ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling.oImmune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)].oInfusion-Related Reactions [see Warnings and Precautions (5.2)].. oImmune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)].. oInfusion-Related Reactions [see Warnings and Precautions (5.2)].. IMFINZI in Combination with ChemotherapyoMost common adverse reactions (>= 20%) of patients with resectable, Stage II/III NSCLC [neoadjuvant /adjuvant]) are anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash. (6.1)IMFINZI as Single AgentoMost common adverse reactions (>= 20%) of patients with unresectable, Stage III NSCLC) are cough, fatigue, pneumonitis/radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash. (6.1)IMFINZI in Combination with Tremelimumab-actl and Platinum-Based ChemotherapyoMost common adverse reactions (>= 20%) of patients with metastatic NSCLC) are nausea, fatigue, musculoskeletal pain, decreased appetite, rash, and diarrhea. (6.1) IMFINZI as Single AgentoMost common adverse reactions (>= 20%) of patients with limited-stage SCLC) are pneumonitis or radiation pneumonitis, and fatigue. (6.1)IMFINZI in Combination with Platinum-Based ChemotherapyoMost common adverse reactions (>= 20%) of patients with extensive-stage SCLC) are nausea, fatigue/asthenia, and alopecia. (6.1)IMFINZI in Combination with Gemcitabine and CisplatinoMost common adverse reactions (>= 20%) of patients with BTC) are fatigue, nausea, constipation, decreased appetite, abdominal pain, rash, and pyrexia. (6.1)IMFINZI in Combination with Tremelimumab-actloMost common adverse reactions (>= 20%) of patients with uHCC) are rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain. (6.1)IMFINZI in Combination with Carboplatin and Paclitaxel, followed by IMFINZI as single agentoMost common adverse reactions (>= 20%) of patients with endometrial cancer) were peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, decreased magnesium, increased ALT, increased AST, diarrhea, vomiting, cough, decreased potassium, dyspnea, headache, and increased alkaline phosphatase. (6.1)IMFINZI in Combination with Gemcitabine and Cisplatin, followed by IMFINZI as single agentoMost common adverse reactions (>= 20% of patients with MIBC) were decreased hemoglobin, decreased neutrophils, increased blood creatinine, decreased sodium, nausea, increased ALT, decreased calcium, decreased platelets, fatigue, increased potassium, decreased lymphocytes, increased AST, constipation, decreased magnesium, decreased appetite, increased alkaline phosphate, rash, pyrexia, diarrhea, vomiting and abdominal pain. (6.1)IMFINZI in Combination with BCGoMost common adverse reactions (>= 20% of patients with BCG-naive high-risk NMIBC) were increased glucose, increased AST, increased lipase, increased ALT, increased GGT, urinary tract infection, increased potassium, dysuria, decreased hemoglobin, hematuria, increased serum creatinine, musculoskeletal pain, decreased lymphocytes, urinary frequency, decreased sodium, fatigue, rash, and pyrexia. (6.1)IMFINZI in Combination with FLOT Chemotherapy followed by IMFINZI as single agentoMost common adverse reactions (>= 20% of patients with resectable GC/GEJC) were diarrhea, nausea, peripheral neuropathy, fatigue, alopecia, decreased appetite, rash, abdominal pain, vomiting, musculoskeletal pain, pyrexia, and stomatitis (6.1).To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. oMost common adverse reactions (>= 20%) of patients with resectable, Stage II/III NSCLC [neoadjuvant /adjuvant]) are anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash. (6.1). oMost common adverse reactions (>= 20%) of patients with unresectable, Stage III NSCLC) are cough, fatigue, pneumonitis/radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash. (6.1). oMost common adverse reactions (>= 20%) of patients with metastatic NSCLC) are nausea, fatigue, musculoskeletal pain, decreased appetite, rash, and diarrhea. (6.1) oMost common adverse reactions (>= 20%) of patients with