in DESTINY-Lung02 [see Clinical Studies (14.4)]. Patients received ENHERTU 5.4 mg/kg intravenously once every three weeks until disease progression or unacceptable toxicity. The median duration of treatment was months (range: 0.7 to 28) for patients who received ENHERTU. The median age was 59 years (range 31 to 84); 64% were female; 23% were White, 64% were Asian, and 14% were other races.Serious adverse reactions occurred in 40% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pleural effusion, thrombocytopenia, dyspnea, nausea, pneumonia, vomiting, myocarditis, pulmonary embolism, and increased troponin I. Fatalities due to adverse reactions occurred in 3% of patients including ILD/pneumonitis, cerebrovascular accident, and pneumococcal sepsis (one patient each).ENHERTU was permanently discontinued due to an adverse reaction in 17% of patients. Adverse reactions which resulted in permanent discontinuation of ENHERTU were ILD/pneumonitis, pneumonia, blood bilirubin increased, hypokalemia, metastases to meninges, and myocarditis. Dose interruptions of ENHERTU due to adverse reactions occurred in 50% of patients. Adverse reactions which required dose interruption (>2%) included neutropenia, COVID-19, ILD/pneumonitis, fatigue, anemia, and pneumonia. Dose reductions due to an adverse reaction occurred in 20% of patients. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, fatigue, and decreased appetite.The most common (>=20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, nausea, decreased white blood cell count, decreased neutrophil count, decreased lymphocyte count, increased aspartate aminotransferase, decreased albumin, decreased platelet count, fatigue, increased alanine aminotransferase, decreased appetite, constipation, increased alkaline phosphatase, vomiting, decreased blood potassium, diarrhea, alopecia, and musculoskeletal pain.Tables 20 and 21 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Lung02.Table 20: Common Adverse Reactions (>=10% All Grades or >=2% Grades or 4) in Patients with Unresectable or Metastatic HER2-Mutant NSCLC in DESTINY-Lung02Adverse ReactionsENHERTU 5.4 mg/kgN=101All Grades%Grades or 4%Events were graded using NCI CTCAE version 5.0. Gastrointestinal Disorders Nausea674 Constipation381 VomitingIncluding vomiting and retching 323 Diarrhea241 StomatitisIncluding mucosal inflammation, stomatitis, and mouth ulceration 170 Abdominal painIncluding abdominal discomfort, abdominal pain, and upper abdominal pain 100General Disorders and Administration Site Conditions FatigueIncluding asthenia, fatigue, and malaise 488Metabolism and Nutrition Disorders Decreased appetite412Skin and Subcutaneous Tissue Disorders Alopecia220Musculoskeletal and Connective Tissue Disorders Musculoskeletal painIncluding back pain, bone pain, musculoskeletal stiffness, musculoskeletal chest pain, arthralgia, musculoskeletal pain, myalgia, and pain in extremity 211Respiratory, Thoracic, and Mediastinal Disorders Interstitial lung diseaseInterstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU including pneumonitis, interstitial lung disease, pulmonary toxicity, and respiratory failure 151Infections and Infestations Upper respiratory tract infectionIncluding influenza, influenza-like illness, upper respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, rhinitis, and laryngitis 120Other clinically relevant adverse reactions reported in less than 10% of patients were:Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (7%), and epistaxis (5%)Nervous System Disorders: headache (7%) [including headache and migraine]Skin and Subcutaneous Disorders: rash (6%) [including rash and rash maculo-papular]Table 21: Select Laboratory Abnormalities in Patients with Unresectable or Metastatic HER2-Mutant NSCLC in DESTINY-Lung02Laboratory ParameterENHERTU 5.4 mg/kgN=101Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. All GradesFrequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities. %Grades or %HematologyThe denominator used to calculate the rate varied from 100 to 101 based on the number of patients with baseline value and at least one post-treatment value. Decreased hemoglobin6812 Decreased white blood cell count667 Decreased neutrophil count5919 Decreased lymphocyte count5626 Decreased platelet count495Chemistry Increased aspartate aminotransferase511 Decreased albumin500 Increased alanine aminotransferase412 Increased alkaline phosphatase370 Decreased blood potassium295HER2-Positive Locally Advanced or Metastatic Gastric CancerThe safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01 [see Clinical Studies (14.5)]. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg once every three weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) in the ENHERTU group and 2.8 months (range: 0.5 to 13.1) in the irinotecan/paclitaxel group.Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%).ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and decreased blood potassium. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia.The most common (>=20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, decreased white blood cell count, decreased neutrophil count, decreased lymphocyte count, decreased platelet count, nausea, decreased appetite, increased aspartate aminotransferase, fatigue, increased blood alkaline phosphatase, increased alanine aminotransferase, diarrhea, decreased blood potassium, vomiting, constipation, increased blood bilirubin, pyrexia, and alopecia.Tables 22 and 23 summarize adverse reactions and laboratory abnormalities observed in patients receiving ENHERTU 6.4 mg/kg in DESTINY-Gastric01.Table 22: Adverse Reactions in >=10% All Grades or >=2% Grades or of Patients Receiving ENHERTU in DESTINY-Gastric01ENHERTU 6.4 mg/kgN=125Irinotecan or PaclitaxelN=62Adverse ReactionsAll Grades%Grades or 4%All Grades%Grades or 4%Events were graded using NCI CTCAE version 4.03.Gastrointestinal DisordersNausea634.8471.6Diarrhea322.4321.6Vomiting26080Constipation240230Abdominal painIncluding abdominal discomfort, gastrointestinal pain, abdominal pain, lower abdominal pain, and upper abdominal pain 140.8153.2StomatitisIncluding stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosal blistering 111.64.80Metabolism and Nutrition DisordersDecreased appetite60174513Dehydration62.43.21.6Blood and Lymphatic System DisordersFebrile neutropenia4.84.83.23.2General Disorders and Administration Site ConditionsFatigueIncluding fatigue, asthenia, and malaise 559444.8Pyrexia240160Peripheral edema10000Skin and Subcutaneous Tissue DisordersAlopecia220150Respiratory, Thoracic and Mediastinal DisordersInterstitial lung diseaseInterstitial lung disease includes events that were adjudicated as drug-induced ILD: pneumonitis, interstitial lung disease, respiratory failure, organizing pneumonia, acute respiratory failure, lung infiltration, lymphangitis, and alveolitis. 102.400Hepatobiliary DisordersAbnormal hepatic function83.21.61.6Other clinically relevant adverse reactions reported in less than 10% of patients were:Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (8%) [see Warnings and Precautions (5.3)] Infections and Infestations: pneumonia (6%)Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.6%)Table 23: Selected Laboratory Abnormalities Occurring in Patients Receiving ENHERTU in DESTINY-Gastric01Laboratory ParameterENHERTU 6.4 mg/kgN=125Irinotecan or PaclitaxelN=62All Grades%Grades or 4%All Grades%Grades or 4%Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.Frequencies were based on NCI CTCAE v.4.03 grade-derived laboratory abnormalities.HematologyDecreased hemoglobin75385523Decreased white blood cell count74295313Decreased neutrophil count72514523Decreased lymphocyte count70285312Decreased platelet count6812125ChemistryIncreased aspartate aminotransferase589328Increased blood alkaline phosphatase5483410Increased alanine aminotransferase479171.7Decreased blood potassium304.8188Increased blood bilirubin24753.4HER2-Positive (IHC 3+) Unresectable or Metastatic Solid TumorsThe safety of ENHERTU was evaluated in 347 adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who received ENHERTU 5.4 mg/kg in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 [see Clinical Studies (14.2 and 14.6)]. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 8.3 months (range 0.7 to 30.2).The median age was 60 years (range 23 to 96); 74% were female; 51% were White, 42% were Asian, 2.9% were Black or African American, 3.5% were of Hispanic or Latino ethnicity; and 51% had an ECOG performance status and 48% had an ECOG performance status of 1.Serious adverse reactions occurred in 34% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were sepsis, pneumonia, vomiting, urinary tract infection, abdominal pain, nausea, pneumonitis, pleural effusion, hemorrhage, COVID-19, fatigue, acute kidney injury, anemia, cellulitis, and dyspnea. Fatalities due to adverse reactions occurred in 6.3% of patients including ILD/pneumonitis (2.3%), cardiac arrest (0.6%), COVID-19 (0.6%), and sepsis (0.6%). The following events occurred in one patient each (0.3%): acute kidney injury, cerebrovascular accident, general physical health deterioration, pneumonia, and hemorrhagic shock.ENHERTU was permanently discontinued in 15% of patients, of which ILD/pneumonitis accounted for 10%. Dose interruptions due to adverse reactions occurred in 48% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count, anemia, COVID-19, fatigue, decreased white blood cell count, and ILD/pneumonitis. Dose reductions occurred in 27% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, decreased neutrophil count, ILD/pneumonitis, and diarrhea.The most common (>=20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count, nausea, decreased hemoglobin, decreased neutrophil count, fatigue, decreased lymphocyte count, decreased platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, increased blood alkaline phosphatase, vomiting, decreased appetite, alopecia, diarrhea, decreased blood potassium, constipation, decreased sodium, stomatitis, and upper respiratory tract infection.Tables 24 and 25 summarize the common adverse reactions and laboratory abnormalities in DESTINY-PanTumor02, DESTINY-Lung01, DESTINY-Breast01, and DESTINY-CRC02.Table 24: Common Adverse Reactions (>=10% All Grades or >=2% Grades or 4) in HER2-positive (IHC 3+) Patients Treated with ENHERTU in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02Adverse ReactionsENHERTU 5.4 mg/kgN= 347All Grades%Grade or 4%Gastrointestinal DisordersNausea697Vomiting353.5Diarrhea314.3Constipation280.6StomatitisIncluding stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, oral mucosa erosion, oral mucosal blistering, oral mucosal eruption, tongue ulceration, cheilitis. 200.9Abdominal painIncluding abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, gastrointestinal pain. 182Dyspepsia120.3General Disorders and Administration Site ConditionsFatigueIncluding fatigue, asthenia, malaise, lethargy. 5910Pyrexia110EdemaIncluding peripheral edema, edema, localized edema, face edema, skin edema, periorbital edema, eyelid edema 110.6Metabolism and Nutrition DisordersDecreased appetite342.6Skin and Subcutaneous Tissue DisordersAlopecia340.3RashIncluding rash, pustular rash, maculo-papular rash, papular rash, macular rash, pruritic rash dermatitis acneiform, dermatitis, eczema, palmar-plantar erythrodysesthesia syndrome. 130.6Infections and InfestationsUpper respiratory tract infectionIncluding influenza, influenza-like illness, upper respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, rhinitis, laryngitis. 200Pneumonia62.3Musculoskeletal and Connective Tissue DisordersMusculoskeletal painIncluding back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, limb discomfort. 190.3Respiratory, Thoracic and Mediastinal DisordersCoughIncluding cough, productive cough, upper-airway cough syndrome 180Interstitial lung diseaseInterstitial lung disease includes events that were adjudicated as drug-induced ILD: pneumonitis, ILD, organizing pneumonia, respiratory failure, acute respiratory failure, alveolitis, lung opacity, lymphangitis, pneumonia, bacterial pneumonia, pulmonary fibrosis, and radiation pneumonitis. Grade adjudicated drug-induced ILD events were pneumonitis, respiratory failure, acute respiratory failure, lymphangitis, pulmonary fibrosis. 160.6DyspneaIncluding dyspnea, exertional dyspnea 121.7Nervous System DisordersHeadacheIncluding migraine, headache, sinus headache. 150InvestigationsDecreased weight100.3Other clinically relevant adverse reactions reported in less than 10% of patients were:Respiratory, Thoracic, and Mediastinal Disorders: epistaxis (9%)Nervous System Disorders: dizziness (9%) [including dizziness, postural dizziness, and vertigo] and dysgeusia (6%)Skin and Subcutaneous Disorders: pruritus (5%) and skin hyperpigmentation (4.3%) [including skin hyperpigmentation, skin discoloration, pigmentation disorder]Eye Disorders: blurred vision (4%) [including blurred vision, visual impairment]Metabolism and Nutrition Disorders: dehydration (3.2%)Gastrointestinal Disorders: abdominal distension (2.6%), flatulence (1.7%) and gastritis (0.9%)Blood and Lymphatic System Disorders: febrile neutropenia (1.7%)Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.4%) [including administration related reaction, anaphylactic reaction, hypersensitivity, infusion-related reaction and infusion-related hypersensitivity reaction]Table 25: Selected Laboratory Abnormalities in HER2-positive (IHC 3+) Patients Treated with ENHERTU in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02Laboratory ParameterENHERTU 5.4 mg/kgN= 347Percentages were calculated using the number of patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. All Grades%Grades or 4%HematologyDecreased white blood cell count7511Decreased hemoglobin6710Decreased neutrophil count6621Decreased lymphocyte count5821Decreased platelet count517ChemistryIncreased aspartate aminotransferase451.5Increased alanine aminotransferase441.5Increased blood alkaline phosphatase361.2Decreased blood potassium296Decreased sodium222.9Increased blood bilirubin150.6Increased blood creatinine140.6. General disorders and administration site conditions: peripheral edema (9%), pyrexia (8%), mucosal inflammation (1.9%). Nervous System Disorders: dysgeusia (9%), dizziness (4.7%). Eye Disorders: dry eye (8%), blurred vision (6%) [including vision blurred, visual impairment]. Gastrointestinal disorders: dyspepsia (8%), gastritis (3.4%), abdominal distension (2.5%), flatulence (0.9%). Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (7%), ILD (4.4%) [including interstitial lung disease, lung opacity, pneumonia fungal, pneumonitis].. Skin and Subcutaneous Tissue Disorders: pruritus (6%) and skin hyperpigmentation (1.6%) [including skin hyperpigmentation and skin discoloration]. Injury, Poisoning, and Procedural Complications: infusion-related reactions (4.7%) Investigations: decreased weight (3.4%). Blood and Lymphatic System Disorders: febrile neutropenia (0.9%). Metabolism and Nutrition Disorders: dehydration (0.3%). Gastrointestinal disorders: dyspepsia (8%), gastritis (2.5%), abdominal distension (1.7%), flatulence (1.5%) Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (4.5%), epistaxis (3.8%). Skin and Subcutaneous Tissue Disorders: pruritus (4.2%), skin hyperpigmentation (3.5%) [including pigmentation disorder, skin discoloration, skin hyperpigmentation] Nervous System Disorders: dysgeusia (3.7%) Eye Disorders: dry eye (2.7%), vision blurred (2.7%) [including vision blurred, visual impairment]. Metabolism and Nutrition Disorders: dehydration (1%). Injury, Poisoning, and Procedural Complications: infusion related reaction (0.7%) [including hypersensitivity, infusion related reaction]. Blood and Lymphatic System Disorders: febrile neutropenia (0.5%). Blood and Lymphatic System Disorders: febrile neutropenia (2.9%). Eye Disorders: blurred vision (4.2%). Gastrointestinal Disorders: abdominal distension (6%), gastritis (3.9%), flatulence (2.4%). General Disorders and Administration Site Conditions: mucosal inflammation (9%). Injury, poisoning, and procedural complications: infusion related reactions (2.6%) [including hypersensitivity and infusion-related reactions]. Metabolism and Nutrition Disorders: dehydration (2.9%). Respiratory, Thoracic, and Mediastinal Disorders: epistaxis (8%), dyspnea (6%). Skin and Subcutaneous Tissue Disorders: dry skin (7%), skin hyperpigmentation (6%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder]. Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (8%). Skin and Subcutaneous Tissue Disorders: pruritus (8%) and skin hyperpigmentation (6%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder]. Nervous System Disorders: dysgeusia (6%). Metabolism and Nutrition Disorders: dehydration (4.3%). Eye Disorders: blurred vision (3.5%). Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (2.7%) [see Warnings and Precautions (5.3)] Injury, Poisoning, and Procedural Complications: infusion-related reactions (2.3%) [including hypersensitivity and infusion-related reactions]. Blood and Lymphatic System Disorders: febrile neutropenia (0.8%). Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (8%) and epistaxis (8%). Skin and Subcutaneous Tissue Disorders: rash (8%) [including rash, pustular rash, maculo-papular rash, and pruritic rash], pruritus (5%), skin hyperpigmentation (5%) [including skin hyperpigmentation and pigmentation disorder]. Nervous System Disorders: dizziness (8%) and dysgeusia (8%). Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (4.2%) [see Warnings and Precautions (5.3)] Eye Disorders: dry eye (6%) and blurred vision [including blurred vision and visual impairment] (3%). Metabolism and Nutrition Disorders: dehydration (2.7%). Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.2%). Blood and Lymphatic System Disorders: febrile neutropenia (0.3%). Injury, Poisoning, and Procedural Complications: infusion-related reactions (2.6%). Blood and Lymphatic System Disorders: febrile neutropenia (1.7%). Nervous System Disorders: dizziness (9%). Investigations: decreased weight (7%). Eye Disorders: dry eye (7%), and blurred vision (5%). Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (6%). Gastrointestinal Disorders: abdominal distension (4.8%), flatulence (2.3%), and gastritis (0.7%). Skin and Subcutaneous Tissue Disorders: pruritus (3.9%), and skin hyperpigmentation (0.9%). Metabolism and Nutrition Disorders: dehydration (1.6%). Blood and lymphatic system disorders: febrile neutropenia (1.2%). Injury, Poisoning, and Procedural Complications: infusion related reaction (1.2%). Nervous System Disorders: dysgeusia (10%). Respiratory, Thoracic and Mediastinal Disorders: cough (10%). Gastrointestinal Disorders: abdominal distension (5%), gastritis (2.7%), flatulence (2.4%). Eye Disorders: blurred vision (4.9%) [including blurred vision and visual impairment]. Skin and Subcutaneous Tissue Disorders: pruritus (3.2%) and skin hyperpigmentation (2.7%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder]. Metabolism and Nutrition Disorders: dehydration (1.9%). Blood and Lymphatic System Disorders: febrile neutropenia (1.1%). Injury, Poisoning, and Procedural Complications: infusion-related reactions (0.5%) [including injection-site reaction and chills]. Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (7%), and epistaxis (5%). Nervous System Disorders: headache (7%) [including headache and migraine]. Skin and Subcutaneous Disorders: rash (6%) [including rash and rash maculo-papular]. Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (8%) [see Warnings and Precautions (5.3)] Infections and Infestations: pneumonia (6%). Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.6%). Respiratory, Thoracic, and Mediastinal Disorders: epistaxis (9%). Nervous System Disorders: dizziness (9%) [including dizziness, postural dizziness, and vertigo] and dysgeusia (6%). Skin and Subcutaneous Disorders: pruritus (5%) and skin hyperpigmentation (4.3%) [including skin hyperpigmentation, skin discoloration, pigmentation disorder]. Eye Disorders: blurred vision (4%) [including blurred vision, visual impairment]. Metabolism and Nutrition Disorders: dehydration (3.2%). Gastrointestinal Disorders: abdominal distension (2.6%), flatulence (1.7%) and gastritis (0.9%). Blood and Lymphatic System Disorders: febrile neutropenia (1.7%). Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.4%) [including administration related reaction, anaphylactic reaction, hypersensitivity, infusion-related reaction and infusion-related hypersensitivity reaction].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 HER2-Positive Early Breast Cancer DESTINY-Breast11The efficacy of ENHERTU followed by THP was evaluated in DESTINY-Breast11 (NCT05113251), randomized, three-arm, open-label, multicenter, global study that enrolled 927 adult patients with HER2-positive, high-risk, early-stage breast cancer. The study included previously untreated adult patients with HER2-positive (IHC 3+ or ISH+), as determined by central laboratory using PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and VENTANA HER2 Dual ISH DNA Probe Cocktail assay, locally advanced high-risk (lymph node positive [N1-3] or with primary tumor stage T3-4) or inflammatory early breast cancer. Patients were excluded for history of ILD/pneumonitis requiring treatment with steroids, ILD/pneumonitis at screening, or ECOG performance status >1.Patients were randomized 1:1:1 to receive eight cycles of neoadjuvant treatment with:ENHERTU (5.4 mg/kg once every weeks) for cycles followed by THP [paclitaxel (80 mg/m2 once week on Days 1, 8, and 15) concurrent with trastuzumab (6 mg/kg once every weeks on Day 1) and pertuzumab (an initial dose of 840 mg followed by 420 mg once every weeks on Day 1)] for cycles.ddAC [doxorubicin (60 mg/m2 once every weeks) and cyclophosphamide (600 mg/m2 once every weeks)] for cycles followed by THP [paclitaxel (80 mg/m2 once week on Days 1, 8, and 15) concurrent with trastuzumab (an initial dose of mg/kg followed by mg/kg once every weeks on Day 1) and pertuzumab (an initial dose of 840 mg followed by 420 mg once every weeks on Day 1)] for cycles.An additional investigational therapy. Randomization was stratified by hormone receptor (HR) status (ER and/or PgR positive vs ER and PR negative) by local assessment and HER2-positive status (IHC 3+ vs other, where other is defined as ISH+ in the absence of IHC 3+ status) by central assessment. Treatment was continued until completion of planned therapy, unacceptable toxicity, or disease progression.The major efficacy outcome was centrally assessed pathological complete response (pCR) rate, defined as the absence of invasive cancer in the breast and axillary lymph nodes (ypT0/Tis ypN0) following surgery. In patients who received ENHERTU followed by THP or ddAC followed by THP, the median age was 50 years (range: 23 to 82), 11% age 65 or older; 100% female; 43% White, 49% Asian, 1.9% Black or African American, 0.3% American Indian or Alaska Native, 2% not reported; 9% Hispanic or Latino. Tumor characteristics were: 73% had HR+ status and 27% had HR- status; 57% had primary Tumor T0- T2 and 43% had T3-4; 89% had nodal involvement (N1+), 10% had no nodal involvement (N0); 51% of patients were overall Stage II and 49% were Stage III.The study demonstrated statistically significant improvement in pCR rate for patients randomized to ENHERTU followed by THP compared to ddAC followed by THP. Efficacy results are summarized in Table 26. At the time of the pCR analysis, 29 (4.5%) patients had EFS events and 12 (1.9%) patients had OS events. Table 26: Efficacy Results in DESTINY-Breast11Efficacy ParameterENHERTU 5.4 mg/kg followed by THP (N=321)ddAC followed by THP (N=320)Pathological Complete Response (pCR) CI confidence interval, THP paclitaxel, trastuzumab, and pertuzumab, ddAC dose dense doxorubicin and cyclophosphamide Number of patients with pCR, 216180pCR rate, (95% CI)67.3 (61.9, 72.4)56.3 (50.6, 61.8)Treatment difference estimate, (95% CI)Based on Miettinen and Nurminen method stratified by HER2 status and HR status 11.2 (3.9, 18.3)p-valueThe 2-sided stratified Miettinen and Nurminen test p-value is compared with the allocated alpha of 0.03 0.003DESTINY-Breast05The efficacy of ENHERTU was evaluated in DESTINY-Breast05 (NCT04622319), randomized, two-arm, open-label, multicenter, global study that enrolled 1635 adult patients with HER2-positive breast cancer with residual invasive disease after neoadjuvant therapy. HER2 expression was confirmed at central laboratory using PATHWAY/VENTANA anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody and HER2 Dual ISH DNA Probe Cocktail assay with HER2 positivity defined as HER2 IHC 3+ or ISH positive. Patients were excluded if they had history of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening or ECOG performance status >1. Patients received concurrent or sequential adjuvant radiotherapy as per investigator discretion and hormonal therapy as per local guidelines. In addition to all patients receiving computed tomography (CT) scans of the chest at screening, patients receiving radiotherapy also received regular CT scans of the chest during treatment period, and after end of treatment.Patients were randomized 1:1 to receive either ENHERTU 5.4mg/kg (N=818) by intravenous infusion every three weeks or trastuzumab emtansine (T-DM1) (N=817) 3.6 mg/kg by intravenous infusion every three weeks for maximum of 14 cycles, or until disease recurrence or unacceptable toxicity. Randomization was stratified by operative status at disease presentation (operable, inoperable), post neoadjuvant pathological nodal status (positive, negative), tumor hormone receptor status (positive, negative), and HER2-targeted neoadjuvant therapy (single, dual). The major efficacy outcome measure was invasive disease-free survival (IDFS), defined as the time from randomization to first occurrence of ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer or death from any cause. Additional efficacy outcome measures included disease-free survival (DFS) and overall survival (OS). The median age was 51 years (range: 21 to 83), 10% age 65 or older; 99.6% female; 39% White, 48% Asian, 2.1% Black or African American, 1.9% American Indian or Alaska Native, 16% Hispanic/Latino, 77% non-Hispanic/non-Latino, and 6% not reported. Tumor characteristics were: 71% had HR+ status and 29% had HR- status; 52% had inoperable tumors at disease presentation (T4, N0-3, M0 or T1-3, N2-3, M0); 81% had post neoadjuvant pathological nodal status (ypN1-3). Neoadjuvant treatment characteristics were: 21% of patients received single HER2-targeted neoadjuvant therapy; 79% received dual HER2-targeted neoadjuvant therapy; 50% of patients received anthracyclines and 100% received taxanes as part of neoadjuvant regimen. Characteristics of adjuvant radiotherapy were: 37% of patients received sequential adjuvant radiotherapy, 56% of patients received concurrent adjuvant RT.Efficacy results are summarized in Table 27 and Figure 1. At the time of the IDFS analysis, total of 47 (2.9%) patients had died across both study arms.Table 27: Efficacy Results in DESTINY-Breast05Efficacy ParameterENHERTU (5.4 mg/kg) N=818Ado-Trastuzumab emtansine (3.6 mg/kg)N=817Invasive Disease-Free Survival (IDFS) CI confidence interval; Number of events (%) 51 (6)102 (12)3-year event free rate, (95% CI)92.4 (89.7, 94.4)83.7 (80.2, 86.7)Hazard ratio (95% CI) 0.47 (0.34, 0.66)p-value The stratified log-rank test p-value is compared with the allocated alpha of 0.0183 for this interim analysis (with 74% of the planned number of events for final analysis). p<0.0001Disease-Free Survival (DFS) Number of events (%) 52 (6)103 (13)3-year event free rate, (95% CI) 92.3 (89.5, 94.3)83.5 (79.9, 86.4)Hazard ratio (95% CI) 0.47 (0.34, 0.66)p-value The stratified log-rank test p-value is compared with the allocated alpha of 0.0144 for this interim analysis (with 70% of the planned number of events for final analysis). p<0.0001Figure 1: Kaplan-Meier plot of invasive disease-free survival (IDFS). ENHERTU (5.4 mg/kg once every weeks) for cycles followed by THP [paclitaxel (80 mg/m2 once week on Days 1, 8, and 15) concurrent with trastuzumab (6 mg/kg once every weeks on Day 1) and pertuzumab (an initial dose of 840 mg followed by 420 mg once every weeks on Day 1)] for cycles.. ddAC [doxorubicin (60 mg/m2 once every weeks) and cyclophosphamide (600 mg/m2 once every weeks)] for cycles followed by THP [paclitaxel (80 mg/m2 once week on Days 1, 8, and 15) concurrent with trastuzumab (an initial dose of mg/kg followed by mg/kg once every weeks on Day 1) and pertuzumab (an initial dose of 840 mg followed by 420 mg once every weeks on Day 1)] for cycles.. An additional investigational therapy. Figure 1. 