limited-stage SCLC) are pneumonitis or radiation pneumonitis, and fatigue. (6.1). oMost common adverse reactions (>= 20%) of patients with extensive-stage SCLC) are nausea, fatigue/asthenia, and alopecia. (6.1). oMost common adverse reactions (>= 20%) of patients with BTC) are fatigue, nausea, constipation, decreased appetite, abdominal pain, rash, and pyrexia. (6.1). oMost common adverse reactions (>= 20%) of patients with uHCC) are rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain. (6.1). oMost common adverse reactions (>= 20%) of patients with endometrial cancer) were peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, decreased magnesium, increased ALT, increased AST, diarrhea, vomiting, cough, decreased potassium, dyspnea, headache, and increased alkaline phosphatase. (6.1). oMost common adverse reactions (>= 20% of patients with MIBC) were decreased hemoglobin, decreased neutrophils, increased blood creatinine, decreased sodium, nausea, increased ALT, decreased calcium, decreased platelets, fatigue, increased potassium, decreased lymphocytes, increased AST, constipation, decreased magnesium, decreased appetite, increased alkaline phosphate, rash, pyrexia, diarrhea, vomiting and abdominal pain. (6.1). oMost common adverse reactions (>= 20% of patients with BCG-naive high-risk NMIBC) were increased glucose, increased AST, increased lipase, increased ALT, increased GGT, urinary tract infection, increased potassium, dysuria, decreased hemoglobin, hematuria, increased serum creatinine, musculoskeletal pain, decreased lymphocytes, urinary frequency, decreased sodium, fatigue, rash, and pyrexia. (6.1). oMost common adverse reactions (>= 20% of patients with resectable GC/GEJC) were diarrhea, nausea, peripheral neuropathy, fatigue, alopecia, decreased appetite, rash, abdominal pain, vomiting, musculoskeletal pain, pyrexia, and stomatitis (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.The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to IMFINZI as single agent in total of 1,889 patients enrolled in the PACIFIC study (a randomized, placebo-controlled study that enrolled 475 patients with unresectable Stage III NSCLC), Study 1108 (an open-label, single-arm, multicohort study that enrolled 970 patients with advanced solid tumors), and an additional open-label, single arm study (ATLANTIC Study) that enrolled 444 patients with advanced solid tumors, including NSCLC. In these studies, IMFINZI was administered at dose of 10 mg/kg every weeks. Among the 1889 patients, 38% were exposed for months or more and 18% were exposed for 12 months or more. The data also reflect exposure to IMFINZI 1,500 mg every weeks as single agent in 262 patients from the ADRIATIC study (a randomized, double-blind study in patients with LS-SCLC) and to IMFINZI in combination with chemotherapy in 265 patients from the CASPIAN study (a randomized, open-label study in patients with ES-SCLC) and in 338 patients from the TOPAZ study (a randomized, double-blind study in patients with BTC). In the CASPIAN and TOPAZ studies, IMFINZI was administered at dose of 1,500 mg every or weeks.The data also reflect exposure to IMFINZI 1,120 mg in combination with carboplatin and paclitaxel (every weeks for up to cycles) followed by IMFINZI 1,500 mg (every weeks) as single agent in 235 patients in DUO-E (a randomized, placebo-controlled trial in endometrial cancer). Among the 235 patients, 77% (181 patients) were exposed to IMFINZI for months or more and 41% (96 patients) for 12 months or more.The data also reflect exposure to IMFINZI 1,500 mg in combination with tremelimumab-actl 300 mg in 388 patients in HIMALAYA. In the HIMALAYA study patients received IMFINZI 1,500 mg in combination with tremelimumab-actl as single intravenous infusion of 300 mg, followed by IMFINZI 1,500 mg every weeks. The pooled safety population (N 596) described in the WARNINGS AND PRECAUTIONS section reflect exposure to IMFINZI 1,500 mg in combination with tremelimumab-actl 75 mg and histology-based platinum chemotherapy