14.2 HER2-Positive Metastatic Breast Cancer DESTINY-Breast09 The efficacy of ENHERTU in combination with pertuzumab was evaluated in DESTINY-Breast09 (NCT04784715), randomized, three-arm, multicenter, global study that enrolled 1157 adult patients with HER2-positive advanced, or metastatic breast cancer who had not received prior chemotherapy or HER2-targeted therapy or had received neoadjuvant or adjuvant HER2-targeted therapy more than months before the diagnosis of advanced or metastatic disease. single line of prior endocrine therapy was permitted for advanced or metastatic breast cancer. HER2 expression was confirmed at central laboratory using PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and HER2 Dual ISH DNA Probe Cocktail with HER2 positivity defined as HER2 IHC 3+ or ISH positive. Patients were excluded for history of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening, patients with symptomatic brain metastases, or ECOG performance status >1, and patients with history of clinically significant cardiac disease.Patients were randomized 1:1:1 to receive either, ENHERTU 5.4 mg/kg plus pertuzumab (N=383), THP (taxane [docetaxel or paclitaxel], trastuzumab, and pertuzumab) (N=387), or an investigational therapy (N=387) by intravenous infusion every weeks until unacceptable toxicity or disease progression. Patients with hormone receptor (HR) positive disease (N=416) were allowed to receive concurrent endocrine therapy after cycles of ENHERTU or after discontinuation of the taxane in the THP arm; this occurred in 13.5% of patients in the ENHERTU in the combination with pertuzumab arm and in 38.3% of patients in the THP arm. Randomization was stratified by prior treatment status (de novo vs recurrent), hormone receptor status, and PIK3CA mutation status. The major efficacy outcome was progression-free survival (PFS) as assessed by blinded independent central review (BICR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Additional efficacy outcome measures were overall survival (OS) and confirmed objective response rate (ORR) assessed by BICR.The median age was 54 years (range: 20-88); 82% were <65 years; 100% were female; 50% of the patients were Asian, 37% were White, 2% were American Indian or Alaska Native, and 3% were Black or African American; 14% were Hispanic or Latino; 8% other or race unknown; 52% had de novo disease and 48% had recurrent disease; 53% were HR-positive and 47% HR-negative; and 31% of patients had PIK3CA mutation. The study demonstrated statistically significant improvement in PFS for patients randomized to ENHERTU in combination with pertuzumab compared to THP. Efficacy results are summarized in Table 28 and Figure 2. At the time of the PFS analysis, OS data was not mature with 126 (16%) of patients who died across both study arms in the overall population.Table 28: Efficacy Results in DESTINY-Breast09Efficacy ParameterENHERTU 5.4 mg/kg Pertuzumab = 383THPTHP taxane (docetaxel or paclitaxel), trastuzumab, and pertuzumab = 387CI confidence interval; NE not estimable, = numberProgression-Free Survival (PFS) per BICRNumber of events (%)118 (31)172 (44)Median, months (95% CI)40.7 (36.5, NE)26.9 (21.8, NE)Hazard ratio (95% CI)0.56 (0.44, 0.71)p-valueThe stratified log-rank test p-value is compared with the allocated alpha of 0.00043 for this interim analysis (with 73% of the planned number of events for final analysis). 0.0001Confirmed Objective Response Rate (ORR) per BICRPatients with Measurable Disease at Baseline, N374371ORR (95% CI) 95% CI was based on Clopper-Pearson method. 87 (83, 90)81 (77, 85) Complete Response, %158 Partial Response, %7273Figure 2: Kaplan-Meier Plot of Progression-Free Survival per BICRDESTINY-Breast03 The efficacy of ENHERTU was evaluated in study DESTINY-Breast03 (NCT03529110), multicenter, open-label, randomized trial that enrolled 524 patients with HER2-positive, unresectable and/or metastatic breast cancer who received prior trastuzumab and taxane therapy for metastatic disease or developed disease recurrence during or within months of completing adjuvant therapy. HER2 expression was based on archival tissue tested at central laboratory prior to enrollment with HER2 positivity defined as HER2 IHC 3+ or ISH positive. Patients were excluded for history of ILD/pneumonitis requiring treatment with steroids, ILD/pneumonitis at screening, or clinically significant cardiac disease. Patients were also excluded for untreated and symptomatic brain metastases, ECOG performance status >1, or prior treatment with an anti-HER2 antibody-drug conjugate in the metastatic setting.Patients were randomized 1:1 to receive either ENHERTU 5.4 mg/kg (N=261) or ado-trastuzumab emtansine 3.6 mg/kg (N=263) by intravenous infusion every weeks until unacceptable toxicity or disease progression. Randomization was stratified by hormone receptor status, prior treatment with pertuzumab, and visceral versus non-visceral disease. Tumor imaging was obtained every weeks and CT/MRI of the brain was mandatory for all patients at baseline. The major efficacy outcomes were progression-free survival (PFS) as assessed by blinded independent central review (BICR) based on RECIST v.1.1 and overall survival (OS). Confirmed objective response rate (ORR) was an additional outcome measure.The median age was 54 years (range: 20-83); 80% were <65 years; 99.6% were female; 60% were Asian, 27% were White, and 3.6% were Black; 11% of patients were of Hispanic/Latino ethnicity. Patients had an ECOG performance status of (63%) or (37%) at baseline. Seventy-three percent had visceral disease, 16% had brain metastases at baseline, 52% were hormone receptor positive (HR+), and 48% of patients had received one line of prior systemic therapy in the metastatic setting. The percentage of patients who had not received prior treatment for metastatic disease was 10%.Efficacy results are summarized in Table 29 and Figures and 4. Table 29: Efficacy Results in DESTINY-Breast03Efficacy ParameterENHERTU 5.4 mg/kgAdo-trastuzumab emtansine 3.6 mg/kgCI confidence interval; NR not reached; NE not estimableProgression-Free Survival (PFS) per BICRN261263Number of events (%)87 (33.3)158 (60.1)Median, months (95% CI)NR (18.5, NE)6.8 (5.6, 8.2)Hazard ratio (95% CI)0.28 (0.22, 0.37)p-valueThe stratified log-rank test p-value is compared with the allocated alpha of 0.0002 for this interim analysis (with 73% of the planned number of events for final analysis). p< 0.0001Overall Survival (OS)N261263Number of events (%)72 (27.6)97 (36.9)Median, months (95% CI)NR (40.5, NE)NR (34.0, NE)Hazard ratio (95% CI)0.64 (0.47, 0.87)p-valueThe stratified log-rank test p-value is compared with the allocated alpha of 0.013 for this interim analysis (with 68% of the planned number of events for final analysis). p=0.0037Confirmed Objective Response Rate (ORR) per BICRAnalysis was performed based on the patients with measurable disease assessed by BICR at baseline. N248241n (%)205 (82.7)87 (36.1)95% CI(77.4, 87.2)(30.0, 42.5)Complete Response (%)39 (15.7)20 (8.3)Partial Response (%)166 (66.9)67 (27.8)Figure 3: Kaplan-Meier Plot of Progression-Free Survival per BICR (Intent-to-Treat Analysis Set)Figure 4: Kaplan-Meier Plot of Overall SurvivalDESTINY-Breast02 The efficacy of ENHERTU was evaluated in study DESTINY-Breast02 (NCT03523585), multicenter, open-label, randomized study that enrolled 608 patients with HER2-positive, unresectable and/or metastatic breast cancer who were previously treated with ado-trastuzumab emtansine. HER2 expression was based on archival tissue tested at central laboratory prior to enrollment with HER2 positivity defined as HER2 IHC 3+ or ISH positive. Patients were randomized 2:1 to receive either ENHERTU 5.4 mg/kg (N=406) by intravenous infusion every weeks or treatment of physicians choice (TPC) (N=202, trastuzumab plus capecitabine or lapatinib plus capecitabine) until unacceptable toxicity or disease progression. Randomization was stratified by hormone receptor status, prior treatment with pertuzumab, and visceral versus non-visceral disease. The major efficacy outcomes were PFS as assessed by BICR based on RECIST v1.1 and OS. The median age was 54 years (range: 22 to 88); 80% were <65 years; 99% were female; 63% were White, 29% were Asian, and 3% were Black or African American; 11% of patients were of Hispanic/Latino ethnicity. Patients had an ECOG performance status of (57%) or (42%) at baseline. Seventy-eight percent had visceral disease, 18% had brain metastases at baseline, 59% were hormone receptor positive (HR+), and 5% of patients had received one line of prior systemic therapy in the metastatic setting.Efficacy results are summarized in Table 30 and Figures and 6.Table 30: Efficacy Results in DESTINY-Breast02Efficacy ParameterENHERTUN=406Treatment of Physicians ChoiceN=202CI confidence interval; NE=not estimablePFS per BICRNumber of events (%)200 (49.3)125 (61.9)Median, months (95% CI)17.8 (14.3, 20.8)6.9 (5.5, 8.4)Hazard ratio (95% CI)0.36 (0.28, 0.45)p-valuep<0.0001Overall Survival (OS)Number of events (%)143 (35.2)86 (42.6)Median, months (95% CI)39.2 (32.7, NE)26.5 (21.0, NE)Hazard ratio (95% CI)0.66 (0.50, 0.86)p-valueThe stratified log-rank test p-value is compared with the allocated alpha of 0.004 for this interim analysis (with 53% of the planned number of events for final analysis) p=0.0021Confirmed Objective Response Rate (ORR) per BICRn (%)283 (69.7)59 (29.2)95% CI(65.0, 74.1)(23.0, 36.0)Complete Response (%)57 (14.0)10 (5.0)Partial Response (%)226 (55.7)49 (24.3)Duration of Response per BICRMedian, months (95% CI)19.6 (15.9, NE)8.3 (5.8, 9.5)Figure 5: Kaplan-Meier Plot of Progression-free Survival Per BICRFigure 6: Kaplan-Meier Plot of Overall SurvivalDESTINY-Breast01The efficacy of ENHERTU was evaluated in study DESTINY-Breast01 (NCT03248492), multicenter, single-arm, trial that enrolled 184 female patients with HER2-positive, unresectable and/or metastatic breast cancer who had received two or more prior anti-HER2 therapies. Patients were excluded for history of treated ILD or current ILD at screening. Patients were also excluded for history of clinically significant cardiac disease, active brain metastases, and ECOG performance status >1. HER2 expression was based on archival tissue tested at central laboratory prior to enrollment with HER2 positivity defined as HER2 IHC 3+ or ISH positive.Patients received ENHERTU 5.4 mg/kg by intravenous infusion every weeks until unacceptable toxicity or disease progression. Tumor imaging was obtained every weeks and CT/MRI of the brain was mandatory for patients with brain metastases at baseline. The major efficacy outcomes were confirmed objective response rate (ORR) assessed by independent central review (ICR) using RECIST v1.1 and duration of response (DOR).The median age was 55 years (range: 28-96); 76% of patients were <65 years. All 184 patients were female, and the majority were White (55%) or Asian (38%). Patients had an ECOG performance status of (55%) or (44%) at baseline. Ninety-two percent had visceral disease, 29% had bone metastases, and 13% had brain metastases. Fifty-three percent were HR+. Sum of diameters of target lesions were <5 cm in 42%, and >=5 cm in 50% (not evaluable by central review in 8% of patients).The median number of prior cancer regimens in the locally advanced/metastatic setting was (range: 2-17). All patients received prior trastuzumab, ado-trastuzumab emtansine, and 66% had prior pertuzumab.Efficacy results are summarized in Table 31.Table 31: Efficacy Results by Independent Central Review in DESTINY-Breast01Efficacy ParameterDESTINY-Breast01N=184ORR 95% CI calculated using Clopper-Pearson method.Confirmed Objective Response Rate (95% CI)60.3% (52.9, 67.4)Complete Response4.3%Partial Response56.0%Duration of ResponseDOR is based on median duration of follow-up of 11.1 months. Median, months (95% CI)Median DOR based on Kaplan-Meier estimate; 95% CI calculated using Brookmeyer-Crowley method.14.8 (13.8, 16.9). Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. 14.3HER2-Low and HER2-Ultralow Metastatic Breast Cancer DESTINY-Breast06The efficacy of ENHERTU was evaluated in study DESTINY-Breast06 (NCT04494425), randomized (1:1), multicenter, open-label study that randomized 866 adult patients with advanced or metastatic HR+ breast cancer with HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC with membrane staining) expression as determined by Ventanas PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody assay and evaluated at central laboratory. HER2-ultralow is defined as membrane staining that is seen in >0 and <=10% of tumor cells. Patients were eligible if they had disease progression on (a) at least lines of endocrine therapy in the metastatic setting or (b) one line of endocrine therapy in the metastatic setting and demonstrated progression within 24 months of the start of adjuvant endocrine therapy, or within months of starting first line endocrine therapy in combination with CDK 4/6 inhibitor in the metastatic setting. Patients with prior chemotherapy in the neoadjuvant or adjuvant setting were eligible if they had disease-free interval greater than 12 months. The study excluded patients with prior chemotherapy for advanced or metastatic disease, patients with history of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening, uncontrolled or significant cardiovascular disease, untreated and symptomatic brain metastases, or ECOG performance status >1.Patients were randomized to receive either ENHERTU 5.4 mg/kg (N=436) by intravenous infusion every three weeks or physicians choice of single agent chemotherapy (N=430, capecitabine 60%, nab-paclitaxel 24%, or paclitaxel 16%). Randomization was stratified by prior CDK4/6 inhibitor use (yes or no), prior taxane use in the non-metastatic setting (yes or no), and HER2 IHC status of tumor samples (IHC 2+/ISH- vs IHC 1+ vs IHC with membrane staining). Treatment with ENHERTU was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity.The major efficacy outcome measure was PFS in patients with HER2-low breast cancer assessed by BICR based on RECIST v1.1. Additional efficacy outcome measures were PFS assessed by BICR based on RECIST v1.1 in the overall population, OS in HER2-low patients, and OS in the overall population.The median age was 57 years (range: 28 to 87); 31% were age 65 or older; 99.9% were female; 53% were White, 35% were Asian, 0.8% were Black or African American, 0.1% were American Indian or Alaska Native, and 7% were of Hispanic/Latino ethnicity. Patients had an ECOG performance status of (59%) or (39%) at baseline; 18% were IHC with membrane staining, 55% were IHC 1+, 27% were IHC 2+/ISH-; 67% had liver metastases, 32% had lung metastases, 8% had brain metastases, and 3% had bone-only metastases. Patients had median of prior lines of endocrine therapy in the metastatic setting (range: to 5) with 17% having and 68% having 2. Eighty-nine percent of patients had prior endocrine therapy in combination with CDK4/6i treatment in the metastatic setting, 41% had prior taxane use in the non-metastatic setting.Efficacy results are summarized in Table 32 and Figure 7. At the time of the PFS final analysis, overall survival (OS) data was immature, and total of 335 (39%) of patients had died across both study arms in the overall population. Table 32: Efficacy Results in DESTINY-Breast06Efficacy ParameterHER2-lowOverall Population (HER2-low and HER2-ultralow)ENHERTU(N=359)Chemotherapy(N=354)ENHERTU(N=436)Chemotherapy(N=430)CI confidence intervalProgression Free Survival (PFS) per BICRNumber of events (%)225 (62.7)232 (65.5)269 (61.7)271 (63.0)Median, months (95% CI)13.2 (11.4, 15.2)8.1 (7.0, 9.0)13.2 (12.0, 15.2)8.1 (7.0, 9.0)Hazard ratio (95% CI)0.62 (0.52, 0.75)Based on stratified analysis with stratification factors prior CDK4/6 inhibitor use (yes vs no) and HER2 IHC status of tumor samples (IHC 1+ vs IHC 2+/ISH-). 0.64 (0.54, 0.76)Based on unstratified analysis. p-value<0.0001 <0.0001 Confirmed Objective Response Rate (ORR) per BICRAnalysis was performed based on the patients with measurable disease assessed by BICR at baseline. N326324393389n (%)202 (62.0)114 (35.2)246 (62.6)134 (34.4)95% CI56.5, 67.330.0, 40.757.6, 67.429.7, 39.4Complete Response (%)9 (2.8)010 (2.5)0Partial Response (%)193 (59.2)114 (35.2)236 (60.1)134 (34.4)Duration of Response (DOR) per BICR Median, months (95% CI)14.1 (11.9, 15.9)8.6 (6.7, 11.3)14.3 (12.5, 15.9)8.6 (6.9, 11.5)In an exploratory analysis of the HER2-ultralow subgroup (n=153), median PFS was 15.1 months (95% CI: 10.0, 17.3) in patients randomized to ENHERTU and 8.3 months (95% CI: 5.8, 15.2) in patients randomized to chemotherapy with hazard ratio of 0.76 (95% CI: 0.49, 1.17). Confirmed ORR (BICR) was 65.7% (95% CI: 53.1, 76.8) and 30.8% (95% CI: 19.9, 43.4) in patients randomized to ENHERTU and chemotherapy and with measurable disease at baseline, respectively. Median DOR was 14.3 months (95% CI: 11.8, not estimable) and 14.1 months (95% CI: 5.9, not estimable) in patients randomized to ENHERTU and chemotherapy, respectively.Figure 7: Kaplan-Meier Plot of Progression Free Survival (Overall Population)DESTINY-Breast04The efficacy of ENHERTU was evaluated in study DESTINY-Breast04 (NCT03734029), randomized, multicenter, open-label study that enrolled 557 adult patients with unresectable or metastatic HER2-low breast cancer. The study included cohorts: 494 hormone receptor-positive (HR+) patients and 63 hormone receptor-negative (HR-) patients. HER2-low expression was defined as IHC 1+ or IHC 2+/ISH-, as determined at central laboratory using Ventanas PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody assay. Patients must have received chemotherapy in the metastatic setting or have developed disease recurrence during or within months of completing adjuvant chemotherapy. Patients who were HR+ must have received at least one endocrine therapy or be ineligible for endocrine therapy. Patients were randomized 2:1 to receive either ENHERTU 5.4 mg/kg (N=373) by intravenous infusion every weeks or physicians choice of chemotherapy (N=184, eribulin, capecitabine, gemcitabine, nab paclitaxel, or paclitaxel). Randomization was stratified by HER2 IHC status of tumor samples (IHC 1+ or IHC 2+/ISH-), number of prior lines of chemotherapy in the metastatic setting (1 or 2), and HR status/prior CDK4/6i treatment (HR+ with prior CDK4/6 inhibitor treatment, HR+ without prior CDK4/6 inhibitor treatment, or HR-). Treatment was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity. The study excluded patients with history of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening and clinically significant cardiac disease. Patients were also excluded for untreated or symptomatic brain metastases or ECOG performance status >1.The major efficacy outcome measure was PFS in patients with HR+ breast cancer assessed by BICR based on RECIST v1.1. Additional efficacy outcome measures were PFS assessed by BICR based on RECIST v1.1 in the overall population (all randomized HR+ and HR- patients), OS in HR+ patients, and OS in the overall population.The median age was 57 years (range: 28 to 81); 24% were age 65 or older; 99.6% were female; 48% were White, 40% were Asian, and 2% were Black or African American; 3.8% of patients were of Hispanic/Latino ethnicity. Patients had an ECOG performance status of (55%) or (45%) at baseline; 58% were IHC 1+, 42% were IHC 2+/ISH-; 70% had liver metastases, 33% had lung metastases, and 6% had brain metastases. In the metastatic setting, patients had median of prior lines of systemic therapy (range: to 9) with 58% having and 41% having prior chemotherapy regimens; 3.9% were early progressors (progression in the neo/adjuvant setting). In HR+ patients, the median number of prior lines of endocrine therapy was (range: to 9) and 70% had prior CDK4/6i treatment.Efficacy results are summarized in Table 33 and Figures and 9.Table 33: Efficacy Results in DESTINY-Breast04Efficacy ParameterHR+ CohortOverall Population(HR+ and HR- Cohorts)ENHERTU(N=331)Chemotherapy(N=163)ENHERTU(N=373)Chemotherapy(N=184)CI confidence intervalOverall SurvivalNumber of events (%)126 (38.1)73 (44.8)149 (39.9)90 (48.9)Median, months (95% CI)23.9 (20.8, 24.8)17.5 (15.2, 22.4)23.4 (20.0, 24.8)16.8 (14.5, 20.0)Hazard ratio (95% CI)0.64 (0.48, 0.86)0.64 (0.49, 0.84)p-value0.00280.001Progression-Free Survival per BICRNumber of events (%)211 (63.7)110 (67.5)243 (65.1)127 (69.0)Median, months (95% CI)10.1 (9.5, 11.5)5.4 (4.4, 7.1)9.9 (9.0, 11.3)5.1 (4.2, 6.8)Hazard ratio (95% CI)0.51 (0.40, 0.64)0.50 (0.40, 0.63)p-value<0.0001<0.0001Confirmed Objective Response Rate per BICRn (%)175 (52.9)27 (16.6)195 (52.3)30 (16.3)95% CI47.3, 58.411.2, 23.247.1, 57.411.3, 22.5Complete Response (%)12 (3.6)1 (0.6)13 (3.5)2 (1.1)Partial Response (%)164 (49.5)26 (16.0)183 (49.1)28 (15.2)Duration of Response per BICRMedian, months (95% CI)10.7 (8.5, 13.7)6.8 (6.5, 9.9)10.7 (8.5, 13.2)6.8 (6.0, 9.9)Figure 8: Kaplan-Meier Plot of Overall Survival (Overall Population)Figure 9: Kaplan-Meier Plot of Progression-Free Survival (Overall Population). Figure 7. Figure 8. Figure 9. 14.4HER2-Mutant Unresectable or Metastatic Non-Small Cell Lung Cancer ENHERTU was evaluated in DESTINY-Lung01 (NCT03505710) and at two dose levels in DESTINY-Lung02 (NCT04644237). Patients were prospectively selected for treatment with ENHERTU based on the presence of activating HER2 (ERBB2) mutations by local testing using tissue. Samples from DESTINY-Lung01 were retrospectively tested using Oncomine(TM) Dx Target Test (Life Technologies Corporation, Tissue-test) and Guardant360(R) CDx test (Guardant Health Inc., Plasma test). Demographic and baseline disease characteristics were similar for patients in DESTINY-Lung01 and DESTINY-Lung02, except for race (34% Asian vs 64% Asian, respectively). Response rates were consistent across dose levels. Increased rates of ILD/pneumonitis were observed at the higher dose. The approved recommended dose of 5.4 mg/kg intravenously every weeks in the DESTINY-Lung02 study is described below [see Adverse Reactions (6.1)]. The efficacy of ENHERTU was evaluated in DESTINY-Lung02, multicenter, multicohort, randomized, blinded, dose-optimization trial. Eligible patients were required to have unresectable or metastatic HER2-mutant non-squamous NSCLC with disease progression after one prior systemic therapy. Patients with history of steroid dependent ILD/pneumonitis, clinically significant cardiac disease, clinically active brain metastases, and ECOG performance status >1 were excluded. Patients received ENHERTU 5.4 mg/kg by intravenous infusion every weeks until disease progression or unacceptable toxicity. Tumor imaging was obtained every weeks and CT/MRI of the brain was mandatory for patients with stable brain metastases at baseline. The major efficacy outcomes were confirmed ORR as assessed by BICR using RECIST v1.1 and DOR. The final analysis occurred after all responders had been followed for at least months from the date of initial response or until disease progression or death, whichever came first. Of the 102 patients randomized to receive ENHERTU 5.4 mg/kg, the median age was 59 years (range 31 to 84); 64% were female; 64% were Asian, 23% were White, and 14% were other races; 28% had an ECOG performance status of and 72% had 1; 34% had stable brain metastases; 97% had mutation in the ERBB2 kinase domain and 3% had mutation in the extracellular domain. The median number of prior regimens was (range: to 12); 100% of patients received prior platinum therapy, 74% received prior immunotherapy, and 50% received both in combination. Fifty-four percent of patients were never-smokers and 46% were former smokers; 98% of patients had adenocarcinoma histology.Efficacy results are provided in Table 34.Table 34: Efficacy Results for DESTINY-Lung02Efficacy ParameterDESTINY-Lung02N=102ORR 95% CI calculated using Clopper-Pearson method NE=not estimableConfirmed Objective Response Rate (95% CI)50.0% (39.9, 60.1)Complete Response2.9%Partial Response47.1%Duration of ResponseMedian, months (95% CI)Median DOR based on Kaplan-Meier estimate; 95% CI calculated using Brookmeyer-Crowley method12.6 (6.4, NE). 14.5HER2-Positive Locally Advanced or Metastatic Gastric Cancer The efficacy of ENHERTU was evaluated in study DESTINY-Gastric01 (NCT03329690), multicenter, open-label, randomized trial conducted in Japan and South Korea that enrolled 188 adult patients with HER2-positive (IHC 3+ or IHC 2+/ISH positive), locally advanced or metastatic gastric or GEJ adenocarcinoma who had progressed on at least two prior regimens including trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy. HER2 expression was determined by central lab on tissue obtained either before or after prior trastuzumab treatment. Patients were excluded for history of treated or current ILD, history of clinically significant cardiac disease, active brain metastases, or ECOG performance status >1. Patients were randomized 2:1 to receive ENHERTU (N=126) 6.4 mg/kg intravenously every weeks or physicians choice of chemotherapy: irinotecan monotherapy (N=55) 150 mg/m2 intravenously every weeks or paclitaxel monotherapy (N=7) 80 mg/m2 intravenously weekly. Randomization was stratified by HER2 status (IHC 3+ or IHC 2+/ISH+), ECOG performance status (0 or 1), and region (Japan or South Korea). Tumor imaging assessments were performed at screening and every weeks from the first treatment dose. Treatment was administered until unacceptable toxicity or disease progression. The major efficacy outcomes were ORR assessed by ICR according to RECIST v1.1 and OS in the intent-to-treat population. Additional efficacy outcomes were PFS and DOR.The median age was 66 years (range 28 to 82); 76% were male; and 100% were Asian. All patients received trastuzumab product. Patients had an ECOG performance status of either (49%) or (51%); 87% had gastric adenocarcinoma and 13% had GEJ adenocarcinoma; 76% were IHC 3+ and 23% were IHC 2+/ISH+; 65% had inoperable advanced cancer; 35% had postoperative recurrent cancer; 54% had liver metastases; 29% had lung metastases; 45% had three or more prior regimens in the locally advanced or metastatic setting. total of 30% of patients were identified as HER2-positive using tissue obtained following prior treatment with trastuzumab product.Efficacy results are summarized in Table 35, and the Kaplan-Meier curve for OS is shown in Figure 10.Table 35: Efficacy Results in DESTINY-Gastric01 Efficacy ParameterENHERTUN=126Irinotecan or PaclitaxelN=62CI confidence interval; NR not reachedOverall Survival (OS)OS was evaluated following statistically significant outcome of ORR. Median, months (95% CI)Median based on Kaplan-Meier estimate; 95% CI for median calculated using Brookmeyer-Crowley method 12.5 (9.6, 14.3)8.4 (6.9,10.7)Hazard ratio (95% CI)Based on the stratified Cox proportional hazards regression model (stratified by region) 0.59 (0.39, 0.88)p-valueBased on the stratified log-rank test (stratified by region) 0.0097Progression-Free Survival (PFS)Assessed by independent central review Median, months (95% CI) 5.6 (4.3, 6.9)3.5 (2.0, 4.3)Hazard ratio (95% CI) 0.47 (0.31, 0.71)Confirmed Objective Response Rate (ORR)n (%)51 (40.5)7 (11.3)95% CI95% exact binomial confidence interval (31.8, 49.6)(4.7, 21.9)p-valueBased on the stratified Cochran-Mantel-Haenszel test (stratified by region) <0.0001Complete Response (%)10 (7.9)0 (0.0)Partial Response (%)41 (32.5)7 (11.3)Duration of Response (DOR)Median, months (95% CI) 11.3 (5.6, NR)3.9 (3.0, 4.9)Figure 10: Kaplan-Meier Plot of Overall Survival Figure 10. 14.6HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors The efficacy of ENHERTU was evaluated in 192 adult patients with previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumors who were enrolled in one of three multicenter trials: DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02. All three studies excluded patients with history of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening and clinically significant cardiac disease. Patients were also excluded for active brain metastases or ECOG performance status >1. Patients received ENHERTU 5.4 mg/kg by intravenous infusion every three weeks. Treatment was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity. The major efficacy outcome measure in all three of the studies was confirmed objective response rate (ORR) and an additional efficacy outcome measure was duration of response (DOR). All outcomes were assessed by independent central review (ICR) based on RECIST v1.1. DESTINY-PanTumor02DESTINY-PanTumor02 (NCT04482309) was multicenter, multicohort, open-label trial that included 111 adult patients with locally advanced, unresectable, or metastatic HER2-positive (IHC 3+ by either local or central assessment) solid tumors that progressed following at least one prior systemic regimen in the advanced/metastatic setting or that had no satisfactory alternative treatment option. The median age was 64 years (range 23 to 85); 59% were female; 58% were White, 34% were Asian, and 4% were Black or African American; 3% of patients were of Hispanic/Latino ethnicity. Patients had an ECOG performance status of either (49%) or (51%) at baseline. The median number of prior regimens in any treatment setting was 2.DESTINY-Lung01DESTINY-Lung01 (NCT03505710) was multicenter, open-label, 2-cohort trial that included 17 patients with previously treated, unresectable, or metastatic, centrally confirmed HER2-positive (IHC 3+) NSCLC. Patients must have relapsed from or be refractory to standard treatment or have no available standard treatment.The median age was 59 years (range 31 to 74); 59% were male; 65% were White, 18% were Asian, and 12% were Black or African American. Patients had an ECOG performance status of either (12%) or (88%) at baseline. The median number of prior regimens in any treatment setting was 3.DESTINY-CRC02 DESTINY-CRC02 (NCT04744831) was multicenter, randomized, 2-arm trial that included 64 patients with previously treated, unresectable or metastatic centrally confirmed HER2-positive (IHC 3+) colorectal cancer (CRC). Unless contraindicated, patients must have received fluoropyrimidine, oxaliplatin and irinotecan. If clinically indicated, patients must have received anti-EGFR treatment, anti-VEGF treatment and anti-PDL1 therapy.The median age was 58 years (range 25 to 78); 53% were male; 55% were Asian and 41% were White; 1.6% of patients were of Hispanic/Latino ethnicity. Patients had an ECOG performance status of either (58%) or (42%) at baseline. The median number of prior regimens in any treatment setting was 4.Efficacy results are summarized in Table 36 and Table 37. Table 36: Efficacy Results in HER2-Positive (IHC 3+) Patients in DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02Efficacy ParameterDESTINY-PanTumor02N=111DESTINY-Lung01N=17 DESTINY-CRC02N=64CI=Confidence intervalConfirmed ORR (95% CI)Assessed by independent central review CI is derived based on the Clopper-Pearson method 51.4% (41.7, 61.0)52.9% (27.8, 77.0)46.9% (34.3, 59.8) Complete Response Rate2.7%5.9%0% Partial Response Rate48.6%47.1%46.9%Duration of Response MedianCalculated using the Kaplan-Meier technique, months (range)19.4 (1.3, 27.9Denotes ongoing response)6.9 (4.0, 11.7)5.5 (1.3+, 9.7)Table 37: Efficacy Results in HER2-positive (IHC 3+) Patients by Tumor Type in DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 Tumor TypePatientsConfirmed ORRAssessed by independent central review DOR RangeN% (95% CI)CI is derived based on the Clopper-Pearson method (months)CI=Confidence interval, NA=Not applicable, PD=Progressive disease, PR=Partial response, SD=Stable diseaseColorectal Cancer6446.9 (34.3, 59.8)(1.3Denotes ongoing response, 9.7)Bladder Cancer2737.0 (19.4, 57.6)(2.8, 19.7)Biliary Tract Cancer2245.5 (24.4, 67.8)(2.1, 22.0)NSCLC1752.9 (27.8, 77.0)(4.0, 11.7)Endometrial Cancer1656.3 (29.9, 80.2)(5.8, 23.7)Ovarian Cancer1566.7 (38.4, 88.2)(1.3, 27.9)Cervical Cancer1070.0 (34.8, 93.3)(7.2, 25.0)Salivary Gland Cancer966.7 (29.9,92.5)(5.6, 20.1)Pancreatic Cancer50 (0, 52.2)NAOropharyngeal Neoplasm1PR15.3Vulvar Cancer1PR2.6Extramammary Pagets Disease1PR19.4Lacrimal Gland Cancer1PR19.8 Lip and/or Oral Cavity Cancer1SDNAEsophageal Adenocarcinoma1PR2.8Esophageal Squamous Cell Carcinoma1PDNA.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.HER2-Positive, HER2-Low, and HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)ENHERTU as MonotherapyThe pooled safety population described in WARNINGS and PRECAUTIONS reflects exposure to ENHERTU 5.4 mg/kg intravenously every weeks in 2233 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast02, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Breast06, DESTINY-Lung01, DESTINY-Lung02, DESTINY-CRC02, and DESTINY-PanTumor02. Among these patients, 67% were exposed for greater than months and 39% were exposed for greater than 12 months. In this pooled safety population, the most common (>=20%) adverse reactions (including laboratory abnormalities) were decreased white blood cell count (73%), nausea (72%), decreased hemoglobin (67%), decreased neutrophil count (65%), decreased lymphocyte count (60%), fatigue (55%), decreased platelet count (48%), increased aspartate aminotransferase (46%), increased alanine aminotransferase (43%), increased blood alkaline phosphatase (39%), vomiting (38%), alopecia (37%), constipation (32%), decreased blood potassium (32%), decreased appetite (31%), diarrhea (30%), and musculoskeletal pain (24%). ENHERTU in Combination with PertuzumabThe pooled safety population described in WARNINGS and PRECAUTIONS reflects exposure to ENHERTU 5.4 mg/kg in combination with pertuzumab intravenously every weeks in 431 patients in DESTINY-Breast07 (n=50), and DESTINY-Breast09 (n=381). Among these patients, 86% were exposed for greater than months and 73% were exposed for greater than 12 months. In this pooled safety population, the most common (>=20%) adverse reactions (including laboratory abnormalities) were decreased white blood cell count (86%), decreased hemoglobin (80%), decreased neutrophil count (79%), nausea (74%), increased alanine aminotransferase (65%), diarrhea (64%), increased aspartate aminotransferase (63%), decreased lymphocyte count (61%), decreased platelet count (55%), increased blood alkaline phosphatase (54%), decreased blood potassium (54%), fatigue (53%), alopecia (48%), vomiting (46%), upper respiratory tract infection (32%), constipation (31%), decreased appetite (31%), decreased weight (28%), musculoskeletal pain (23%), increased blood bilirubin (23%), and abdominal pain (22%). ENHERTU followed by THPThe data described in the WARNINGS and PRECAUTIONS reflect exposure to ENHERTU 5.4 mg/kg intravenously every weeks for four cycles followed by THP for four cycles in 320 patients in Study DESTINY-Breast11.HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)The data described in WARNINGS and PRECAUTIONS reflect exposure to ENHERTU 6.4 mg/kg intravenously every weeks in 125 patients in DESTINY-Gastric01.HER2-Positive Early Breast CancerDESTINY-Breast11The safety of ENHERTU followed by THP was evaluated in 320 patients with HER2-positive (IHC 3+ or ISH+) early breast cancer who received at least one dose of ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11 [see Clinical Studies (14.1)]. ENHERTU was administered by intravenous infusion once every three weeks for four cycles followed by THP for four cycles. The median duration of treatment was 5.6 months (range: 0.7 to 9.1) for patients who received ENHERTU followed by THP.Serious adverse reactions occurred in 11% of patients receiving ENHERTU followed by THP, including COVID-19 (0.9%) and ILD/pneumonitis (0.6%). Fatal adverse reactions occurred in 0.6% of patients, including ILD/pneumonitis and death not otherwise specified (one patient each).In patients treated with ENHERTU followed by THP, the permanent discontinuation of ENHERTU due to adverse reactions occurred in 1.3%, of which ILD/pneumonitis accounted for 0.6%. Dose interruptions of ENHERTU due to adverse reactions occurred in 11% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count and COVID-19. Dose reductions of ENHERTU occurred in 2.5% of patients treated with ENHERTU. The most common (>=20%) adverse reactions in patients treated with ENHERTU followed by THP, including laboratory abnormalities, were decreased hemoglobin, increased alanine aminotransferase, increased aspartate aminotransferase, decreased white blood cell count, nausea, peripheral neuropathy, diarrhea, decreased neutrophil count, alopecia, fatigue, decreased lymphocyte count, rash, musculoskeletal pain, decreased blood potassium, constipation, vomiting, stomatitis, and decreased appetite.Tables and summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast11.Table 4: Common Adverse Reactions (>=10% All Grades or >=2% Grades or 4) Patients in DESTINY-Breast11Adverse ReactionsENHERTU 5.4 mg/kg followed by THPN 320ddAC followed by THP = 312All Grades%Grade or 4%All Grades%Grade or 4%THP= paclitaxel, trastuzumab, and pertuzumab; ddAC=dose dense doxorubicin and cyclophosphamide; Events were graded using NCI CTCAE version 5.0.Gastrointestinal DisordersNausea651.9520.3Diarrhea596543.2Constipation290.3240Vomiting290.9210.6Stomatitis Including aphthous ulcer, cheilitis, glossitis, mouth ulceration, mucosal inflammation, and stomatitis. 230.3361.0Abdominal painIncluding abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and gastrointestinal pain. 160120Nervous System DisordersPeripheral neuropathyIncluding dysesthesia, hypoesthesia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy. 592.5472.2HeadacheIncluding headache, migraine, and sinus headache. 180160Skin and Subcutaneous Tissue DisordersAlopecia480490RashIncluding dermatitis, dermatitis acneiform, dermatitis bullous, eczema, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, skin exfoliation, and urticarial dermatitis. 310.9251.0General Disorders and Administration Site ConditionsFatigueIncluding asthenia, fatigue, and malaise. 410.6552.2Musculoskeletal and Connective Tissue DisordersMusculoskeletal painIncluding arthralgia, back pain, bone pain, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and pain in extremity. 300280.3Metabolism and Nutrition DisordersDecreased appetite200180.3Respiratory, Thoracic and Mediastinal DisordersEpistaxis150100Cough100140Infections and InfestationsUpper respiratory tract infectionIncluding influenza, influenza-like illness, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection. 130.6200.3COVID-19100.9110.3Other clinically relevant adverse reactions reported in less than 10% of patients in the ENHERTU followed by THP treated group were: General disorders and administration site conditions: peripheral edema (9%), pyrexia (8%), mucosal inflammation (1.9%)Nervous System Disorders: dysgeusia (9%), dizziness (4.7%)Eye Disorders: dry eye (8%), blurred vision (6%) [including vision blurred, visual impairment]Gastrointestinal disorders: dyspepsia (8%), gastritis (3.4%), abdominal distension (2.5%), flatulence (0.9%)Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (7%), ILD (4.4%) [including interstitial lung disease, lung opacity, pneumonia fungal, pneumonitis].Skin and Subcutaneous Tissue Disorders: pruritus (6%) and skin hyperpigmentation (1.6%) [including skin hyperpigmentation and skin discoloration]Injury, Poisoning, and Procedural Complications: infusion-related reactions (4.7%) Investigations: decreased weight (3.4%)Blood and Lymphatic System Disorders: febrile neutropenia (0.9%)Metabolism and Nutrition Disorders: dehydration (0.3%)Table 5: Selected Laboratory Abnormalities in Patients in DESTINY-Breast11Laboratory ParameterENHERTU 5.4 mg/kg followed by THPN=320ddAC followed by THPN 312All Grades%Grades 3-4%All Grades%Grades 3-4%THP= paclitaxel, trastuzumab, and pertuzumab; ddAC= dose dense doxorubicin and cyclophosphamide Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.Hematology Decreased hemoglobin832.29710 Decreased white blood cell count6788731 Decreased neutrophil count58176638 Decreased lymphocyte count403.19339 Decreased platelet count80.9282.9Chemistry Increased alanine aminotransferase795774.2 Increased aspartate aminotransferase742.5681 Decreased blood potassium294.1254.5 Increased blood alkaline phosphatase190240 Decreased sodium191.9232.6 Increased blood creatinine80.681.3 Increased blood bilirubin704.20.6DESTINY-Breast05The safety of ENHERTU was evaluated in 806 patients with HER2-positive breast cancer with residual invasive disease following neoadjuvant HER2-targeted therapy who then received at least one dose of ENHERTU 5.4 mg/kg [see Clinical Studies (14.1)]. ENHERTU was administered by intravenous infusion once every three weeks for 14 cycles. The median duration of treatment was 10 months (range: 0.7 to 16) for patients who received ENHERTU.Serious adverse reactions occurred in 17% of patients receiving ENHERTU. Serious adverse reactions in >=1% of patients who received ENHERTU were ILD/pneumonitis, radiation pneumonitis, pneumonia, and platelet count decreased. Fatal adverse reactions occurred in 0.4% of patients including ILD/pneumonitis (2 patients) and respiratory tract infection (one patient). Permanent discontinuation of ENHERTU due to an adverse reaction occurred in 18% of patients. The adverse reaction which resulted in permanent discontinuation of ENHERTU >2% included ILD/pneumonitis. Dose interruptions of ENHERTU due to an adverse reaction occurred in 50% of patients. Adverse reactions which required dosage interruptions in >2% included radiation pneumonitis, neutrophil count decreased, COVID-19, white blood cell count decreased, ILD/pneumonitis, platelet count decreased, upper respiratory tract infection, fatigue, cough, and pyrexia. Dose reductions of ENHERTU due to an adverse reaction occurred in 26% of patients. Adverse reactions which required dose reductions in >2% of patients included nausea, fatigue, platelet count decreased, ILD/pneumonitis, and neutrophil count decreased.The most common (>=20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count, decreased lymphocyte count, decreased neutrophil count, nausea, decreased hemoglobin, increased aspartate aminotransferase, fatigue, increased alanine aminotransferase, decreased platelet count, increased blood alkaline phosphatase, constipation, vomiting, decreased blood potassium, diarrhea, musculoskeletal pain, and decreased appetite.Tables and summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast05.Table 6: Common Adverse Reactions (>=10% All Grades or >=2% Grades 3-4) in Patients Treated with ENHERTU in DESTINY-Breast05Adverse ReactionsENHERTU 5.4 mg/kgN= 806Ado-Trastuzumab Emtansine (T-DM1) 3.6mg/kgN=801All Grades%Grade or 4%All Grades%Grades or 4%Events were graded using NCI CTCAE version 5.0.Gastrointestinal DisordersNausea714.5290.1Constipation320160.1Vomiting311.190.1Diarrhea231.290.4Abdominal painIncluding abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and gastrointestinal pain. 150.290.1StomatitisIncluding aphthous ulcer, cheilitis, mouth ulceration, mucosal inflammation, pharyngeal inflammation, and stomatitis. 100.260.1General Disorders and Administration Site ConditionsFatigueIncluding asthenia, fatigue, lethargy, and malaise. 546371.0Pyrexia100.1120.2Musculoskeletal and Connective Tissue DisordersMusculoskeletal painIncluding arthralgia, back pain, bone pain, limb discomfort, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and pain in extremity. 230.7320.6Metabolism and Nutrition DisordersDecreased appetite200.9100Infections and InfestationsUpper respiratory tract infectionIncluding influenza, influenza like illness, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection. 180.1170.5COVID-19170.5200.4Respiratory, Thoracic and Mediastinal DisordersInterstitial lung diseaseIncluding COVID-19 pneumonia, interstitial lung disease, lung opacity, organizing pneumonia, pneumocystis jirovecii pneumonia, pneumonia, and pneumonitis which was adjudicated as ILD (irrespective of causality). Adjudicated drug-related ILD for ENHERTU was 10% for all Grades and 0.9% for Grades or and for T-DM1, 1.6% for all Grades and 0% for Grades or 4. 171.13.70.2Cough130110Nervous System DisordersHeadacheIncluding headache, migraine, and sinus headache. 160.2210.1Peripheral neuropathyIncluding dysesthesia, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy. 130.4201.1DizzinessIncluding dizziness, dizziness postural, vertigo, and vertigo positional. 110.470.1Skin and Subcutaneous Tissue DisordersAlopecia1601.20RashIncluding dermatitis, dermatitis acneiform, dermatitis exfoliative generalized, drug eruption, dyshidrotic eczema, eczema, eczema asteatotic, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, skin exfoliation, and Stevens-Johnson syndrome. 100.4140.1InvestigationsDecreased weight120.270.1Other clinically relevant adverse reactions reported in less than 10% of patients in the ENHERTU-treated group were:Gastrointestinal disorders: dyspepsia (8%), gastritis (2.5%), abdominal distension (1.7%), flatulence (1.5%) Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (4.5%), epistaxis (3.8%)Skin and Subcutaneous Tissue Disorders: pruritus (4.2%), skin hyperpigmentation (3.5%) [including pigmentation disorder, skin discoloration, skin hyperpigmentation] Nervous System Disorders: dysgeusia (3.7%) Eye Disorders: dry eye (2.7%), vision blurred (2.7%) [including vision blurred, visual impairment]Metabolism and Nutrition Disorders: dehydration (1%)Injury, Poisoning, and Procedural Complications: infusion related reaction (0.7%) [including hypersensitivity, infusion related reaction]Blood and Lymphatic System Disorders: febrile neutropenia (0.5%)Table 7: Selected Laboratory Abnormalities in Patients in DESTINY-Breast05Laboratory ParameterENHERTU5.4 mg/kgN=806Ado-Trastuzumab Emtansine (T-DM1) 3.6mg/kgN 801All Grades%Grades 3-4%All Grades%Grades 3-4%Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.Hematology Decreased white blood cell count8017462.3 Decreased lymphocyte count72355417 Decreased neutrophil count7223384.9 Decreased hemoglobin612.9362 Decreased platelet count4689333Chemistry Increased aspartate aminotransferase601914.3 Increased alanine aminotransferase531804.2 Increased blood alkaline phosphatase390530.1 Decreased blood potassium271.7442.1 Increased blood creatinine130.290.1 Increased blood bilirubin90200Radiotherapy-Related Pneumonitis and Skin Injury in the Post Neoadjuvant Early Breast Cancer SettingAmong patients receiving sequential or concurrent adjuvant radiotherapy in DESTINY-Breast05, radiation pneumonitis occurred in 31% of patients receiving ENHERTU 5.4 mg/kg (N=757) and 31% of patients receiving ado-trastuzumab emtansine (T-DM1) 3.6 mg/kg (N=750), as reported by the investigator. All cases of patients receiving ENHERTU and adjuvant radiotherapy (ART) were either Grade (27%) or Grade (4.9%). Similarly, all cases of patients receiving T-DM1 and ART were either Grade (24%) or Grade (7%). higher incidence of radiation pneumonitis was reported for patients who received sequential vs. concurrent ART, irrespective of treatment arm: 34% for ENHERTU vs. 37% for T-DM1, respectively, with sequential ART and 29% vs. 27%, respectively, with concurrent ART. For patients treated with ENHERTU, median time to onset of first event of radiation pneumonitis was 4.1 months (range: 1.3 11.6 months).Among patients receiving ART and ENHERTU, radiation skin injury occurred in 20% of all patients, of which 1.6% were Grade and none were Grade 4. Among patients receiving ART and T-DM1, radiation skin injury occurred in 18% of all patients, of which 0.4% were Grade and none were Grade 4. HER2-Positive Metastatic Breast CancerDESTINY-Breast09 The safety of ENHERTU 5.4 mg/kg in combination with pertuzumab was evaluated in DESTINY-Breast09, randomized, three-arm, multicenter study including 763 patients with HER2-positive (IHC 3+ or ISH+) unresectable or metastatic breast cancer [see Clinical Studies (14.2)]. Three hundred eighty-one patients received ENHERTU in combination with pertuzumab and 382 patients received THP (taxane [docetaxel or paclitaxel], trastuzumab, and pertuzumab). Among patients who received ENHERTU in combination with pertuzumab, the median duration of treatment was 22 months (range: 0.3 months to 44.5 months). Serious adverse reactions occurred in 27% of patients receiving ENHERTU in combination with pertuzumab. Serious adverse reactions in >1% of patients were diarrhea, pneumonia, febrile neutropenia, hypokalemia, vomiting, ILD, pulmonary embolism, and sepsis. Fatalities due to adverse reactions occurred in 3.4% of patients including pneumonia (n=3), ILD (n=2), sepsis (n=2), pulmonary embolism, septic shock, acute kidney injury, dyspnea, febrile neutropenia, and intestinal ischemia (one patient each). ENHERTU was discontinued for adverse reactions in 21% of patients. The most frequent adverse reactions (>2%) associated with permanent discontinuation was ILD/pneumonitis (6%).Dose interruptions due to adverse reactions occurred in 69% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were COVID-19, neutropenia, upper respiratory tract infection, fatigue, anemia, hypokalemia, ILD/pneumonitis, thrombocytopenia, pneumonia, diarrhea, transaminase increased, leukopenia, cough, pyrexia, decreased appetite, and blood bilirubin increased. Dose reductions occurred in 46% of patients treated with ENHERTU in combination with pertuzumab. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, neutropenia, nausea, diarrhea, ILD/pneumonitis, thrombocytopenia, vomiting, transaminases increased, decreased weight, febrile neutropenia, and hypokalemia. The most common (>=20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, nausea, increased alanine aminotransferase, diarrhea, increased aspartate aminotransferase decreased lymphocyte count, decreased platelet count, increased blood alkaline phosphatase, decreased blood potassium, fatigue, alopecia, vomiting, upper respiratory tract infection, constipation, decreased appetite, decreased weight, COVID-19, musculoskeletal pain, increased blood bilirubin, and abdominal pain.Tables and summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast09. Table 8: Common Adverse Reactions (>=10% All Grades or >=2% Grades or 4) in Patients Treated with ENHERTU in Combination with Pertuzumab in DESTINY-Breast09Adverse ReactionsENHERTU 5.4 mg/kg PertuzumabN= 381THPTHP=taxane [docetaxel or paclitaxel], trastuzumab, and pertuzumab N=382All Grades%Grade 3-4%All Grades%Grades 3-4%Gastrointestinal DisordersNausea755340.3Diarrhea648626Vomiting462.4180.5Constipation330.3120Abdominal painIncluding abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and gastrointestinal pain. 230.3130StomatitisIncluding aphthous ulcer, mouth ulceration, oral mucosal eruption, and stomatitis. 161.3171.3Dyspepsia12060General Disorders and Administration Site Conditions FatigueIncluding asthenia, fatigue, lethargy, and malaise. 538422.1Pyrexia160181.0Skin and Subcutaneous Tissue DisordersAlopecia480530.5RashIncluding rash, rash macular, rash maculo-papular, rash pruritic, and rash pustular. 170.3220.3Pruritus110110.3Infections and InfestationsUpper respiratory tract infectionIncluding Influenza, Influenza like illness, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection. 331.6300.5COVID-19280.3220.3Metabolism and Nutrition DisordersDecreased appetite322.4180.8Hypoalbuminemia110.380.3InvestigationsDecreased weight303.1110.8Musculoskeletal and Connective Tissue DisordersMusculoskeletal painIncluding back pain, bone pain, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and pain in extremity. 241330.3Nervous System DisordersHeadacheIncluding headache and migraine. 190.3140Dysgeusia13090Dizziness120.3100Respiratory, Thoracic, and Mediastinal DisordersCough170.3130Interstitial lung diseaseInterstitial lung disease includes chronic obstructive pulmonary disease (n=1), interstitial lung disease (n=23), pneumonia (n=3), and pneumonitis (n=22). These events were adjudicated as ILD and related to use of ENHERTU 12010Eye DisordersDry eye11060Other clinically relevant adverse reactions reported in less than 10% of patients treated with ENHERTU in combination with pertuzumab were: Blood and Lymphatic System Disorders: febrile neutropenia (2.9%)Eye Disorders: blurred vision (4.2%)Gastrointestinal Disorders: abdominal distension (6%), gastritis (3.9%), flatulence (2.4%)General Disorders and Administration Site Conditions: mucosal inflammation (9%)Injury, poisoning, and procedural complications: infusion related reactions (2.6%) [including hypersensitivity and infusion-related reactions]Metabolism and Nutrition Disorders: dehydration (2.9%)Respiratory, Thoracic, and Mediastinal Disorders: epistaxis (8%), dyspnea (6%)Skin and Subcutaneous Tissue Disorders: dry skin (7%), skin hyperpigmentation (6%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder]Table 9: Selected Laboratory Abnormalities in Patients in DESTINY-Breast09Laboratory ParameterENHERTU 5.4 mg/kg PertuzumabN= 381THPTHP=taxane [docetaxel or paclitaxel], trastuzumab, and pertuzumab] N=382All Grades%Grade 3-4%All Grades%Grades 3-4%Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.HematologyDecreased white blood cell count87118231Decreased hemoglobin8012866Decreased neutrophil count78296640Decreased lymphocyte count62145811Decreased platelet count568201.9ChemistryIncreased alanine aminotransferase663.2451.9Increased aspartate aminotransferase622.1411.9Increased blood alkaline phosphatase550.3360.3Decreased blood potassium5420296Increased blood bilirubin230.3100.3Increased blood creatinine91.870.3DESTINY-Breast03The safety of ENHERTU was evaluated in 257 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast03 [see Clinical Studies (14.2)]. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 14 months (range: 0.7 to 30) for patients who received ENHERTU and months (range: 0.7 to 25) for patients who received ado-trastuzumab emtansine.Serious adverse reactions occurred in 19% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. Fatalities due to adverse reactions occurred in 0.8% of patients including COVID-19 and sudden death (one patient each).ENHERTU was permanently discontinued in 14% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 44% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis. Dose reductions occurred in 21% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, neutropenia, and fatigue.The most common (>=20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased neutrophil count, increased aspartate aminotransferase, decreased hemoglobin, decreased lymphocyte count, increased alanine aminotransferase, decreased platelet count, fatigue, vomiting, increased blood alkaline phosphatase, alopecia, decreased blood potassium, constipation, musculoskeletal pain, diarrhea, decreased appetite, headache, respiratory infection, abdominal pain, increased blood bilirubin, and stomatitis. Tables 10 and 11 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast03.Table 10: Common Adverse Reactions (>=10% All Grades or >=2% Grades 3-4) in Patients Treated with ENHERTU in DESTINY-Breast03Adverse ReactionsENHERTU5.4 mg/kgN=257Ado-trastuzumab emtansine3.6 mg/kgN=261All Grades%Grades 3-4%All Grades%Grades 3-4%Events were graded using NCI CTCAE version 5.0.Gastrointestinal Disorders Nausea767300.4 Vomiting491.6100.8 Constipation340200 Diarrhea291.270.4 Abdominal painIncluding abdominal pain, abdominal discomfort, lower abdominal pain, and upper abdominal pain. 210.880.4 StomatitisIncluding stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosal eruption. 200.850 Dyspepsia11060General Disorders and Administration Site Conditions FatigueIncluding fatigue, asthenia, malaise, and lethargy. 496350.8Skin and Subcutaneous Tissue Disorders AlopeciaThis Grade event was reported by the investigator. Per NCI CTCAE v.5.0, the highest NCI CTCAE grade for alopecia is Grade 2. 370.43.10Musculoskeletal and Connective Tissue Disorders Musculoskeletal painIncluding back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, and limb discomfort. 311.2250.4Metabolism and Nutrition Disorders Decreased appetite291.6170.4Investigations Decreased weight171.260.4Respiratory, Thoracic, and Mediastinal Disorders Respiratory infectionIncluding respiratory tract infection, lower and upper respiratory tract infection, pneumonia, influenza, influenza-like illness, viral upper respiratory infection, bronchitis, and respiratory syncytial virus infection. 220.8121.1 Epistaxis110160.4 Cough110.4100 Interstitial lung diseaseInterstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU: pneumonitis, interstitial lung disease, organizing pneumonia, pneumonia, and pulmonary mass. For ado-trastuzumab emtansine: pneumonitis, interstitial lung disease, organizing pneumonia, and pulmonary embolism. 110.81.90Nervous System Disorders HeadacheIncluding headache and migraine. 220.4160 Peripheral neuropathyIncluding peripheral neuropathy, peripheral sensory neuropathy, and paresthesia. 130.4140.4 Dizziness130.480Other clinically relevant adverse reactions reported in less than 10% of patients in the ENHERTU-treated group were: Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (8%)Skin and Subcutaneous Tissue Disorders: pruritus (8%) and skin hyperpigmentation (6%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder]Nervous System Disorders: dysgeusia (6%)Metabolism and Nutrition Disorders: dehydration (4.3%)Eye Disorders: blurred vision (3.5%)Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (2.7%) [see Warnings and Precautions (5.3)] Injury, Poisoning, and Procedural Complications: infusion-related reactions (2.3%) [including hypersensitivity and infusion-related reactions]Blood and Lymphatic System Disorders: febrile neutropenia (0.8%)Table 11: Selected Laboratory Abnormalities in Patients in DESTINY-Breast03Laboratory ParameterENHERTU5.4 mg/kg N=257Ado-trastuzumab emtansine 3.6 mg/kgN=261All Grades%Grades 3-4%All Grades%Grades 3-4%Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.Hematology Decreased white blood cell count748240.8 Decreased neutrophil count7018302.3 Decreased hemoglobin647386 Decreased lymphocyte count5514233.9 Decreased platelet count5277924Chemistry Increased aspartate aminotransferase670.8835 Increased alanine aminotransferase531.6676 Increased blood alkaline phosphatase490.8460.8 Decreased blood potassium354.7391.5 Increased blood bilirubin200140 Increased blood creatinine160.880.4DESTINY-Breast02The safety of ENHERTU was evaluated in 404 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast02 [see Clinical Studies (14.2)]. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 11 months (range: 0.7 to 45) for patients who received ENHERTU.Serious adverse reactions occurred in 26% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were COVID-19, ILD, pneumonia, vomiting, fatigue, and nausea. Fatalities due to adverse reactions occurred in 2.5% of patients including pneumonitis (2 patients), acute myeloid leukemia, brain edema, COVID-19, hemorrhage, hepatitis B, malignant pleural effusion, pneumonia, and vasogenic cerebral edema (one patient each).ENHERTU was permanently discontinued in 20% of patients, of which ILD accounted for 9%. Dose interruptions due to adverse reactions occurred in 45% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, COVID-19, anemia, fatigue, leukopenia, upper respiratory tract infection, and thrombocytopenia. Dose reductions occurred in 25% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, neutropenia, and vomiting.The most common (>=20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, fatigue, decreased lymphocyte count, decreased platelet count, increased alanine aminotransferase, vomiting, increased aspartate aminotransferase, alopecia, increased blood alkaline phosphatase, constipation, decreased appetite, decreased blood potassium, diarrhea, musculoskeletal pain, increased blood bilirubin, abdominal pain, and headache. Tables 12 and 13 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast02.Table 12: Common Adverse Reactions (>=10% All Grades or >=2% Grades 3-4) in Patients Treated with ENHERTU in DESTINY-Breast02Adverse ReactionsENHERTU 5.4 mg/kg N=404Treatment of Physicians Choice N=195All Grades %Grades 3-4 %All Grades %Grades 3-4 %Events were graded using NCI CTCAE version 5.0.Gastrointestinal Disorders Nausea737372.6 Vomiting383.7131 Constipation350.3110.5 Diarrhea272.7547 Abdominal painIncluding abdominal discomfort, abdominal pain, upper abdominal pain, lower abdominal pain, and gastrointestinal pain 221202.1 Dyspepsia12090 StomatitisIncluding aphthous ulcer, mouth ulceration, and stomatitis 121211General Disorders and Administration Site Conditions FatigueIncluding asthenia, fatigue, lethargy, and malaise 629371Skin and Subcutaneous Tissue Disorders Alopecia370.34.10Metabolism and Nutrition Disorders Decreased appetite311.7180.5Musculoskeletal and Connective Tissue Disorders Musculoskeletal painIncluding back pain, bone pain, limb discomfort, musculoskeletal chest pain, musculoskeletal pain, muscle spasms, myalgia, neck pain, and pain in extremity 250.7180.5Nervous System Disorders HeadacheIncluding headache and migraine 200.360Investigations Decreased weight180.33.60Respiratory, Thoracic, and Mediastinal Disorders Cough130100 Interstitial lung diseaseInterstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU: pneumonitis, interstitial lung disease, idiopathic interstitial pneumonia, lung disorder, pulmonary toxicity, and pneumonia. 100.70.50.5Other clinically relevant adverse reactions reported in less than 10% of patients in the ENHERTU-treated group were:Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (8%) and epistaxis (8%)Skin and Subcutaneous Tissue Disorders: rash (8%) [including rash, pustular rash, maculo-papular rash, and pruritic rash], pruritus (5%), skin hyperpigmentation (5%) [including skin hyperpigmentation and pigmentation disorder]Nervous System Disorders: dizziness (8%) and dysgeusia (8%)Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (4.2%) [see Warnings and Precautions (5.3)] Eye Disorders: dry eye (6%) and blurred vision [including blurred vision and visual impairment] (3%)Metabolism and Nutrition Disorders: dehydration (2.7%)Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.2%)Blood and Lymphatic System Disorders: febrile neutropenia (0.3%)Table 13: Selected Laboratory Abnormalities in Patients in DESTINY-Breast02Laboratory ParameterENHERTU 5.4 mg/kg N=404Treatment of Physicians Choice N=195All Grades %Grades 3-4 %All Grades %Grades 3-4 %Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.Hematology Decreased white blood cell count7012423.2 Decreased hemoglobin679543.2 Decreased neutrophil count6416344.7 Decreased lymphocyte count5817384.7 Decreased platelet count482.7311.6Chemistry Increased alanine aminotransferase431321.6 Increased aspartate aminotransferase370.7292.1 Increased blood alkaline phosphatase370170 Decreased blood potassium303.7298 Increased blood bilirubin230.3442.1 Increased blood creatinine70.3130DESTINY-Breast01 and Study DS8201-A-J101The safety of ENHERTU was evaluated in pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101 (NCT02564900) [see Clinical Studies (14.2)]. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was months (range: 0.7 to 31).In the pooled 234 patients, the median age was 56 years (range: 28-96), 74% of patients were <65 years, 99.6% of patients were female, and the majority were White (51%) or Asian (42%). Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of (58%) or (42%) at baseline. Ninety-four percent had visceral disease, 31% had bone metastases, and 13% had brain metastases.Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, decreased blood potassium, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.The most common (>=20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, fatigue, vomiting, alopecia, increased aspartate aminotransferase, increased alanine aminotransferase, decreased platelet count, constipation, decreased appetite, diarrhea, decreased blood potassium, and cough.Tables 14 and 15 summarize common adverse reactions and laboratory abnormalities observed in ENHERTU-treated patients in DESTINY-Breast01 and Study DS8201-A-J101.Table 14: Common Adverse Reactions (>=10% All Grades or >=2% Grades or 4) in Patients in DESTINY-Breast01 and Study DS8201-A-J101Adverse ReactionsENHERTU 5.4 mg/kgN=234All Grades%Grades or 4%Events were graded using NCI CTCAE version 4.03. Gastrointestinal Disorders Nausea797 Vomiting473.8 Constipation350.9 Diarrhea291.7 Abdominal painIncluding abdominal discomfort, gastrointestinal pain, abdominal pain, lower abdominal pain, and upper abdominal pain 191.3 StomatitisIncluding stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosa blistering. One Grade event of aphthous ulcer was not included in the summary of grouped term stomatitis (from DESTINY-Breast01). 140.9 Dyspepsia120General Disorders and Administration Site Conditions FatigueIncluding fatigue and asthenia 596Skin and Subcutaneous Tissue Disorders Alopecia460.4This Grade event was reported by the investigator. Per NCI CTCAE v.4.03, the highest NCI CTCAE grade for alopecia is Grade 2. RashIncluding rash, pustular rash, and maculo-papular rash 100Metabolism and Nutrition Disorders Decreased appetite321.3Respiratory, Thoracic, and Mediastinal Disorders Cough200 Dyspnea131.3 Epistaxis130 Interstitial lung diseaseInterstitial lung disease includes events that were adjudicated as drug-induced ILD: pneumonitis, interstitial lung disease, respiratory failure, organizing pneumonia, acute respiratory failure, lung infiltration, lymphangitis, and alveolitis. 92.6All events had fatal outcomes (n=6). Nervous System Disorders HeadacheIncluding headache, sinus headache, and migraine 190 Dizziness100Infections and Infestations Upper respiratory tract infectionIncluding influenza, influenza-like illness, and upper respiratory tract infection 150Eye Disorders Dry eye110.4This Grade event was reported by the investigator. Per NCI CTCAE v.4.03, the highest NCI CTCAE grade for dry eye is Grade 3. Other clinically relevant adverse reactions reported in less than 10% of patients were:Injury, Poisoning, and Procedural Complications: infusion-related reactions (2.6%)Blood and Lymphatic System Disorders: febrile neutropenia (1.7%)Table 15: Selected Laboratory Abnormalities in Patients with Unresectable or Metastatic HER2-positive Breast Cancer Treated with ENHERTU in DESTINY-Breast01 and Study DS8201-A-J101Laboratory ParameterENHERTU 5.4 mg/kgN=234All Grades%Grades or 4%Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.Frequencies were based on NCI CTCAE v.4.03 grade-derived laboratory abnormalities.HematologyDecreased white blood cell count707Decreased hemoglobin707Decreased neutrophil count6216Decreased platelet count373.4ChemistryIncreased aspartate aminotransferase410.9Increased alanine aminotransferase380.4Decreased blood potassium263HER2-Low and HER2-Ultralow Metastatic Breast CancerDESTINY-Breast06The safety of ENHERTU was evaluated in 434 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC with membrane staining) breast cancer who received ENHERTU 5.4 mg/kg in DESTINY-Breast06 [see Clinical Studies (14.3)]. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 11 months (range: 0.4 to 39.6) for patients who received ENHERTU.Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease (ILD)/pneumonitis, COVID-19, febrile neutropenia, and hypokalemia. Fatalities due to adverse reactions occurred in 2.8% of patients including ILD (0.7%); sepsis (0.5%); and COVID-19 pneumonia, bacterial meningoencephalitis, neutropenic sepsis, peritonitis, cerebrovascular accident, general physical health deterioration (0.2% each). ENHERTU was permanently discontinued in 14% of patients. The most frequent adverse reactions (>2%) associated with permanent discontinuation was ILD/pneumonitis. Dose interruptions due to adverse reactions occurred in 48% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were COVID-19, decreased neutrophil count, anemia, pyrexia, pneumonia, decreased white blood cell count, and ILD. Dose reductions occurred in 25% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, fatigue, decreased platelet count, and decreased neutrophil count.The most common (>=20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count, decreased neutrophil count, nausea, decreased hemoglobin, decreased lymphocyte count, fatigue, decreased platelet count, alopecia, increased alanine aminotransferase, increased blood alkaline phosphatase, increased aspartate aminotransferase, decreased blood potassium, diarrhea, vomiting, constipation, decreased appetite, COVID-19, and musculoskeletal pain.Tables 16 and 17 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast06.Table 16: Common Adverse Reactions (>=10% All Grades or >=2% Grades or 4) in Patients Treated with ENHERTU in DESTINY-Breast06Adverse ReactionsENHERTU5.4 mg/kgChemotherapyN=434N=417All Grades%Grades or 4%All Grades%Grades or 4%Events were graded using NCI CTCAE version 5.0. Gastrointestinal Disorders Nausea702.1300.5 Diarrhea342.3272.6 Vomiting341.4120.2 Constipation320.7150.5 Abdominal painIncluding abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, and gastrointestinal pain. 200.5140.2 StomatitisIncluding stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, oral mucosal blistering, and oral mucosal eruption. 150110.5 Dyspepsia1204.80General Disorders and Administration Site Conditions FatigueIncluding fatigue, asthenia, malaise, and lethargy. 534.4402.4 Pyrexia120.270Skin and Subcutaneous Tissue Disorders Alopecia480210.5 RashIncluding dermatitis, dermatitis allergic, dermatitis contact, eczema, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. 120.2438Metabolism and Nutrition Disorders Decreased appetite261.4120.5Infections and Infestations COVID-19Including COVID-19, COVID-19 pneumonia. 260.9131 Upper respiratory tract infectionIncluding influenza, influenza-like illness, upper respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, rhinitis, and laryngitis. 19090Musculoskeletal and Connective Tissue Disorders Musculoskeletal painIncluding back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, and limb discomfort. 240.5231.9Nervous System Disorders HeadacheIncluding migraine, headache, and sinus headache. 180.5100 Dysgeusia120.260Respiratory, Thoracic, and Mediastinal Disorders Cough16090 Interstitial lung diseaseIncluding bronchiectasis, interstitial lung disease, lower respiratory tract infection, pneumonia, pneumonia bacterial, pneumonitis, and pulmonary toxicity. 110.70.20 Epistaxis1003.60.2Other clinically relevant adverse reactions reported in less than 10% of patients in the ENHERTU-treated group were:Nervous System Disorders: dizziness (9%)Investigations: decreased weight (7%)Eye Disorders: dry eye (7%), and blurred vision (5%)Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (6%)Gastrointestinal Disorders: abdominal distension (4.8%), flatulence (2.3%), and gastritis (0.7%)Skin and Subcutaneous Tissue Disorders: pruritus (3.9%), and skin hyperpigmentation (0.9%)Metabolism and Nutrition Disorders: dehydration (1.6%)Blood and lymphatic system disorders: febrile neutropenia (1.2%)Injury, Poisoning, and Procedural Complications: infusion related reaction (1.2%)Table 17: Selected Laboratory Abnormalities in Patients in DESTINY-Breast06Laboratory ParameterENHERTU5.4 mg/kgChemotherapyN=434N=417All Grades%Grades or 4%All Grades%Grades or 4%Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.Hematology Decreased white blood cell count86137111 Decreased neutrophil count75275320 Decreased hemoglobin699585 Decreased lymphocyte count6619468 Decreased platelet count486251Chemistry Increased alanine aminotransferase443.2300.7 Increased blood alkaline phosphatase430.2220.2 Increased aspartate aminotransferase412.6271.2 Decreased blood potassium358152.9 Increased blood bilirubin161.9231.5 Increased blood creatinine101.981DESTINY-Breast04The safety of ENHERTU was evaluated in 371 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who received ENHERTU 5.4 mg/kg in DESTINY-Breast04 [see Clinical Studies (14.3)]. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was months (range: 0.2 to 33) for patients who received ENHERTU.Serious adverse reactions occurred in 28% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to adverse reactions occurred in 4.0% of patients including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each).ENHERTU was permanently discontinued in 16% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 39% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia. Dose reductions occurred in 23% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia.The most common (>=20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, fatigue, decreased platelet count, alopecia, vomiting, increased aspartate aminotransferase, increased alanine aminotransferase, constipation, increased blood alkaline phosphatase, decreased appetite, musculoskeletal pain, diarrhea, and decreased blood potassium.Tables 18 and 19 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast04.Table 18: Common Adverse Reactions (>=10% All Grades or >=2% Grades or 4) in Patients Treated with ENHERTU in DESTINY-Breast04Adverse ReactionsENHERTU5.4 mg/kgChemotherapyN=371N=172All Grades%Grades or 4%All Grades%Grades or 4%Events were graded using NCI CTCAE version 5.0. Gastrointestinal Disorders Nausea764.6300 Vomiting401.6130 Constipation340.8220 Diarrhea271.3221.7 Abdominal painIncluding abdominal pain, abdominal discomfort, lower abdominal pain, and upper abdominal pain 180.5130 StomatitisIncluding stomatitis, aphthous ulcer, mouth ulceration, and pharyngeal inflammation 130.3120.6General Disorders and Administration Site Conditions FatigueIncluding fatigue, asthenia, and malaise 549484.7 Pyrexia120.3130Skin and Subcutaneous Tissue Disorders Alopecia400330 RashIncluding rash, pustular rash, pruritic rash, maculo-papular rash, palmar-plantar erythrodysesthesia syndrome, papular rash, macular rash, eczema, erythema multiforme, dermatitis, urticarial dermatitis, drug eruption, and dermatitis bullous 130234.7Metabolism and Nutrition Disorders Decreased appetite322.4191.2Musculoskeletal and Connective Tissue Disorders Musculoskeletal painIncluding back pain, myalgia, pain in extremity, musculoskeletal pain, bone pain, musculoskeletal chest pain, arthralgia, noncardiac chest pain, musculoskeletal stiffness, arthritis, spinal pain, and neck pain 321.3310.6Investigations Decreased weight160.380Vascular Disorders HemorrhageIncluding esophageal varices, hemorrhage, hemorrhoidal hemorrhage, epistaxis, hematuria, conjunctival hemorrhage, vaginal hemorrhage, gingival bleeding, genital hemorrhage, eye hemorrhage, hemoptysis, hemorrhagic cystitis, pharyngeal hemorrhage, rectal hemorrhage, upper gastrointestinal hemorrhage, and esophageal hemorrhage 1603.50Nervous System Disorders HeadacheIncluding headache and migraine 150.360 Peripheral neuropathyIncluding peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, polyneuropathy, paresthesia, hypoesthesia, dysesthesia, and neuralgia 130295 DizzinessIncluding dizziness, postural dizziness, and vertigo 110.560Infections and Infestations Upper respiratory tract infectionIncluding upper respiratory tract infection, influenza, influenza-like illness, nasopharyngitis, pharyngitis, sinusitis, and rhinitis 140.350Respiratory, Thoracic and Mediastinal Disorders Interstitial lung diseaseInterstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU: interstitial lung disease, pneumonitis, organizing pneumonia, pneumonia, and radiation pneumonitis. 121.30.60 Dyspnea101.391.2Other clinically relevant adverse reactions reported in less than 10% of patients treated with ENHERTU:Nervous System Disorders: dysgeusia (10%)Respiratory, Thoracic and Mediastinal Disorders: cough (10%)Gastrointestinal Disorders: abdominal distension (5%), gastritis (2.7%), flatulence (2.4%)Eye Disorders: blurred vision (4.9%) [including blurred vision and visual impairment]Skin and Subcutaneous Tissue Disorders: pruritus (3.2%) and skin hyperpigmentation (2.7%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder]Metabolism and Nutrition Disorders: dehydration (1.9%)Blood and Lymphatic System Disorders: febrile neutropenia (1.1%)Injury, Poisoning, and Procedural Complications: infusion-related reactions (0.5%) [including injection-site reaction and chills]Table 19: Selected Laboratory Abnormalities in Patients in DESTINY-Breast04Laboratory ParameterENHERTU5.4 mg/kgChemotherapyN=371N=172All Grades%Grades or 4%All Grades%Grades or 4%Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.Hematology Decreased white blood cell count7097825 Decreased hemoglobin648536 Decreased neutrophil count64147338 Decreased lymphocyte count55184011 Decreased platelet count446210.6Chemistry Increased aspartate aminotransferase382.2384.1 Increased alanine aminotransferase360.8384.1 Increased blood alkaline phosphatase340.3240 Decreased blood potassium253.3171.2 Increased blood bilirubin162.7150.6 Increased blood creatinine151.190.6HER2-Mutant Unresectable or Metastatic NSCLCDESTINY-Lung02 evaluated two dose levels (5.4 mg/kg [n=101] and 6.4 mg/kg [n=50]); however, only the results for the recommended dose of 5.4 mg/kg intravenously every weeks are described below due to increased toxicity observed with the higher dose in patients with NSCLC, including ILD/pneumonitis.The safety of ENHERTU was evaluated in 101 patients in DESTINY-Lung02 [see Clinical Studies (14.4)]. Patients received ENHERTU 5.4 mg/kg intravenously once every three weeks until disease progression or unacceptable toxicity. The median duration of treatment was months (range: 0.7 to 28) for patients who received ENHERTU. The median age was 59 years (range 31 to 84); 64% were female; 23% were White, 64% were Asian, and 14% were other races.Serious adverse reactions occurred in 40% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pleural effusion, thrombocytopenia, dyspnea, nausea, pneumonia, vomiting, myocarditis, pulmonary embolism, and increased troponin I. Fatalities due to adverse reactions occurred in 3% of patients including ILD/pneumonitis, cerebrovascular accident, and pneumococcal sepsis (one patient each).ENHERTU was permanently discontinued due to an adverse reaction in 17% of patients. Adverse reactions which resulted in permanent discontinuation of ENHERTU were ILD/pneumonitis, pneumonia, blood bilirubin increased, hypokalemia, metastases to meninges, and myocarditis. Dose interruptions of ENHERTU due to adverse reactions occurred in 50% of patients. Adverse reactions which required dose interruption (>2%) included neutropenia, COVID-19, ILD/pneumonitis, fatigue, anemia, and pneumonia. Dose reductions due to an adverse reaction occurred in 20% of patients. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, fatigue, and decreased appetite.The most common (>=20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, nausea, decreased white blood cell count, decreased neutrophil count, decreased lymphocyte count, increased aspartate aminotransferase, decreased albumin, decreased platelet count, fatigue, increased alanine aminotransferase, decreased appetite, constipation, increased alkaline phosphatase, vomiting, decreased blood potassium, diarrhea, alopecia, and musculoskeletal pain.Tables 20 and 21 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Lung02.Table 20: Common Adverse Reactions (>=10% All Grades or >=2% Grades or 4) in Patients with Unresectable or Metastatic HER2-Mutant NSCLC in DESTINY-Lung02Adverse ReactionsENHERTU 5.4 mg/kgN=101All Grades%Grades or 4%Events were graded using NCI CTCAE version 5.0. Gastrointestinal Disorders Nausea674 Constipation381 VomitingIncluding vomiting and retching 323 Diarrhea241 StomatitisIncluding mucosal inflammation, stomatitis, and mouth ulceration 170 Abdominal painIncluding abdominal discomfort, abdominal pain, and upper abdominal pain 100General Disorders and Administration Site Conditions FatigueIncluding asthenia, fatigue, and malaise 488Metabolism and Nutrition Disorders Decreased appetite412Skin and Subcutaneous Tissue Disorders Alopecia220Musculoskeletal and Connective Tissue Disorders Musculoskeletal painIncluding back pain, bone pain, musculoskeletal stiffness, musculoskeletal chest pain, arthralgia, musculoskeletal pain, myalgia, and pain in extremity 211Respiratory, Thoracic, and Mediastinal Disorders Interstitial lung diseaseInterstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU including pneumonitis, interstitial lung disease, pulmonary toxicity, and respiratory failure 151Infections and Infestations Upper respiratory tract infectionIncluding influenza, influenza-like illness, upper respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, rhinitis, and laryngitis 120Other clinically relevant adverse reactions reported in less than 10% of patients were:Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (7%), and epistaxis (5%)Nervous System Disorders: headache (7%) [including headache and migraine]Skin and Subcutaneous Disorders: rash (6%) [including rash and rash maculo-papular]Table 21: Select Laboratory Abnormalities in Patients with Unresectable or Metastatic HER2-Mutant NSCLC in DESTINY-Lung02Laboratory ParameterENHERTU 5.4 mg/kgN=101Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. All GradesFrequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities. %Grades or %HematologyThe denominator used to calculate the rate varied from 100 to 101 based on the number of patients with baseline value and at least one post-treatment value. Decreased hemoglobin6812 Decreased white blood cell count667 Decreased neutrophil count5919 Decreased lymphocyte count5626 Decreased platelet count495Chemistry Increased aspartate aminotransferase511 Decreased albumin500 Increased alanine aminotransferase412 Increased alkaline phosphatase370 Decreased blood potassium295HER2-Positive Locally Advanced or Metastatic Gastric CancerThe safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01 [see Clinical Studies (14.5)]. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg once every three weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) in the ENHERTU group and 2.8 months (range: 0.5 to 13.1) in the irinotecan/paclitaxel group.Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%).ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and decreased blood potassium. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia.The most common (>=20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, decreased white blood cell count, decreased neutrophil count, decreased lymphocyte count, decreased platelet count, nausea, decreased appetite, increased aspartate aminotransferase, fatigue, increased blood alkaline phosphatase, increased alanine aminotransferase, diarrhea, decreased blood potassium, vomiting, constipation, increased blood bilirubin, pyrexia, and alopecia.Tables 22 and 23 summarize adverse reactions and laboratory abnormalities observed in patients receiving ENHERTU 6.4 mg/kg in DESTINY-Gastric01.Table 22: Adverse Reactions in >=10% All Grades or >=2% Grades or of Patients Receiving ENHERTU in DESTINY-Gastric01ENHERTU 6.4 mg/kgN=125Irinotecan or PaclitaxelN=62Adverse ReactionsAll Grades%Grades or 4%All Grades%Grades or 4%Events were graded using NCI CTCAE version 4.03.Gastrointestinal DisordersNausea634.8471.6Diarrhea322.4321.6Vomiting26080Constipation240230Abdominal painIncluding abdominal discomfort, gastrointestinal pain, abdominal pain, lower abdominal pain, and upper abdominal pain 140.8153.2StomatitisIncluding stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosal blistering 111.64.80Metabolism and Nutrition DisordersDecreased appetite60174513Dehydration62.43.21.6Blood and Lymphatic System DisordersFebrile neutropenia4.84.83.23.2General Disorders and Administration Site ConditionsFatigueIncluding fatigue, asthenia, and malaise 559444.8Pyrexia240160Peripheral edema10000Skin and Subcutaneous Tissue DisordersAlopecia220150Respiratory, Thoracic and Mediastinal DisordersInterstitial lung diseaseInterstitial lung disease includes events that were adjudicated as drug-induced ILD: pneumonitis, interstitial lung disease, respiratory failure, organizing pneumonia, acute respiratory failure, lung infiltration, lymphangitis, and alveolitis. 102.400Hepatobiliary DisordersAbnormal hepatic function83.21.61.6Other clinically relevant adverse reactions reported in less than 10% of patients were:Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (8%) [see Warnings and Precautions (5.3)] Infections and Infestations: pneumonia (6%)Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.6%)Table 23: Selected Laboratory Abnormalities Occurring in Patients Receiving ENHERTU in DESTINY-Gastric01Laboratory ParameterENHERTU 6.4 mg/kgN=125Irinotecan or PaclitaxelN=62All Grades%Grades or 4%All Grades%Grades or 4%Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.Frequencies were based on NCI CTCAE v.4.03 grade-derived laboratory abnormalities.HematologyDecreased hemoglobin75385523Decreased white blood cell count74295313Decreased neutrophil count72514523Decreased lymphocyte count70285312Decreased platelet count6812125ChemistryIncreased aspartate aminotransferase589328Increased blood alkaline phosphatase5483410Increased alanine aminotransferase479171.7Decreased blood potassium304.8188Increased blood bilirubin24753.4HER2-Positive (IHC 3+) Unresectable or Metastatic Solid TumorsThe safety of ENHERTU was evaluated in 347 adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who received ENHERTU 5.4 mg/kg in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 [see Clinical Studies (14.2 and 14.6)]. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 8.3 months (range 0.7 to 30.2).The median age was 60 years (range 23 to 96); 74% were female; 51% were White, 42% were Asian, 2.9% were Black or African American, 3.5% were of Hispanic or Latino ethnicity; and 51% had an ECOG performance status and 48% had an ECOG performance status of 1.Serious adverse reactions occurred in 34% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were sepsis, pneumonia, vomiting, urinary tract infection, abdominal pain, nausea, pneumonitis, pleural effusion, hemorrhage, COVID-19, fatigue, acute kidney injury, anemia, cellulitis, and dyspnea. Fatalities due to adverse reactions occurred in 6.3% of patients including ILD/pneumonitis (2.3%), cardiac arrest (0.6%), COVID-19 (0.6%), and sepsis (0.6%). The following events occurred in one patient each (0.3%): acute kidney injury, cerebrovascular accident, general physical health deterioration, pneumonia, and hemorrhagic shock.ENHERTU was permanently discontinued in 15% of patients, of which ILD/pneumonitis accounted for 10%. Dose interruptions due to adverse reactions occurred in 48% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count, anemia, COVID-19, fatigue, decreased white blood cell count, and ILD/pneumonitis. Dose reductions occurred in 27% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, decreased neutrophil count, ILD/pneumonitis, and diarrhea.The most common (>=20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count, nausea, decreased hemoglobin, decreased neutrophil count, fatigue, decreased lymphocyte count, decreased platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, increased blood alkaline phosphatase, vomiting, decreased appetite, alopecia, diarrhea, decreased blood potassium, constipation, decreased sodium, stomatitis, and upper respiratory tract infection.Tables 24 and 25 summarize the common adverse reactions and laboratory abnormalities in DESTINY-PanTumor02, DESTINY-Lung01, DESTINY-Breast01, and DESTINY-CRC02.Table 24: Common Adverse Reactions (>=10% All Grades or >=2% Grades or 4) in HER2-positive (IHC 3+) Patients Treated with ENHERTU in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02Adverse ReactionsENHERTU 5.4 mg/kgN= 347All Grades%Grade or 4%Gastrointestinal DisordersNausea697Vomiting353.5Diarrhea314.3Constipation280.6StomatitisIncluding stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, oral mucosa erosion, oral mucosal blistering, oral mucosal eruption, tongue ulceration, cheilitis. 200.9Abdominal painIncluding abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, gastrointestinal pain. 182Dyspepsia120.3General Disorders and Administration Site ConditionsFatigueIncluding fatigue, asthenia, malaise, lethargy. 5910Pyrexia110EdemaIncluding peripheral edema, edema, localized edema, face edema, skin edema, periorbital edema, eyelid edema 110.6Metabolism and Nutrition DisordersDecreased appetite342.6Skin and Subcutaneous Tissue DisordersAlopecia340.3RashIncluding rash, pustular rash, maculo-papular rash, papular rash, macular rash, pruritic rash dermatitis acneiform, dermatitis, eczema, palmar-plantar erythrodysesthesia syndrome. 130.6Infections and InfestationsUpper respiratory tract infectionIncluding influenza, influenza-like illness, upper respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, rhinitis, laryngitis. 200Pneumonia62.3Musculoskeletal and Connective Tissue DisordersMusculoskeletal painIncluding back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, limb discomfort. 190.3Respiratory, Thoracic and Mediastinal DisordersCoughIncluding cough, productive cough, upper-airway cough syndrome 180Interstitial lung diseaseInterstitial lung disease includes events that were adjudicated as drug-induced ILD: pneumonitis, ILD, organizing pneumonia, respiratory failure, acute respiratory failure, alveolitis, lung opacity, lymphangitis, pneumonia, bacterial pneumonia, pulmonary fibrosis, and radiation pneumonitis. Grade adjudicated drug-induced ILD events were pneumonitis, respiratory failure, acute respiratory failure, lymphangitis, pulmonary fibrosis. 160.6DyspneaIncluding dyspnea, exertional dyspnea 121.7Nervous System DisordersHeadacheIncluding migraine, headache, sinus headache. 150InvestigationsDecreased weight100.3Other clinically relevant adverse reactions reported in less than 10% of patients were:Respiratory, Thoracic, and Mediastinal Disorders: epistaxis (9%)Nervous System Disorders: dizziness (9%) [including dizziness, postural dizziness, and vertigo] and dysgeusia (6%)Skin and Subcutaneous Disorders: pruritus (5%) and skin hyperpigmentation (4.3%) [including skin hyperpigmentation, skin discoloration, pigmentation disorder]Eye Disorders: blurred vision (4%) [including blurred vision, visual impairment]Metabolism and Nutrition Disorders: dehydration (3.2%)Gastrointestinal Disorders: abdominal distension (2.6%), flatulence (1.7%) and gastritis (0.9%)Blood and Lymphatic System Disorders: febrile neutropenia (1.7%)Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.4%) [including administration related reaction, anaphylactic reaction, hypersensitivity, infusion-related reaction and infusion-related hypersensitivity reaction]Table 25: Selected Laboratory Abnormalities in HER2-positive (IHC 3+) Patients Treated with ENHERTU in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02Laboratory ParameterENHERTU 5.4 mg/kgN= 347Percentages were calculated using the number of patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. All Grades%Grades or 4%HematologyDecreased white blood cell count7511Decreased hemoglobin6710Decreased neutrophil count6621Decreased lymphocyte count5821Decreased platelet count517ChemistryIncreased aspartate aminotransferase451.5Increased alanine aminotransferase441.5Increased blood alkaline phosphatase361.2Decreased blood potassium296Decreased sodium222.9Increased blood bilirubin150.6Increased blood creatinine140.6. General disorders and administration site conditions: peripheral edema (9%), pyrexia (8%), mucosal inflammation (1.9%). Nervous System Disorders: dysgeusia (9%), dizziness (4.7%). Eye Disorders: dry eye (8%), blurred vision (6%) [including vision blurred, visual impairment]. Gastrointestinal disorders: dyspepsia (8%), gastritis (3.4%), abdominal distension (2.5%), flatulence (0.9%). Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (7%), ILD (4.4%) [including interstitial lung disease, lung opacity, pneumonia fungal, pneumonitis].. Skin and Subcutaneous Tissue Disorders: pruritus (6%) and skin hyperpigmentation (1.6%) [including skin hyperpigmentation and skin discoloration]. Injury, Poisoning, and Procedural Complications: infusion-related reactions (4.7%) Investigations: decreased weight (3.4%). Blood and Lymphatic System Disorders: febrile neutropenia (0.9%). Metabolism and Nutrition Disorders: dehydration (0.3%). Gastrointestinal disorders: dyspepsia (8%), gastritis (2.5%), abdominal distension (1.7%), flatulence (1.5%) Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (4.5%), epistaxis (3.8%). Skin and Subcutaneous Tissue Disorders: pruritus (4.2%), skin hyperpigmentation (3.5%) [including pigmentation disorder, skin discoloration, skin hyperpigmentation] Nervous System Disorders: dysgeusia (3.7%) Eye Disorders: dry eye (2.7%), vision blurred (2.7%) [including vision blurred, visual impairment]. Metabolism and Nutrition Disorders: dehydration (1%). Injury, Poisoning, and Procedural Complications: infusion related reaction (0.7%) [including hypersensitivity, infusion related reaction]. Blood and Lymphatic System Disorders: febrile neutropenia (0.5%). Blood and Lymphatic System Disorders: febrile neutropenia (2.9%). Eye Disorders: blurred vision (4.2%). Gastrointestinal Disorders: abdominal distension (6%), gastritis (3.9%), flatulence (2.4%). General Disorders and Administration Site Conditions: mucosal inflammation (9%). Injury, poisoning, and procedural complications: infusion related reactions (2.6%) [including hypersensitivity and infusion-related reactions]. Metabolism and Nutrition Disorders: dehydration (2.9%). Respiratory, Thoracic, and Mediastinal Disorders: epistaxis (8%), dyspnea (6%). Skin and Subcutaneous Tissue Disorders: dry skin (7%), skin hyperpigmentation (6%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder]. Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (8%). Skin and Subcutaneous Tissue Disorders: pruritus (8%) and skin hyperpigmentation (6%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder]. Nervous System Disorders: dysgeusia (6%). Metabolism and Nutrition Disorders: dehydration (4.3%). Eye Disorders: blurred vision (3.5%). Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (2.7%) [see Warnings and Precautions (5.3)] Injury, Poisoning, and Procedural Complications: infusion-related reactions (2.3%) [including hypersensitivity and infusion-related reactions]. Blood and Lymphatic System Disorders: febrile neutropenia (0.8%). Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (8%) and epistaxis (8%). Skin and Subcutaneous Tissue Disorders: rash (8%) [including rash, pustular rash, maculo-papular rash, and pruritic rash], pruritus (5%), skin hyperpigmentation (5%) [including skin hyperpigmentation and pigmentation disorder]. Nervous System Disorders: dizziness (8%) and dysgeusia (8%). Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (4.2%) [see Warnings and Precautions (5.3)] Eye Disorders: dry eye (6%) and blurred vision [including blurred vision and visual impairment] (3%). Metabolism and Nutrition Disorders: dehydration (2.7%). Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.2%). Blood and Lymphatic System Disorders: febrile neutropenia (0.3%). Injury, Poisoning, and Procedural Complications: infusion-related reactions (2.6%). Blood and Lymphatic System Disorders: febrile neutropenia (1.7%). Nervous System Disorders: dizziness (9%). Investigations: decreased weight (7%). Eye Disorders: dry eye (7%), and blurred vision (5%). Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (6%). Gastrointestinal Disorders: abdominal distension (4.8%), flatulence (2.3%), and gastritis (0.7%). Skin and Subcutaneous Tissue Disorders: pruritus (3.9%), and skin hyperpigmentation (0.9%). Metabolism and Nutrition Disorders: dehydration (1.6%). Blood and lymphatic system disorders: febrile neutropenia (1.2%). Injury, Poisoning, and Procedural Complications: infusion related reaction (1.2%). Nervous System Disorders: dysgeusia (10%). Respiratory, Thoracic and Mediastinal Disorders: cough (10%). Gastrointestinal Disorders: abdominal distension (5%), gastritis (2.7%), flatulence (2.4%). Eye Disorders: blurred vision (4.9%) [including blurred vision and visual impairment]. Skin and Subcutaneous Tissue Disorders: pruritus (3.2%) and skin hyperpigmentation (2.7%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder]. Metabolism and Nutrition Disorders: dehydration (1.9%). Blood and Lymphatic System Disorders: febrile neutropenia (1.1%). Injury, Poisoning, and Procedural Complications: infusion-related reactions (0.5%) [including injection-site reaction and chills]. Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (7%), and epistaxis (5%). Nervous System Disorders: headache (7%) [including headache and migraine]. Skin and Subcutaneous Disorders: rash (6%) [including rash and rash maculo-papular]. Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (8%) [see Warnings and Precautions (5.3)] Infections and Infestations: pneumonia (6%). Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.6%). Respiratory, Thoracic, and Mediastinal Disorders: epistaxis (9%). Nervous System Disorders: dizziness (9%) [including dizziness, postural dizziness, and vertigo] and dysgeusia (6%). Skin and Subcutaneous Disorders: pruritus (5%) and skin hyperpigmentation (4.3%) [including skin hyperpigmentation, skin discoloration, pigmentation disorder]. Eye Disorders: blurred vision (4%) [including blurred vision, visual impairment]. Metabolism and Nutrition Disorders: dehydration (3.2%). Gastrointestinal Disorders: abdominal distension (2.6%), flatulence (1.7%) and gastritis (0.9%). Blood and Lymphatic System Disorders: febrile neutropenia (1.7%). Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.4%) [including administration related reaction, anaphylactic reaction, hypersensitivity, infusion-related reaction and infusion-related hypersensitivity reaction].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status of females of reproductive potential prior to initiation of ENHERTU.ContraceptionFemalesENHERTU can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for months after the last dose.MalesBecause of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for months after the last dose [see Nonclinical Toxicology (13.1)].InfertilityBased on findings in animal toxicity studies, ENHERTU may impair male reproductive function and fertility [see Nonclinical Toxicology (13.1)].

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. No dose adjustment of ENHERTU is recommended in patients with mild (creatinine clearance [CLcr] 60 to <90 mL/min) or moderate (CLcr 30 to <60 mL/min) renal impairment [see Clinical Pharmacology (12.3)]. higher incidence of Grade and ILD/pneumonitis has been observed in patients with moderate renal impairment [see Warnings and Precautions (5.1)]. Monitor patients with moderate renal impairment more frequently. The recommended dosage of ENHERTU has not been established for patients with severe renal impairment (CLcr <30 mL/min) [see Clinical Pharmacology (12.3)].

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 05/2026 Medication GuideENHERTU(R) (en-HER-too)(fam-trastuzumab deruxtecan-nxki) for injectionWhat is the most important information should know about ENHERTUENHERTU can cause serious side effects, including:Lung problems that may be severe, life-threatening or that may lead to death. If you develop lung problems your healthcare provider may treat you with corticosteroid medicines. Tell your healthcare provider right away if you get any of the following signs and symptoms: coughtrouble breathing or shortness of breathfeverother new or worsening breathing symptoms (such as chest tightness, wheezing) Low white blood cell count (neutropenia). Low white blood cell counts are common with ENHERTU and can sometimes be severe. Your healthcare provider will check your white blood cell counts before starting ENHERTU and before starting each dose. Tell your healthcare provider right away if you develop any signs or symptoms of an infection or have fever or chills during treatment with ENHERTU.Heart problems that may affect your hearts ability to pump blood. Your healthcare provider will check your heart function before starting treatment with ENHERTU and during treatment if needed. Tell your healthcare provider right away if you get any of the following signs and symptoms:new or worsening shortness of breathcoughingfeeling tiredswelling of your ankles or legsirregular heartbeatsudden weight gaindizziness or feeling light-headedloss of consciousnessYour healthcare provider will check you for these side effects during your treatment with ENHERTU. Your healthcare provider may reduce your dose, delay treatment or completely stop treatment with ENHERTU if you have severe side effects. Harm to your unborn baby. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with ENHERTU. If you are able to become pregnant, your healthcare provider should do pregnancy test before you start treatment with ENHERTU.Females who are able to become pregnant should use effective birth control (contraception) during treatment with ENHERTU and for months after the last dose.Males who have female partners that are able to become pregnant should use effective birth control (contraception) during treatment with ENHERTU and for months after the last dose. See What are the possible side effects of ENHERTU for more information about side effects.What is ENHERTUENHERTU is prescription medicine used to treat adults with:Human epidermal growth factor receptor (HER2)-positive stage II or stage III early breast cancer followed by taxane, trastuzumab and pertuzumab (THP) before surgery. Your healthcare provider will perform test to make sure ENHERTU is right for you.HER2-positive breast cancer that cannot be removed by surgery or has spread to other parts of the body (metastatic) in combination with pertuzumab as your first treatment. Your healthcare provider will perform test to make sure ENHERTU in combination with pertuzumab is right for you. ENHERTU alone is prescription medicine used to treat adults with:HER2-positive early breast cancer who have received trastuzumab (with or without pertuzumab) and taxane-based treatment before surgery and have cancer remaining in the tissue removed during surgery.HER2-positive breast cancer that cannot be removed by surgery or that has spread to other parts of the body (metastatic), and who have received prior anti-HER2 breast cancer treatment:for metastatic disease, or have breast cancer that has come back during or within months of completing treatment for their early-stage breast cancer. HER2-low breast cancer that cannot be removed by surgery or that has spread to other parts of the body (metastatic), and who have received prior chemotherapy:for metastatic disease, or whose disease has returned during or within months of completing adjuvant chemotherapy (after surgery). Your healthcare provider will perform test to make sure ENHERTU is right for you. Hormone receptor (HR)-positive, HER2-low or HR-positive, HER2-ultralow breast cancer that cannot be removed by surgery or that has spread to other parts of the body (metastatic), and who have received one or more endocrine treatments for metastatic disease. Your healthcare provider will perform test to make sure ENHERTU is right for you.non-small cell lung cancer (NSCLC) that has certain mutation in the HER2 gene and cannot be removed by surgery or has spread to other parts of your body (metastatic), and who have received prior treatment. Your healthcare provider will perform test to make sure ENHERTU is right for you.stomach cancer called gastric or gastroesophageal junction (GEJ) adenocarcinoma that is HER2-positive and has spread to areas near your stomach (locally advanced) or that has spread to other parts of your body (metastatic), and who have received prior trastuzumab-based regimen.solid tumors that are HER2-positive (IHC 3+) and that cannot be removed by surgery or have spread to other parts of your body (metastatic), and who have received prior treatment and have no other satisfactory treatment options. Your healthcare provider will perform test to make sure ENHERTU is right for you.It is not known if ENHERTU is safe and effective in children.Before you receive ENHERTU, tell your healthcare provider about all of your medical conditions, including if you:have lung or breathing problemshave signs or symptoms of an infectionhave or have had any heart problemsare breastfeeding or plan to breastfeed. It is not known if ENHERTU passes into your breast milk. Do not breastfeed during treatment with ENHERTU and for months after the last dose.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive ENHERTUYou will receive ENHERTU into your vein through an intravenous (IV) line by your healthcare provider.For the treatment of early breast cancer: Before surgery, ENHERTU is given time every three weeks (21-day treatment cycle) for cycles followed by THP for cycles.After HER2-targeted treatment and surgery, ENHERTU is given time every three weeks (21-day treatment cycle) for 14 cycles.For the treatment of metastatic breast cancer, lung cancer, gastric cancer or other HER2-positive solid tumors:ENHERTU is given time every three weeks (21-day treatment cycle).Your healthcare provider will decide how many treatments you need.Your healthcare provider will give you medicines before your infusion to help prevent nausea and vomiting.Your healthcare provider may slow down or temporarily stop your infusion of ENHERTU if you have an infusion-related reaction, or permanently stop ENHERTU if you have severe infusion reactions.If you miss planned dose of ENHERTU, call your healthcare provider right away to schedule an appointment. Do not wait until the next planned treatment cycle.What are the possible side effects of ENHERTUENHERTU can cause serious side effects. See What is the most important information should know about ENHERTUThe most common side effects of ENHERTU, when used in people with HER2-positive, HER2-Low and HER2-Ultralow breast cancer, HER2-mutant non-small cell lung cancer, and other HER2-positive solid tumors include:low white blood cell countsnausealow red blood cell countsfeeling tiredlow platelet countsincreased liver function testsvomitinghair loss constipationlow levels of blood potassium decreased appetitediarrheamuscle or bone painThe most common side effects of ENHERTU followed by THP, in people with HER2-positive stage II or stage III early breast cancer, include:low red blood cell countsincreased liver function testslow white blood cell countsnauseainflammation of the nerves causing numbness, weakness, tingling or burning pain of the arms and legs diarrheahair lossfeeling tiredrashmuscle or bone pain low levels of blood potassiumconstipationvomitingsores in or around your mouth decreased appetiteThe most common side effects of ENHERTU in combination with pertuzumab, when used in people with HER2-positive breast cancer include:low white blood cell countslow red blood cell countsnauseaincreased liver function testsdiarrhealow platelet countslow levels of blood potassiumfeeling tiredhair lossvomitingupper respiratory tract infectionconstipationdecreased appetiteweight lossCOVID-19muscle or bone painincreased levels of blood bilirubinstomach painThe most common side effects of ENHERTU, when used in people with HER2-positive gastric or GEJ adenocarcinoma, include:low red blood cell counts low white blood cell countslow platelet countsnauseadecreased appetiteincreased liver function testsfeeling tireddiarrhealow levels of blood potassium vomitingconstipationincreased levels of blood bilirubinfeverhair loss ENHERTU may cause fertility problems in males, which may affect the ability to father children. Talk to your healthcare provider if you have concerns about fertility.These are not all of the possible side effects of ENHERTU. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of ENHERTU.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your pharmacist or healthcare provider for information about ENHERTU that is written for healthcare professionals.What are the ingredients in ENHERTUActive Ingredient: fam-trastuzumab deruxtecan-nxki. Inactive Ingredients: L-histidine, L-histidine hydrochloride monohydrate, polysorbate 80, and sucrose. Manufactured by: Daiichi Sankyo, Inc., Basking Ridge, NJ 07920 U.S. License No. 2128 Marketed by: Daiichi Sankyo, Inc., Basking Ridge, NJ 07920 and AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850ENHERTU(R) is registered trademark of Daiichi Sankyo Company, Ltd.(C) 2026 Daiichi Sankyo Co., Ltd.USMG-ENH-C22-0526-r012 For more information, call 1-877-437-7763 or go to https://www.ENHERTU.com. Lung problems that may be severe, life-threatening or that may lead to death. If you develop lung problems your healthcare provider may treat you with corticosteroid medicines. Tell your healthcare provider right away if you get any of the following signs and symptoms: coughtrouble breathing or shortness of breathfeverother new or worsening breathing symptoms (such as chest tightness, wheezing) cough. trouble breathing or shortness of breath. fever. other new or worsening breathing symptoms (such as chest tightness, wheezing). Low white blood cell count (neutropenia). Low white blood cell counts are common with ENHERTU and can sometimes be severe. Your healthcare provider will check your white blood cell counts before starting ENHERTU and before starting each dose. Tell your healthcare provider right away if you develop any signs or symptoms of an infection or have fever or chills during treatment with ENHERTU.. Heart problems that may affect your hearts ability to pump blood. Your healthcare provider will check your heart function before starting treatment with ENHERTU and during treatment if needed. Tell your healthcare provider right away if you get any of the following signs and symptoms:. new or worsening shortness of breath. coughing. feeling tired. swelling of your ankles or legs. irregular heartbeat. sudden weight gain. dizziness or feeling light-headed. loss of consciousness. Harm to your unborn baby. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with ENHERTU. If you are able to become pregnant, your healthcare provider should do pregnancy test before you start treatment with ENHERTU.Females who are able to become pregnant should use effective birth control (contraception) during treatment with ENHERTU and for months after the last dose.Males who have female partners that are able to become pregnant should use effective birth control (contraception) during treatment with ENHERTU and for months after the last dose. If you are able to become pregnant, your healthcare provider should do pregnancy test before you start treatment with ENHERTU.. Females who are able to become pregnant should use effective birth control (contraception) during treatment with ENHERTU and for months after the last dose.. Males who have female partners that are able to become pregnant should use effective birth control (contraception) during treatment with ENHERTU and for months after the last dose.. Human epidermal growth factor receptor (HER2)-positive stage II or stage III early breast cancer followed by taxane, trastuzumab and pertuzumab (THP) before surgery. Your healthcare provider will perform test to make sure ENHERTU is right for you.. HER2-positive breast cancer that cannot be removed by surgery or has spread to other parts of the body (metastatic) in combination with pertuzumab as your first treatment. Your healthcare provider will perform test to make sure ENHERTU in combination with pertuzumab is right for you. HER2-positive early breast cancer who have received trastuzumab (with or without pertuzumab) and taxane-based treatment before surgery and have cancer remaining in the tissue removed during surgery.. HER2-positive breast cancer that cannot be removed by surgery or that has spread to other parts of the body (metastatic), and who have received prior anti-HER2 breast cancer treatment:for metastatic disease, or have breast cancer that has come back during or within months of completing treatment for their early-stage breast cancer. for metastatic disease, or have breast cancer that has come back during or within months of completing treatment for their early-stage breast cancer. HER2-low breast cancer that cannot be removed by surgery or that has spread to other parts of the body (metastatic), and who have received prior chemotherapy:for metastatic disease, or whose disease has returned during or within months of completing adjuvant chemotherapy (after surgery). Your healthcare provider will perform test to make sure ENHERTU is right for you. for metastatic disease, or whose disease has returned during or within months of completing adjuvant chemotherapy (after surgery). Your healthcare provider will perform test to make sure ENHERTU is right for you.. Hormone receptor (HR)-positive, HER2-low or HR-positive, HER2-ultralow breast cancer that cannot be removed by surgery or that has spread to other parts of the body (metastatic), and who have received one or more endocrine treatments for metastatic disease. Your healthcare provider will perform test to make sure ENHERTU is right for you.. non-small cell lung cancer (NSCLC) that has certain mutation in the HER2 gene and cannot be removed by surgery or has spread to other parts of your body (metastatic), and who have received prior treatment. Your healthcare provider will perform test to make sure ENHERTU is right for you.. stomach cancer called gastric or gastroesophageal junction (GEJ) adenocarcinoma that is HER2-positive and has spread to areas near your stomach (locally advanced) or that has spread to other parts of your body (metastatic), and who have received prior trastuzumab-based regimen.. solid tumors that are HER2-positive (IHC 3+) and that cannot be removed by surgery or have spread to other parts of your body (metastatic), and who have received prior treatment and have no other satisfactory treatment options. Your healthcare provider will perform test to make sure ENHERTU is right for you.. have lung or breathing problems. have signs or symptoms of an infection. have or have had any heart problems. are breastfeeding or plan to breastfeed. It is not known if ENHERTU passes into your breast milk. Do not breastfeed during treatment with ENHERTU and for months after the last dose.. You will receive ENHERTU into your vein through an intravenous (IV) line by your healthcare provider.. For the treatment of early breast cancer: Before surgery, ENHERTU is given time every three weeks (21-day treatment cycle) for cycles followed by THP for cycles.After HER2-targeted treatment and surgery, ENHERTU is given time every three weeks (21-day treatment cycle) for 14 cycles.. Before surgery, ENHERTU is given time every three weeks (21-day treatment cycle) for cycles followed by THP for cycles.. After HER2-targeted treatment and surgery, ENHERTU is given time every three weeks (21-day treatment cycle) for 14 cycles.. For the treatment of metastatic breast cancer, lung cancer, gastric cancer or other HER2-positive solid tumors:ENHERTU is given time every three weeks (21-day treatment cycle).Your healthcare provider will decide how many treatments you need.. ENHERTU is given time every three weeks (21-day treatment cycle).. Your healthcare provider will decide how many treatments you need.. Your healthcare provider will give you medicines before your infusion to help prevent nausea and vomiting.. Your healthcare provider may slow down or temporarily stop your infusion of ENHERTU if you have an infusion-related reaction, or permanently stop ENHERTU if you have severe infusion reactions.. If you miss planned dose of ENHERTU, call your healthcare provider right away to schedule an appointment. Do not wait until the next planned treatment cycle.. low white blood cell counts. nausea. low red blood cell counts. feeling tired. low platelet counts. increased liver function tests. vomiting. hair loss constipation. low levels of blood potassium decreased appetite. diarrhea. muscle or bone pain. low red blood cell counts. increased liver function tests. low white blood cell counts. nausea. inflammation of the nerves causing numbness, weakness, tingling or burning pain of the arms and legs diarrhea. hair loss. feeling tired. rash. muscle or bone pain low levels of blood potassium. constipation. vomiting. sores in or around your mouth decreased appetite. low white blood cell counts. low red blood cell counts. nausea. increased liver function tests. diarrhea. low platelet counts. low levels of blood potassium. feeling tired. hair loss. vomiting. upper respiratory tract infection. constipation. decreased appetite. weight loss. COVID-19. muscle or bone pain. increased levels of blood bilirubin. stomach pain. low red blood cell counts low white blood cell counts. low platelet counts. nausea. decreased appetite. increased liver function tests. feeling tired. diarrhea. low levels of blood potassium vomiting. constipation. increased levels of blood bilirubin. fever. hair loss.

BOXED WARNING SECTION.

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY. Interstitial Lung Disease (ILD) and pneumonitis, including severe, life-threatening, and fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade or higher ILD/pneumonitis. Advise patients of the risk and the need to immediately report symptoms [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].Embryo-Fetal Toxicity: Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].. Interstitial Lung Disease (ILD) and pneumonitis, including severe, life-threatening, and fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade or higher ILD/pneumonitis. Advise patients of the risk and the need to immediately report symptoms [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].. Embryo-Fetal Toxicity: Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].. WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITYSee full prescribing information for complete boxed warning.Interstitial lung disease (ILD) and pneumonitis, including severe, life threatening, and fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms. (2.3, 5.1)Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception. (5.4, 8.1, 8.3). Interstitial lung disease (ILD) and pneumonitis, including severe, life threatening, and fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms. (2.3, 5.1). Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception. (5.4, 8.1, 8.3).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with fam-trastuzumab deruxtecan-nxki.The topoisomerase inhibitor component of fam-trastuzumab deruxtecan-nxki, DXd, was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay and was not mutagenic in an in vitro bacterial reverse mutation assay.Fertility studies have not been conducted with fam-trastuzumab deruxtecan-nxki. In six-week repeat-dose toxicity study in rats, intravenous administration of fam-trastuzumab deruxtecan-nxki resulted in spermatid retention at 20 mg/kg and 60 mg/kg (approximately and times the human recommended dose of 5.4 mg/kg based on AUC, respectively). Decreased testes and epididymides weights, tubular atrophy/degeneration in testes, and reduced sperm count in epididymides were observed at dose of 197 mg/kg (19 times the human recommended dose of 5.4 mg/kg based on AUC). In three-month repeat-dose toxicity study in monkeys, intravenous administration of fam-trastuzumab deruxtecan-nxki resulted in decreased numbers of round spermatids in the testes at seminiferous tubule stages to VI at >=30 mg/kg (>=7 times the human recommended dose of 5.4 mg/kg based on AUC). Evidence of reversibility was observed in monkeys by the end of three-month recovery period.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Fam-trastuzumab deruxtecan-nxki is HER2-directed antibody-drug conjugate. The antibody is humanized anti-HER2 IgG1. The small molecule, DXd, is topoisomerase inhibitor attached to the antibody by cleavable linker. Following binding to HER2 on tumor cells, fam-trastuzumab deruxtecan-nxki undergoes internalization and intracellular linker cleavage by lysosomal enzymes. Upon release, the membrane-permeable DXd causes DNA damage and apoptotic cell death.. 12.2 Pharmacodynamics. Exposure-Response RelationshipsExposure-response relationship for efficacy has not been fully characterized. Higher systemic exposure to fam-trastuzumab deruxtecan-nxki was associated with higher incidence rate of any grade ILD.Cardiac ElectrophysiologyAt the dosage of ENHERTU 6.4 mg/kg every weeks, mean increase in the QTc interval >20 ms was not observed.. 12.3 Pharmacokinetics. The pharmacokinetics of fam-trastuzumab deruxtecan-nxki and its payload DXd were evaluated in patients with cancer and are presented as mean (% coefficient of variation), unless otherwise specified. At dose of 5.4 mg/kg, the maximum concentration (Cmax ss) of fam-trastuzumab deruxtecan-nxki is 132 ug/mL (20%) and of DXd is 4.7 ng/mL (48%) and the AUCss of fam-trastuzumab deruxtecan-nxki is 772 ugday/mL (27%) and of DXd is 29 ngday/mL (48%). At dose of 6.4 mg/kg, the Cmax,ss of fam-trastuzumab deruxtecan-nxki is 126 ug/mL (18%) and of DXd is 5.2 ng/mL (42%) and the AUCss of fam-trastuzumab deruxtecan-nxki is 743 ugday/mL (26%) and of DXd is 33 ngday/mL (43%), respectively. Following single dose, Cmax and AUC of fam-trastuzumab deruxtecan-nxki and DXd increase in dose proportional manner over dose range of 3.2 mg/kg to mg/kg (approximately 0.5 to 1.25 times the highest approved dose). Accumulation of fam-trastuzumab deruxtecan-nxki is approximately 1.4-fold at steady-state (Cycle 3).DistributionThe estimated volume of distribution of the central compartment (Vc) of fam-trastuzumab deruxtecan-nxki is 2.7 (% CV 16%).DXd plasma protein binding is approximately 97% and the blood-to-plasma ratio is approximately 0.6 in vitro.EliminationThe median elimination half-life of fam-trastuzumab deruxtecan-nxki is 5.4 to 5.7 days. The estimated systemic clearance of fam-trastuzumab deruxtecan-nxki is 0.4 L/day (24%).The median elimination half-life of DXd is 5.4-6.1 days. The estimated systemic clearance of DXd is 18 L/h (28%).MetabolismThe monoclonal antibody is expected to be degraded into small peptides and amino acids via catabolic pathways.DXd is primarily metabolized by CYP3A4.Specific PopulationsNo clinically significant differences in the pharmacokinetics of fam-trastuzumab deruxtecan-nxki or DXd were observed for age (20-96 years); race (Asian [48%] vs Non-Asian [52%]), including White (43%), and Black or African American (1.9%); sex; body weight (27-138 kg); tumor types; mild hepatic impairment; and mild or moderate renal impairment.The pharmacokinetics of fam-trastuzumab deruxtecan-nxki or DXd in patients with moderate to severe hepatic impairment or severe renal impairment is unknown.Drug Interaction StudiesClinical StudiesNo clinically significant differences in pharmacokinetics of fam-trastuzumab deruxtecan-nxki or DXd were observed when used concomitantly with itraconazole (strong CYP3A inhibitor) or ritonavir (strong CYP3A inhibitor and OATP inhibitor).In Vitro StudiesCYP450 Enzymes: DXd does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A nor induce CYP1A2, CYP2B6, or CYP3A.UGT Enzymes: DXd is not substrate of UGT.Transporter Systems: DXd is not an inhibitor of OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, P-gp, BCRP, or BSEP.DXd is substrate of OATP1B1, OATP1B3, MATE2-K, P-gp, MRP1, and BCRP.. 12.6 Immunogenicity. The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of fam-trastuzumab deruxtecan-nxki or of other fam-trastuzumab deruxtecan products.Among patients who received ENHERTU as single agent over 6 to month treatment period in 13 clinical trials, anti-fam-trastuzumab deruxtecan-nxki antibodies developed in 2.2% (49/2,231) of patients who received ENHERTU 5.4 mg/kg every three weeks and in 2.6% (21/793) of patients who received ENHERTU 6.4 mg/kg every three weeks. Among patients who received ENHERTU (5.4 mg/kg every three weeks) in combination with pertuzumab for median of 16 months in clinical trials, anti-fam-trastuzumab deruxtecan-nxki antibodies developed in 7.7% (33/426) of patients. These anti-drug antibodies have no clinically significant effect on the pharmacokinetics or safety of fam-trastuzumab deruxtecan-nxki. Because of the low occurrence of anti-drug antibodies, the effect of antibodies on the effectiveness of fam-trastuzumab deruxtecan-nxki products is unknown. Among patients with anti-drug antibodies, neutralizing antibodies against fam-trastuzumab deruxtecan-nxki were detected in 6% (4/70) of patients who received ENHERTU as single agent (5.4 mg/kg or 6.4 mg/kg every weeks) and in 18% (6/33) of patients who received ENHERTU (5.4 mg/kg every weeks) in combination with pertuzumab.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Fam-trastuzumab deruxtecan-nxki is HER2-directed antibody and topoisomerase inhibitor conjugate. Fam-trastuzumab deruxtecan-nxki is an antibody-drug conjugate (ADC) composed of three components: 1) humanized anti-HER2 IgG1 monoclonal antibody (mAb), covalently linked to 2) topoisomerase inhibitor, via 3) tetrapeptide-based cleavable linker. Deruxtecan is composed of protease-cleavable maleimide tetrapeptide linker and the topoisomerase inhibitor, DXd, which is an exatecan derivative.The antibody is produced in Chinese hamster ovary cells by recombinant DNA technology, and the topoisomerase inhibitor and linker are produced by chemical synthesis. Approximately molecules of deruxtecan are attached to each antibody molecule. Fam-trastuzumab deruxtecan-nxki has the following structure:ENHERTU (fam-trastuzumab deruxtecan-nxki) is sterile, white to yellowish white, preservative-free lyophilized powder in single-dose vials. Each vial delivers 100 mg of fam-trastuzumab deruxtecan-nxki, L-histidine (4.45 mg), L-histidine hydrochloride monohydrate (20.2 mg), polysorbate 80 (1.5 mg), and sucrose (450 mg). Following reconstitution with mL of Sterile Water for Injection, USP, the resulting concentration of fam-trastuzumab deruxtecan-nxki is 20 mg/mL with pH of 5.5. The resulting solution is administered by intravenous infusion following dilution.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Do not substitute ENHERTU for or with trastuzumab or ado-trastuzumab emtansine. (2.2, 2.4)For intravenous infusion only. Do not administer as an intravenous push or bolus. DO NOT use Sodium Chloride Injection, USP. (2.4)Premedicate for prevention of chemotherapy-induced nausea and vomiting. (2.2)HER2-Positive Early Breast Cancer Neoadjuvant: ENHERTU 5.4 mg/kg every weeks for cycles, followed by THP regimen for cycles. (2.2, 2.3)Post Neoadjuvant: ENHERTU 5.4 mg/kg every weeks for 14 cycles unless disease recurrence or unacceptable toxicity. (2.2, 2.3)HER2-Positive, HER2-Low, or HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and HER2-Positive (IHC 3+) Solid Tumors: ENHERTU 5.4 mg/kg every weeks until disease progression or unacceptable toxicity. (2.2, 2.3)HER2-Positive First-line Metastatic Breast Cancer: ENHERTU 5.4 mg/kg every weeks in combination with pertuzumab until disease progression or unacceptable toxicity. Cycle 1, Day 1: ENHERTU 5.4 mg/kg followed by pertuzumab 840 mg. (2.2, 2.3)Subsequent cycles, Day 1: ENHERTU 5.4 mg/kg followed by pertuzumab 420 mg. (2.2, 2.3)HER2-Positive Gastric Cancer: 6.4 mg/kg every weeks until disease progression or unacceptable toxicity. (2.2, 2.3)Management of adverse reactions (ILD, neutropenia, thrombocytopenia, or left ventricular dysfunction) may require temporary interruption, dose reduction, or discontinuation of ENHERTU. (2.3). Do not substitute ENHERTU for or with trastuzumab or ado-trastuzumab emtansine. (2.2, 2.4). For intravenous infusion only. Do not administer as an intravenous push or bolus. DO NOT use Sodium Chloride Injection, USP. (2.4). Premedicate for prevention of chemotherapy-induced nausea and vomiting. (2.2). HER2-Positive Early Breast Cancer Neoadjuvant: ENHERTU 5.4 mg/kg every weeks for cycles, followed by THP regimen for cycles. (2.2, 2.3)Post Neoadjuvant: ENHERTU 5.4 mg/kg every weeks for 14 cycles unless disease recurrence or unacceptable toxicity. (2.2, 2.3). Neoadjuvant: ENHERTU 5.4 mg/kg every weeks for cycles, followed by THP regimen for cycles. (2.2, 2.3). Post Neoadjuvant: ENHERTU 5.4 mg/kg every weeks for 14 cycles unless disease recurrence or unacceptable toxicity. (2.2, 2.3). HER2-Positive, HER2-Low, or HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and HER2-Positive (IHC 3+) Solid Tumors: ENHERTU 5.4 mg/kg every weeks until disease progression or unacceptable toxicity. (2.2, 2.3). HER2-Positive First-line Metastatic Breast Cancer: ENHERTU 5.4 mg/kg every weeks in combination with pertuzumab until disease progression or unacceptable toxicity. Cycle 1, Day 1: ENHERTU 5.4 mg/kg followed by pertuzumab 840 mg. (2.2, 2.3)Subsequent cycles, Day 1: ENHERTU 5.4 mg/kg followed by pertuzumab 420 mg. (2.2, 2.3). Cycle 1, Day 1: ENHERTU 5.4 mg/kg followed by pertuzumab 840 mg. (2.2, 2.3). Subsequent cycles, Day 1: ENHERTU 5.4 mg/kg followed by pertuzumab 420 mg. (2.2, 2.3). HER2-Positive Gastric Cancer: 6.4 mg/kg every weeks until disease progression or unacceptable toxicity. (2.2, 2.3). Management of adverse reactions (ILD, neutropenia, thrombocytopenia, or left ventricular dysfunction) may require temporary interruption, dose reduction, or discontinuation of ENHERTU. (2.3). 2.1Patient Selection HER2-Positive Early Breast CancerSelect patients for the treatment of HER2-positive early breast cancer with ENHERTU based on HER2-positive (IHC 3+ or ISH+) status [see Clinical Studies (14.1)]. HER2-Positive Metastatic Breast Cancer Select patients for treatment of unresectable or metastatic HER2-positive breast cancer with ENHERTU in combination with pertuzumab based on confirmed HER2-positive status or HER2 gene amplification (IHC 3+ or ISH+) [see Clinical Studies (14.2)]. HER2-Low or HER2-Ultralow Unresectable or Metastatic Breast CancerSelect patients for treatment of unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC with membrane staining) breast cancer with ENHERTU based on HER2 expression [see Clinical Studies (14.3)].HER2-Mutant Unresectable or Metastatic NSCLCSelect patients for the treatment of unresectable or metastatic HER2-mutant NSCLC with ENHERTU based on the presence of activating HER2 (ERBB2) mutations in tumor or plasma specimens [see Clinical Studies (14.4)]. If no mutation is detected in plasma specimen, test tumor tissue.HER2-Positive Locally Advanced or Metastatic Gastric CancerSelect patients with locally advanced or metastatic HER2-positive gastric cancer based on HER2 protein overexpression or HER2 gene amplification (IHC 3+ or IHC 2+/ISH+). Reassess HER2 status if it is feasible to obtain new tumor specimen after prior trastuzumab-based therapy and before treatment with ENHERTU.HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors Select patients for treatment of unresectable or metastatic solid tumors with ENHERTU based on HER2-positive (IHC 3+) specimens [see Clinical Studies (14.6)]. An FDA-authorized test for the detection of HER2-positive (IHC 3+) solid tumors for treatment with ENHERTU is not currently available.Additional Patient Selection InformationInformation on FDA-authorized tests for the detection of HER2 protein expression, HER2 gene amplification, and activating HER2 mutations is available at: http://www.fda.gov/CompanionDiagnostics. 2.2Recommended Dosage Do not substitute ENHERTU for or with trastuzumab or ado-trastuzumab emtansine.Slow or interrupt the infusion rate if the patient develops infusion-related symptoms.Permanently discontinue ENHERTU in case of severe infusion reactions.PremedicationENHERTU is highly emetogenic [see Adverse Reactions (6.1)], which includes delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting.The recommended dosages for ENHERTU as monotherapy and ENHERTU in combination with pertuzumab are presented in Table 1. Administer ENHERTU as an intravenous infusion [see Dosage and Administration (2.4)]. Table 1: Recommended DosageIndicationRecommended ENHERTU DosageDuration of TherapyAs MonotherapyHER2-Positive Early Breast Cancer Post Neoadjuvant Treatment ENHERTU 5.4 mg/kg every weeks 14 cycles unless disease recurrence or unacceptable toxicity HER2-Positive, HER2-Low, or HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant Unresectable or Metastatic NSCLC, and HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors as monotherapyENHERTU 5.4 mg/kg every weeksUntil disease progression or unacceptable toxicityHER2-Positive Locally Advanced or Metastatic Gastric Cancer as monotherapyENHERTU 6.4 mg/kg every weeksUntil disease progression or unacceptable toxicityIn CombinationHER2-Positive Metastatic Breast Cancer in combination with pertuzumabCycle 1, Day 1: ENHERTU 5.4 mg/kg, followed by pertuzumab 840 mgAdminister pertuzumab 30 minutes after ENHERTU. Subsequent cycles, Day 1: ENHERTU 5.4 mg/kg, followed by pertuzumab 420 mg every weeks Until disease progression or unacceptable toxicityIn SequenceHER2-Positive Early Breast Cancer followed by THPENHERTU 5.4 mg/kg every weeks for cycles, followed by THP regimenTHP regimen: taxane concurrent with trastuzumab (6 mg/kg every weeks) and pertuzumab (an initial dose of 840 mg followed by 420 mg every weeks) for cycles4 cycles of ENHERTU followed by cycles of THP.. 2.3Dosage Modifications for Adverse Reactions. Management of adverse reactions may require temporary interruption, dose reduction, or treatment discontinuation of ENHERTU as described in Tables and 3. Refer to the Prescribing Information for pertuzumab for dose modification recommendations. Pertuzumab is not to be administered as single agent. Do not re-escalate the ENHERTU dose after dose reduction is made.If planned dose is delayed or missed, administer as soon as possible; do not wait until the next planned cycle. Adjust the schedule of administration to maintain 3-week interval between doses. Administer the infusion at the dose and rate the patient tolerated in the most recent infusion.Table 2: Dosage Reduction ScheduleDose Reduction ScheduleBreast Cancer, NSCLC, and IHC 3+ Solid TumorsGastric CancerRecommended starting dose5.4 mg/kg6.4 mg/kgFirst dose reduction4.4 mg/kg5.4 mg/kgSecond dose reduction3.2 mg/kg4.4 mg/kgRequirement for further dose reductionDiscontinue treatment.Discontinue treatment.Table 3: Dosage Modifications for Adverse ReactionsAdverse ReactionSeverityTreatment ModificationToxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v.5.0).Interstitial Lung Disease (ILD)/ PneumonitisIn the adjuvant setting, if drug-induced ILD is suspected, rule out radiotherapy-related pneumonitis. If only radiotherapy-related pneumonitis is suspected, consider interruption of ENHERTU for Grade and permanently discontinue ENHERTU for Grade >=3. [see Warnings and Precautions (5.1)] Asymptomatic ILD/pneumonitis(Grade 1)Interrupt ENHERTU until resolved to Grade 0, then: if resolved in 28 days or less from date of onset, maintain dose.if resolved in greater than 28 days from date of onset, reduce dose one level (see Table 2).consider corticosteroid treatment as soon as ILD/pneumonitis is suspected. Symptomatic ILD/pneumonitis(Grade or greater)Permanently discontinue ENHERTU. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected.Neutropenia [see Warnings and Precautions (5.2)] Grade (less than 1.0 to 0.5 109/L)Interrupt ENHERTU until resolved to Grade or less, then maintain dose.Grade (less than 0.5 109/L)Interrupt ENHERTU until resolved to Grade or less.Reduce dose by one level (see Table 2).Febrile Neutropenia [see Warnings and Precautions (5.2)] Absolute neutrophil count of less than 1.0 109/L and temperature greater than 38.3C or sustained temperature of 38C or greater for more than one hourInterrupt ENHERTU until resolved.Reduce dose by one level (see Table 2).Thrombocytopenia [see Adverse Reactions (6.1)] Grade (platelets less than 50 to 25 109/L)Interrupt ENHERTU until resolved to Grade or less, then maintain dose.Grade (platelets less than 25 109/L)Interrupt ENHERTU until resolved to Grade or less.Reduce dose by one level (see Table 2).Left Ventricular Dysfunction (LVD) [see Warnings and Precautions (5.3)] Left Ventricular Ejection Fraction (LVEF) greater than 45% and absolute decrease from baseline is 10% to 20%Continue treatment with ENHERTU.LVEF 40% to 45%And absolute decrease from baseline is less than 10%Continue treatment with ENHERTU.Repeat LVEF assessment within weeks.And absolute decrease from baseline is 10% to 20%Interrupt ENHERTU.Repeat LVEF assessment within weeks.If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU.If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose.LVEF less than 40% or absolute decrease from baseline is greater than 20% Interrupt ENHERTU.Repeat LVEF assessment within weeks.If LVEF of less than 40% or absolute decrease from baseline of greater than 20% is confirmed, permanently discontinue ENHERTU.Symptomatic congestive heart failure (CHF)Permanently discontinue ENHERTU.. if resolved in 28 days or less from date of onset, maintain dose.. if resolved in greater than 28 days from date of onset, reduce dose one level (see Table 2).. consider corticosteroid treatment as soon as ILD/pneumonitis is suspected.. Permanently discontinue ENHERTU. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected.. Interrupt ENHERTU until resolved to Grade or less, then maintain dose.. Interrupt ENHERTU until resolved to Grade or less.. Reduce dose by one level (see Table 2).. Interrupt ENHERTU until resolved.. Reduce dose by one level (see Table 2).. Interrupt ENHERTU until resolved to Grade or less, then maintain dose.. Interrupt ENHERTU until resolved to Grade or less.. Reduce dose by one level (see Table 2).. Continue treatment with ENHERTU.. Continue treatment with ENHERTU.. Repeat LVEF assessment within weeks.. Interrupt ENHERTU.. Repeat LVEF assessment within weeks.. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU.. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose.. Interrupt ENHERTU.. Repeat LVEF assessment within weeks.. If LVEF of less than 40% or absolute decrease from baseline of greater than 20% is confirmed, permanently discontinue ENHERTU.. Permanently discontinue ENHERTU.. 2.4Preparation and Administration In order to prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is ENHERTU (fam-trastuzumab deruxtecan-nxki) and not trastuzumab or ado-trastuzumab emtansine.Reconstitute and further dilute ENHERTU prior to intravenous infusion. Use appropriate aseptic technique.ENHERTU (fam-trastuzumab deruxtecan-nxki) is hazardous drug. Follow applicable special handling and disposal procedures.1 ReconstitutionReconstitute immediately before dilution.More than one vial may be needed for full dose. Calculate the dose (mg), the total volume of reconstituted ENHERTU solution required, and the number of vial(s) of ENHERTU needed [see Dosage and Administration (2.2)].Reconstitute each 100 mg vial by using sterile syringe to slowly inject mL of Sterile Water for Injection, USP into each vial to obtain final concentration of 20 mg/mL.Swirl the vial gently until completely dissolved. Do not shake.If not used immediately, store the reconstituted ENHERTU vials in refrigerator at 2C to 8C (36F to 46F) for up to 24 hours from the time of reconstitution, protect the vial from light. Do not freeze.The product does not contain preservative. Discard unused reconstituted ENHERTU after 24 hours refrigerated.DilutionWithdraw the calculated amount from the vial(s) using sterile syringe. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should be clear and colorless to light yellow. Do not use if visible particles are observed or if the solution is cloudy or discolored.Dilute the calculated volume of reconstituted ENHERTU in an intravenous infusion bag containing 100 mL of 5% Dextrose Injection, USP. DO NOT use Sodium Chloride Injection, USP. ENHERTU is compatible with an infusion bag made of polyvinylchloride or polyolefin (copolymer of ethylene and polypropylene).Gently invert the infusion bag to thoroughly mix the solution. Do not shake.Cover the infusion bag to protect from light.Discard any unused portion left in the vials.AdministrationIf not used immediately, store the diluted ENHERTU in refrigerator at 2C to 8C (36F to 46F) for up to 24 hours or at room temperature between 20C to 25C (68F to 77 F) for up to hours including preparation and infusion time. Protect from light. Do not freeze.The maximum time from reconstitution of the vial through the end of administration should not exceed 24 hours.If the prepared infusion solution was stored refrigerated (2C to 8C [36F to 46F]), allow the solution to reach room temperature prior to administration. Cover the infusion bag to protect from light.Administer ENHERTU as an intravenous infusion only with an infusion set made of polyolefin or polybutadiene.Administer ENHERTU with 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter. Do NOT administer as an intravenous push or bolus.Cover the infusion bag to protect from light during administration.Do not mix ENHERTU with other drugs or administer other drugs through the same intravenous line.First infusion: Administer infusion over 90 minutes.Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated.. Reconstitute immediately before dilution.. More than one vial may be needed for full dose. Calculate the dose (mg), the total volume of reconstituted ENHERTU solution required, and the number of vial(s) of ENHERTU needed [see Dosage and Administration (2.2)].. Reconstitute each 100 mg vial by using sterile syringe to slowly inject mL of Sterile Water for Injection, USP into each vial to obtain final concentration of 20 mg/mL.. Swirl the vial gently until completely dissolved. Do not shake.. If not used immediately, store the reconstituted ENHERTU vials in refrigerator at 2C to 8C (36F to 46F) for up to 24 hours from the time of reconstitution, protect the vial from light. Do not freeze.. The product does not contain preservative. Discard unused reconstituted ENHERTU after 24 hours refrigerated.. Withdraw the calculated amount from the vial(s) using sterile syringe. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should be clear and colorless to light yellow. Do not use if visible particles are observed or if the solution is cloudy or discolored.. Dilute the calculated volume of reconstituted ENHERTU in an intravenous infusion bag containing 100 mL of 5% Dextrose Injection, USP. DO NOT use Sodium Chloride Injection, USP. ENHERTU is compatible with an infusion bag made of polyvinylchloride or polyolefin (copolymer of ethylene and polypropylene).. Gently invert the infusion bag to thoroughly mix the solution. Do not shake.. Cover the infusion bag to protect from light.. Discard any unused portion left in the vials.. If not used immediately, store the diluted ENHERTU in refrigerator at 2C to 8C (36F to 46F) for up to 24 hours or at room temperature between 20C to 25C (68F to 77 F) for up to hours including preparation and infusion time. Protect from light. Do not freeze.. The maximum time from reconstitution of the vial through the end of administration should not exceed 24 hours.. If the prepared infusion solution was stored refrigerated (2C to 8C [36F to 46F]), allow the solution to reach room temperature prior to administration. Cover the infusion bag to protect from light.. Administer ENHERTU as an intravenous infusion only with an infusion set made of polyolefin or polybutadiene.. Administer ENHERTU with 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter. Do NOT administer as an intravenous push or bolus.. Cover the infusion bag to protect from light during administration.. Do not mix ENHERTU with other drugs or administer other drugs through the same intravenous line.. First infusion: Administer infusion over 90 minutes.. Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. For injection: 100 mg of fam-trastuzumab deruxtecan-nxki as white to yellowish white lyophilized powder in single-dose vial for reconstitution and further dilution. For injection: 100 mg lyophilized powder in single-dose vial (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use. ENHERTU as Monotherapy Of the 2233 patients treated with ENHERTU 5.4 mg/kg, 28% were 65 years or older and 6% were 75 years or older. No overall differences in efficacy within clinical studies were observed between patients >=65 years of age compared to younger patients. There was higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years or older (56%) as compared to younger patients (49%).Of the 125 patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were 65 years or older and 14% were 75 years or older. No overall differences in efficacy or safety were observed between patients >=65 years of age compared to younger patients. ENHERTU in Combination with PertuzumabIn patients with HER2-positive unresectable or metastatic breast cancer treated with ENHERTU 5.4 mg/kg in combination with pertuzumab (N=431), 17% were 65 years or older and 3% were 75 years or older. No overall differences in efficacy or safety were observed between patients >=65 years of age compared to younger patients.ENHERTU followed by THPOf the 320 patients with HER2-positive early breast cancer treated with ENHERTU 5.4 mg/kg followed by THP, 12% were 65 years or older and 1.6% were 75 years or older. No overall difference in efficacy was observed between patients >=65 years of age compared to younger patients. There was higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years or older (38%) as compared to younger patients (30%).

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. No dose adjustment of ENHERTU is recommended in patients with mild (total bilirubin <=ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to times ULN and any AST) hepatic impairment. In patients with moderate hepatic impairment, due to potentially increased exposure, monitor for increased adverse reactions related to the topoisomerase inhibitor, DXd [see Dosage and Administration (2.3)]. The recommended dosage of ENHERTU has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST) [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How Supplied/Storage ENHERTU (fam-trastuzumab deruxtecan-nxki) for injection is white to yellowish white lyophilized powder supplied as:Carton ContentsNDCOne 100 mg single-dose vialNDC 65597-406-01. Store vials in refrigerator at 2C to 8C (36F to 46F) in the original carton to protect from light until time of reconstitution. Do not freeze. Do not shake the reconstituted or diluted solution [see Dosage and Administration (2.4)].Special Handling ENHERTU (fam-trastuzumab deruxtecan-nxki) is hazardous drug. Follow applicable special handling and disposal procedures.1.

IMMUNOGENICITY.

12.6 Immunogenicity. The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of fam-trastuzumab deruxtecan-nxki or of other fam-trastuzumab deruxtecan products.Among patients who received ENHERTU as single agent over 6 to month treatment period in 13 clinical trials, anti-fam-trastuzumab deruxtecan-nxki antibodies developed in 2.2% (49/2,231) of patients who received ENHERTU 5.4 mg/kg every three weeks and in 2.6% (21/793) of patients who received ENHERTU 6.4 mg/kg every three weeks. Among patients who received ENHERTU (5.4 mg/kg every three weeks) in combination with pertuzumab for median of 16 months in clinical trials, anti-fam-trastuzumab deruxtecan-nxki antibodies developed in 7.7% (33/426) of patients. These anti-drug antibodies have no clinically significant effect on the pharmacokinetics or safety of fam-trastuzumab deruxtecan-nxki. Because of the low occurrence of anti-drug antibodies, the effect of antibodies on the effectiveness of fam-trastuzumab deruxtecan-nxki products is unknown. Among patients with anti-drug antibodies, neutralizing antibodies against fam-trastuzumab deruxtecan-nxki were detected in 6% (4/70) of patients who received ENHERTU as single agent (5.4 mg/kg or 6.4 mg/kg every weeks) and in 18% (6/33) of patients who received ENHERTU (5.4 mg/kg every weeks) in combination with pertuzumab.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. ENHERTU is HER2-directed antibody and topoisomerase inhibitor conjugate indicated for:HER2-Positive Early Breast Canceras neoadjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) Stage II or III breast cancer, as determined by an FDA-authorized test followed by taxane, trastuzumab, and pertuzumab (THP). (1.1)as adjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) breast cancer who have residual invasive disease following neoadjuvant trastuzumab (with or without pertuzumab) and taxane-based treatment. (1.1)HER2-Positive Metastatic Breast Cancerin combination with pertuzumab as first-line treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer, as determined by an FDA-authorized test. (1.2)as monotherapy for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer who have received prior anti-HER2-based regimen either in the metastatic setting, or, in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy. (1.2)HER2-Low and HER2-Ultralow Metastatic Breast Canceras monotherapy for the treatment of adult patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC with membrane staining) breast cancer, as determined by an FDA-authorized test, that has progressed on one or more endocrine therapies in the metastatic setting. (1.3)as monotherapy for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-authorized test, who have received prior chemotherapy in the metastatic setting; or developed disease recurrence during or within months of completing adjuvant chemotherapy. (1.3)HER2-Mutant Unresectable or Metastatic Non-Small Cell Lung Canceras monotherapy for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-authorized test, and who have received prior systemic therapy (1.4)HER2-Positive Locally Advanced or Metastatic Gastric Canceras monotherapy for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction adenocarcinoma who have received prior trastuzumab-based regimen. (1.5)HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumorsas monotherapy for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options (1.6) These indications are approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial. (14.3, 14.5) as neoadjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) Stage II or III breast cancer, as determined by an FDA-authorized test followed by taxane, trastuzumab, and pertuzumab (THP). (1.1). as adjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) breast cancer who have residual invasive disease following neoadjuvant trastuzumab (with or without pertuzumab) and taxane-based treatment. (1.1). in combination with pertuzumab as first-line treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer, as determined by an FDA-authorized test. (1.2). as monotherapy for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer who have received prior anti-HER2-based regimen either in the metastatic setting, or, in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy. (1.2). as monotherapy for the treatment of adult patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC with membrane staining) breast cancer, as determined by an FDA-authorized test, that has progressed on one or more endocrine therapies in the metastatic setting. (1.3). as monotherapy for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-authorized test, who have received prior chemotherapy in the metastatic setting; or developed disease recurrence during or within months of completing adjuvant chemotherapy. (1.3). as monotherapy for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-authorized test, and who have received prior systemic therapy (1.4). as monotherapy for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction adenocarcinoma who have received prior trastuzumab-based regimen. (1.5). as monotherapy for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options (1.6) 1.1HER2-Positive Early Breast Cancer ENHERTU followed by taxane, trastuzumab, and pertuzumab (THP) is indicated for the neoadjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) Stage II or III breast cancer as determined by an FDA-authorized test [see Dosage and Administration (2.1)]. ENHERTU is indicated for the adjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) breast cancer who have residual invasive disease following neoadjuvant trastuzumab (with or without pertuzumab) and taxane-based treatment.. ENHERTU followed by taxane, trastuzumab, and pertuzumab (THP) is indicated for the neoadjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) Stage II or III breast cancer as determined by an FDA-authorized test [see Dosage and Administration (2.1)]. ENHERTU is indicated for the adjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) breast cancer who have residual invasive disease following neoadjuvant trastuzumab (with or without pertuzumab) and taxane-based treatment.. 1.2HER2-Positive Metastatic Breast Cancer ENHERTU, in combination with pertuzumab, is indicated for the first-line treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer, as determined by an FDA-authorized test [see Dosage and Administration (2.1)]. ENHERTU, as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer who have received prior anti-HER2-based regimen either in the metastatic setting, or, in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy. ENHERTU, in combination with pertuzumab, is indicated for the first-line treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer, as determined by an FDA-authorized test [see Dosage and Administration (2.1)]. ENHERTU, as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer who have received prior anti-HER2-based regimen either in the metastatic setting, or, in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy. 1.3HER2-Low and HER2-Ultralow Metastatic Breast Cancer ENHERTU, as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic Hormone receptor (HR)-positive HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC with membrane staining) breast cancer, as determined by an FDA-authorized test, that has progressed on one or more endocrine therapies in the metastatic setting [see Dosage and Administration (2.1)]. HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-authorized test, who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within months of completing adjuvant chemotherapy [see Dosage and Administration (2.1)]. Hormone receptor (HR)-positive HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC with membrane staining) breast cancer, as determined by an FDA-authorized test, that has progressed on one or more endocrine therapies in the metastatic setting [see Dosage and Administration (2.1)]. HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-authorized test, who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within months of completing adjuvant chemotherapy [see Dosage and Administration (2.1)]. 1.4HER2-Mutant Unresectable or Metastatic Non-Small Cell Lung Cancer ENHERTU, as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-authorized test, and who have received prior systemic therapy.This indication is approved under accelerated approval based on objective response rate and duration of response [see Clinical Studies (14.4)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial.. 1.5HER2-Positive Locally Advanced or Metastatic Gastric Cancer ENHERTU, as monotherapy, is indicated for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received prior trastuzumab-based regimen.. 1.6HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors ENHERTU, as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.This indication is approved under accelerated approval based on objective response rate and duration of response [see Clinical Studies (14.6)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).Interstitial Lung DiseaseInform patients of the risks of severe or fatal ILD. Advise patients to contact their healthcare provider immediately for any of the following: cough, shortness of breath, fever, or other new or worsening respiratory symptoms [see Warnings and Precautions (5.1)].NeutropeniaAdvise patients of the possibility of developing neutropenia and to immediately contact their healthcare provider should they develop fever, particularly in association with any signs of infection [see Warnings and Precautions (5.2)].Left Ventricular DysfunctionAdvise patients to contact their healthcare provider immediately for any of the following: new onset or worsening shortness of breath, cough, fatigue, swelling of ankles/legs, palpitations, sudden weight gain, dizziness, loss of consciousness [see Warnings and Precautions (5.3)].Embryo-Fetal ToxicityInform female patients of the potential risk to fetus. Advise female patients to contact their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for months after the last dose [see Use in Specific Populations (8.3)].Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for months after the last dose [see Use in Specific Populations (8.3)].LactationAdvise women not to breastfeed during treatment and for months after the last dose of ENHERTU [see Use in Specific Populations (8.2)].InfertilityAdvise males of reproductive potential that ENHERTU may impair fertility [see Use in Specific Populations (8.3)].. Inform patients of the risks of severe or fatal ILD. Advise patients to contact their healthcare provider immediately for any of the following: cough, shortness of breath, fever, or other new or worsening respiratory symptoms [see Warnings and Precautions (5.1)].. Advise patients of the possibility of developing neutropenia and to immediately contact their healthcare provider should they develop fever, particularly in association with any signs of infection [see Warnings and Precautions (5.2)].. Advise patients to contact their healthcare provider immediately for any of the following: new onset or worsening shortness of breath, cough, fatigue, swelling of ankles/legs, palpitations, sudden weight gain, dizziness, loss of consciousness [see Warnings and Precautions (5.3)].. Inform female patients of the potential risk to fetus. Advise female patients to contact their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for months after the last dose [see Use in Specific Populations (8.3)].. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for months after the last dose [see Use in Specific Populations (8.3)].. Advise women not to breastfeed during treatment and for months after the last dose of ENHERTU [see Use in Specific Populations (8.2)].. Advise males of reproductive potential that ENHERTU may impair fertility [see Use in Specific Populations (8.3)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no data regarding the presence of fam-trastuzumab deruxtecan-nxki in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed child, advise women not to breastfeed during treatment with ENHERTU and for months after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Fam-trastuzumab deruxtecan-nxki is HER2-directed antibody-drug conjugate. The antibody is humanized anti-HER2 IgG1. The small molecule, DXd, is topoisomerase inhibitor attached to the antibody by cleavable linker. Following binding to HER2 on tumor cells, fam-trastuzumab deruxtecan-nxki undergoes internalization and intracellular linker cleavage by lysosomal enzymes. Upon release, the membrane-permeable DXd causes DNA damage and apoptotic cell death.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with fam-trastuzumab deruxtecan-nxki.The topoisomerase inhibitor component of fam-trastuzumab deruxtecan-nxki, DXd, was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay and was not mutagenic in an in vitro bacterial reverse mutation assay.Fertility studies have not been conducted with fam-trastuzumab deruxtecan-nxki. In six-week repeat-dose toxicity study in rats, intravenous administration of fam-trastuzumab deruxtecan-nxki resulted in spermatid retention at 20 mg/kg and 60 mg/kg (approximately and times the human recommended dose of 5.4 mg/kg based on AUC, respectively). Decreased testes and epididymides weights, tubular atrophy/degeneration in testes, and reduced sperm count in epididymides were observed at dose of 197 mg/kg (19 times the human recommended dose of 5.4 mg/kg based on AUC). In three-month repeat-dose toxicity study in monkeys, intravenous administration of fam-trastuzumab deruxtecan-nxki resulted in decreased numbers of round spermatids in the testes at seminiferous tubule stages to VI at >=30 mg/kg (>=7 times the human recommended dose of 5.4 mg/kg based on AUC). Evidence of reversibility was observed in monkeys by the end of three-month recovery period.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 100 mg Vial Carton. NDC 65597-406-01Rx onlyENHERTU(R) (fam-trastuzumab deruxtecan-nxki)For Injection100 mg per vialFor Intravenous Infusion OnlyDispense the enclosed Medication Guide to each patient.Reconstitute and Dilute prior to administrationSingle-Dose VialDiscard Unused PortionHazardous DrugKEEP REFRIGERATED1 vialDaiichi-SankyoAstraZeneca. PRINCIPAL DISPLAY PANEL 100 mg Vial Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of ENHERTU have not been established in pediatric patients.Animal Data Juvenile animal studies have not been conducted with fam-trastuzumab deruxtecan-nxki. In six-week repeat-dose toxicity study in rats, intravenous administration of fam-trastuzumab deruxtecan-nxki resulted in incisor tooth toxicity including single cell necrosis in the base area (e.g., ameloblasts, odontoblasts) and degeneration of the enamel at >=60 mg/kg (approximately >=9 times the human recommended dose of 5.4 mg/kg based on AUC), abnormal formation or hypoplasia of the dentin, hemorrhage in the sub-enamel organ tissue, and focal lack of the cementum at 197 mg/kg (approximately 19 times the human recommended dose of 5.4 mg/kg based on AUC). Degeneration of the enamel organ, abnormal dentin formation, hemorrhage in the sub-enamel organ tissue, focal lack of the cementum, and root fracture were observed at 197 mg/kg following 9-week recovery period.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Exposure-Response RelationshipsExposure-response relationship for efficacy has not been fully characterized. Higher systemic exposure to fam-trastuzumab deruxtecan-nxki was associated with higher incidence rate of any grade ILD.Cardiac ElectrophysiologyAt the dosage of ENHERTU 6.4 mg/kg every weeks, mean increase in the QTc interval >20 ms was not observed.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of fam-trastuzumab deruxtecan-nxki and its payload DXd were evaluated in patients with cancer and are presented as mean (% coefficient of variation), unless otherwise specified. At dose of 5.4 mg/kg, the maximum concentration (Cmax ss) of fam-trastuzumab deruxtecan-nxki is 132 ug/mL (20%) and of DXd is 4.7 ng/mL (48%) and the AUCss of fam-trastuzumab deruxtecan-nxki is 772 ugday/mL (27%) and of DXd is 29 ngday/mL (48%). At dose of 6.4 mg/kg, the Cmax,ss of fam-trastuzumab deruxtecan-nxki is 126 ug/mL (18%) and of DXd is 5.2 ng/mL (42%) and the AUCss of fam-trastuzumab deruxtecan-nxki is 743 ugday/mL (26%) and of DXd is 33 ngday/mL (43%), respectively. Following single dose, Cmax and AUC of fam-trastuzumab deruxtecan-nxki and DXd increase in dose proportional manner over dose range of 3.2 mg/kg to mg/kg (approximately 0.5 to 1.25 times the highest approved dose). Accumulation of fam-trastuzumab deruxtecan-nxki is approximately 1.4-fold at steady-state (Cycle 3).DistributionThe estimated volume of distribution of the central compartment (Vc) of fam-trastuzumab deruxtecan-nxki is 2.7 (% CV 16%).DXd plasma protein binding is approximately 97% and the blood-to-plasma ratio is approximately 0.6 in vitro.EliminationThe median elimination half-life of fam-trastuzumab deruxtecan-nxki is 5.4 to 5.7 days. The estimated systemic clearance of fam-trastuzumab deruxtecan-nxki is 0.4 L/day (24%).The median elimination half-life of DXd is 5.4-6.1 days. The estimated systemic clearance of DXd is 18 L/h (28%).MetabolismThe monoclonal antibody is expected to be degraded into small peptides and amino acids via catabolic pathways.DXd is primarily metabolized by CYP3A4.Specific PopulationsNo clinically significant differences in the pharmacokinetics of fam-trastuzumab deruxtecan-nxki or DXd were observed for age (20-96 years); race (Asian [48%] vs Non-Asian [52%]), including White (43%), and Black or African American (1.9%); sex; body weight (27-138 kg); tumor types; mild hepatic impairment; and mild or moderate renal impairment.The pharmacokinetics of fam-trastuzumab deruxtecan-nxki or DXd in patients with moderate to severe hepatic impairment or severe renal impairment is unknown.Drug Interaction StudiesClinical StudiesNo clinically significant differences in pharmacokinetics of fam-trastuzumab deruxtecan-nxki or DXd were observed when used concomitantly with itraconazole (strong CYP3A inhibitor) or ritonavir (strong CYP3A inhibitor and OATP inhibitor).In Vitro StudiesCYP450 Enzymes: DXd does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A nor induce CYP1A2, CYP2B6, or CYP3A.UGT Enzymes: DXd is not substrate of UGT.Transporter Systems: DXd is not an inhibitor of OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, P-gp, BCRP, or BSEP.DXd is substrate of OATP1B1, OATP1B3, MATE2-K, P-gp, MRP1, and BCRP.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on its mechanism of action, ENHERTU can cause fetal harm when administered to pregnant woman. There are no available data on the use of ENHERTU in pregnant women. In postmarketing reports, use of HER2-directed antibody during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death (see Data ). Based on its mechanism of action, the topoisomerase inhibitor component of ENHERTU, DXd, can also cause embryo-fetal harm when administered to pregnant woman because it is genotoxic and targets actively dividing cells [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. Advise patients of the potential risks to fetus.There are clinical considerations if ENHERTU is used in pregnant women, or if patient becomes pregnant within months after the last dose of ENHERTU (see Clinical Considerations ).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.Clinical ConsiderationsFetal/Neonatal Adverse ReactionsMonitor women who received ENHERTU during pregnancy or within months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.DataHuman DataThere are no available data on the use of ENHERTU in pregnant women. In postmarketing reports in pregnant women receiving HER2-directed antibody, cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported. These case reports described oligohydramnios in pregnant women who received HER2-directed antibody either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after use of HER2-directed antibody was stopped.Animal DataThere were no animal reproductive or developmental toxicity studies conducted with fam-trastuzumab deruxtecan-nxki.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1.1)05/2026Indications and Usage (1.2)12/2025Dosage and Administration (2.1, 2.2, 2.3)05/2026Dosage and Administration (2.1, 2.2, 2.3)12/2025Warnings and Precautions (5.1, 5.2, 5.3) 05/2026Warnings and Precautions (5.1, 5.2, 5.3)12/2025.

REFERENCES SECTION.

15 REFERENCES. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

SPL UNCLASSIFIED SECTION.

1.1HER2-Positive Early Breast Cancer ENHERTU followed by taxane, trastuzumab, and pertuzumab (THP) is indicated for the neoadjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) Stage II or III breast cancer as determined by an FDA-authorized test [see Dosage and Administration (2.1)]. ENHERTU is indicated for the adjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) breast cancer who have residual invasive disease following neoadjuvant trastuzumab (with or without pertuzumab) and taxane-based treatment.. ENHERTU followed by taxane, trastuzumab, and pertuzumab (THP) is indicated for the neoadjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) Stage II or III breast cancer as determined by an FDA-authorized test [see Dosage and Administration (2.1)]. ENHERTU is indicated for the adjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) breast cancer who have residual invasive disease following neoadjuvant trastuzumab (with or without pertuzumab) and taxane-based treatment.

STORAGE AND HANDLING SECTION.

Store vials in refrigerator at 2C to 8C (36F to 46F) in the original carton to protect from light until time of reconstitution. Do not freeze. Do not shake the reconstituted or diluted solution [see Dosage and Administration (2.4)].Special Handling ENHERTU (fam-trastuzumab deruxtecan-nxki) is hazardous drug. Follow applicable special handling and disposal procedures.1.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2)Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of ENHERTU. (8.3). Lactation: Advise not to breastfeed. (8.2). Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of ENHERTU. (8.3). 8.1 Pregnancy. Risk SummaryBased on its mechanism of action, ENHERTU can cause fetal harm when administered to pregnant woman. There are no available data on the use of ENHERTU in pregnant women. In postmarketing reports, use of HER2-directed antibody during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death (see Data ). Based on its mechanism of action, the topoisomerase inhibitor component of ENHERTU, DXd, can also cause embryo-fetal harm when administered to pregnant woman because it is genotoxic and targets actively dividing cells [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. Advise patients of the potential risks to fetus.There are clinical considerations if ENHERTU is used in pregnant women, or if patient becomes pregnant within months after the last dose of ENHERTU (see Clinical Considerations ).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.Clinical ConsiderationsFetal/Neonatal Adverse ReactionsMonitor women who received ENHERTU during pregnancy or within months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.DataHuman DataThere are no available data on the use of ENHERTU in pregnant women. In postmarketing reports in pregnant women receiving HER2-directed antibody, cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported. These case reports described oligohydramnios in pregnant women who received HER2-directed antibody either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after use of HER2-directed antibody was stopped.Animal DataThere were no animal reproductive or developmental toxicity studies conducted with fam-trastuzumab deruxtecan-nxki.. 8.2 Lactation. Risk SummaryThere is no data regarding the presence of fam-trastuzumab deruxtecan-nxki in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed child, advise women not to breastfeed during treatment with ENHERTU and for months after the last dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status of females of reproductive potential prior to initiation of ENHERTU.ContraceptionFemalesENHERTU can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for months after the last dose.MalesBecause of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for months after the last dose [see Nonclinical Toxicology (13.1)].InfertilityBased on findings in animal toxicity studies, ENHERTU may impair male reproductive function and fertility [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. Safety and effectiveness of ENHERTU have not been established in pediatric patients.Animal Data Juvenile animal studies have not been conducted with fam-trastuzumab deruxtecan-nxki. In six-week repeat-dose toxicity study in rats, intravenous administration of fam-trastuzumab deruxtecan-nxki resulted in incisor tooth toxicity including single cell necrosis in the base area (e.g., ameloblasts, odontoblasts) and degeneration of the enamel at >=60 mg/kg (approximately >=9 times the human recommended dose of 5.4 mg/kg based on AUC), abnormal formation or hypoplasia of the dentin, hemorrhage in the sub-enamel organ tissue, and focal lack of the cementum at 197 mg/kg (approximately 19 times the human recommended dose of 5.4 mg/kg based on AUC). Degeneration of the enamel organ, abnormal dentin formation, hemorrhage in the sub-enamel organ tissue, focal lack of the cementum, and root fracture were observed at 197 mg/kg following 9-week recovery period. 8.5 Geriatric Use. ENHERTU as Monotherapy Of the 2233 patients treated with ENHERTU 5.4 mg/kg, 28% were 65 years or older and 6% were 75 years or older. No overall differences in efficacy within clinical studies were observed between patients >=65 years of age compared to younger patients. There was higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years or older (56%) as compared to younger patients (49%).Of the 125 patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were 65 years or older and 14% were 75 years or older. No overall differences in efficacy or safety were observed between patients >=65 years of age compared to younger patients. ENHERTU in Combination with PertuzumabIn patients with HER2-positive unresectable or metastatic breast cancer treated with ENHERTU 5.4 mg/kg in combination with pertuzumab (N=431), 17% were 65 years or older and 3% were 75 years or older. No overall differences in efficacy or safety were observed between patients >=65 years of age compared to younger patients.ENHERTU followed by THPOf the 320 patients with HER2-positive early breast cancer treated with ENHERTU 5.4 mg/kg followed by THP, 12% were 65 years or older and 1.6% were 75 years or older. No overall difference in efficacy was observed between patients >=65 years of age compared to younger patients. There was higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years or older (38%) as compared to younger patients (30%).. 8.6 Renal Impairment. No dose adjustment of ENHERTU is recommended in patients with mild (creatinine clearance [CLcr] 60 to <90 mL/min) or moderate (CLcr 30 to <60 mL/min) renal impairment [see Clinical Pharmacology (12.3)]. higher incidence of Grade and ILD/pneumonitis has been observed in patients with moderate renal impairment [see Warnings and Precautions (5.1)]. Monitor patients with moderate renal impairment more frequently. The recommended dosage of ENHERTU has not been established for patients with severe renal impairment (CLcr <30 mL/min) [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment. No dose adjustment of ENHERTU is recommended in patients with mild (total bilirubin <=ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to times ULN and any AST) hepatic impairment. In patients with moderate hepatic impairment, due to potentially increased exposure, monitor for increased adverse reactions related to the topoisomerase inhibitor, DXd [see Dosage and Administration (2.3)]. The recommended dosage of ENHERTU has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST) [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Neutropenia: Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. Manage through treatment interruption or dose reduction. (2.3, 5.2)Left Ventricular Dysfunction (LVD): Assess left ventricular ejection fraction (LVEF) prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage through treatment interruption or discontinuation. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure (CHF). (2.3, 5.3). Neutropenia: Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. Manage through treatment interruption or dose reduction. (2.3, 5.2). Left Ventricular Dysfunction (LVD): Assess left ventricular ejection fraction (LVEF) prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage through treatment interruption or discontinuation. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure (CHF). (2.3, 5.3). 5.1Interstitial Lung Disease/Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU [see Adverse Reactions (6.1)]. higher incidence of Grade and ILD/pneumonitis has been observed in patients with moderate renal impairment.Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with pulmonologist. For asymptomatic (Grade 1) ILD, consider corticosteroid treatment (e.g., >=0.5 mg/kg/day prednisolone or equivalent). Withhold ENHERTU until recovery [see Dosage and Administration (2.3)]. In cases of symptomatic ILD (Grade or greater), promptly initiate systemic corticosteroid treatment (e.g., >=1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least weeks. Permanently discontinue ENHERTU in patients who are diagnosed with symptomatic (Grade or greater) ILD [see Dosage and Administration (2.3)].HER2-Positive, HER2-Low, and HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)ENHERTU as MonotherapyIn patients treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Median time to first onset was 5.5 months (range: 0.9 to 31.5). Fatal outcomes due to ILD and/or pneumonitis occurred in 0.9% of patients treated with ENHERTU. ENHERTU in Combination with Pertuzumab In patients treated with ENHERTU 5.4 mg/kg in combination with pertuzumab (N=431), ILD occurred in 12% of patients. Median time to first onset was 8.0 months (range: 0.6 to 33.8). Fatal outcomes due to ILD and/or pneumonitis occurred in 0.5% of patients treated with ENHERTU in combination with pertuzumab.ENHERTU followed by THPIn patients treated with ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11, ILD occurred in 4.4% of patients. Median time to first onset was 2.7 months (range: 1.1 to 6.0). Fatal outcomes due to ILD and/or pneumonitis occurred in one patient (0.3%) treated with ENHERTU followed by THP.HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21).. 5.2Neutropenia Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU.Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. Based on the severity of neutropenia, ENHERTU may require dose interruption or reduction [see Dosage and Administration (2.3)].HER2-Positive, HER2-Low, and HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)ENHERTU as Monotherapy In patients treated with ENHERTU 5.4 mg/kg, decrease in neutrophil count was reported in 65% of patients. Nineteen percent had Grade or decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: to 939). Febrile neutropenia was reported in 1% of patients. ENHERTU in Combination with Pertuzumab In patients treated with ENHERTU 5.4 mg/kg in combination with pertuzumab (N=431), decreased neutrophil count occurred in 79% of patients. Median time to first onset was 22 days (range: to 994). Twenty-nine percent had Grades or decreased neutrophil count. Febrile neutropenia was reported in 2.6% of patients. ENHERTU followed by THPIn patients treated with ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11, decrease in neutrophil count was reported in 58% of patients. Seventeen percent had Grade or decreased neutrophil count. Median time to first onset of decreased neutrophil count was 42 days (range: 11 to 165). Febrile neutropenia was reported in 0.9% of patients.HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade or decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: to 187). Febrile neutropenia was reported in 4.8% of patients.. 5.3Left Ventricular Dysfunction Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular dysfunction (LVD) has been observed with anti-HER2 therapies, including ENHERTU.Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVD through treatment interruption. Permanently discontinue ENHERTU if LVEF of less than 40% or absolute decrease from baseline of greater than 20% is confirmed. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure (CHF) [see Dosage and Administration (2.3)].Treatment with ENHERTU has not been studied in patients with history of clinically significant cardiac disease or LVEF less than 50% prior to initiation of treatment.HER2-Positive, HER2-Low, and HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)ENHERTU as Monotherapy In patients treated with ENHERTU 5.4 mg/kg, LVD was reported in 4.6% of patients, of which 0.6% were Grade or 4. ENHERTU in Combination with PertuzumabIn patients treated with ENHERTU 5.4 mg/kg in combination with pertuzumab (N=431), LVEF decrease was reported in 11% of patients, of which 2.1% were Grade or 4. ENHERTU followed by THPIn patients treated with ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11, LVD was reported in 1.3% of patients, of which 0.3% were Grade 3.HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade decrease in LVEF.. 5.4Embryo-Fetal Toxicity Based on its mechanism of action, ENHERTU can cause fetal harm when administered to pregnant woman. In postmarketing reports, use of HER2-directed antibody during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Based on its mechanism of action, the topoisomerase inhibitor component of ENHERTU, DXd, can also cause embryo-fetal harm when administered to pregnant woman because it is genotoxic and targets actively dividing cells [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. Advise patients of the potential risks to fetus.Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for months after the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for months after the last dose of ENHERTU [see Use in Specific Populations (8.1, 8.3)].