regimens in 330 patients in POSEIDON [see Clinical Studies (14.1)], and 266 patients with ES-SCLC in CASPIAN who received up to four cycles of platinum-etoposide plus IMFINZI 1,500 mg with tremelimumab-actl 75 mg every weeks, followed by IMFINZI 1,500 mg every weeks (an unapproved regimen for extensive stage small cell lung cancer). Among the 596 patients, 55% were exposed to IMFINZI for months or more and 24% were exposed for 12 months or more.data described in this section reflect exposure to IMFINZI in patients with unresectable Stage III NSCLC enrolled in the PACIFIC study, in patients with metastatic NSCLC enrolled in the POSEIDON study, in patients with LS-SCLC enrolled in the ADRIATIC study, in patients with ES-SCLC enrolled in the CASPIAN study, in patients with BTC enrolled in the TOPAZ study, in patients with uHCC included in the HIMALAYA study, in patients with dMMR endometrial cancer enrolled in the DUO-E study, in patients with resectable NSCLC enrolled in the AEGEAN study, in patients with BCG-naive, high-risk NMIBC enrolled in the POTOMAC study, and in patients with MIBC enrolled in the NIAGARA study.Non-Small Cell Lung CancerNeoadjuvant and Adjuvant Treatment of Resectable NSCLC AEGEANThe safety of IMFINZI in combination with neoadjuvant platinum-containing chemotherapy followed by surgery, and continued adjuvant treatment with IMFINZI as single agent after surgery, was investigated in AEGEAN, randomized, double-blind, placebo-controlled, multicenter study for patients with resectable NSCLC (Stage IIA to select Stage IIIB [AJCC, 8th edition]); squamous or non-squamous) [see Clinical Studies (14.1)]. Safety data are available for the 799 patients who received IMFINZI in combination with chemotherapy (n=401) or placebo in combination with chemotherapy (n=398).The median duration of exposure to IMFINZI 1,500 mg every weeks in the neoadjuvant phase was 12 weeks (range: to 19 weeks). The median duration of exposure to IMFINZI 1,500 mg every weeks in the adjuvant phase was 37 weeks (range: to 67 weeks). The median age of patients who received IMFINZI was 65 years (range: 30 to 88), 52% age 65 or older, 12% age 75 or older; 65% male; 54% White, 41% Asian, 1% Black, 3% Other races; and 17% Hispanic or Latino.The most common adverse reactions (occurring in >= 20% of patients) were anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash.Table summarizes the adverse reactions that occurred in (>= 10%) patients treated with IMFINZI in combination with chemotherapy.Table 5. Adverse Reactions Occurring in >= 10% of Patients in the AEGEAN StudyAdverse ReactionIMFINZI with ChemotherapyN=401Placebo with ChemotherapyN=398All Grades (%)Grade or (%)All Grades (%)Grade or (%)Gastrointestinal disordersNausea250.2290.3Constipation250.2210Diarrheaincludes colitis, diarrhea, enteritis, and proctitis. 141131.3 Vomiting110.7111.0General disorders and administration site conditionsFatigueincludes fatigue and asthenia. 250251.5Skin and subcutaneous tissue disordersRashincludes dermatitis, dermatitis acneiform, drug eruption, eczema, eczema asteatotic, erythema, palmar-erythrodysaesthesia syndrome, pemphigoid, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular, skin exfoliation, and urticarial dermatitis. 220.5140.3Pruritus120.260Musculoskeletal and connective tissue disordersMusculoskeletal painincludes arthralgia, arthritis, back pain, bone pain, chest pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, musculoskeletal stiffness,myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain. 241290.5Metabolism and nutrition disordersDecreased appetite180.2180.3Nervous system disordersPeripheral neuropathyincludes dysaesthesia, hypoaesthesia, neuralgia, neuropathy peripheral, paraesthesia, peripheral sensory neuropathy, and polyneuropathy. 160.5220.8Endocrine disordersHypothyroidismincludes blood thyroid stimulating hormone increased and hypothyroidism. 1103.80Respiratory, thoracic and mediastinal disordersCough Productive cough110130Pneumoniaincludes lower respiratory tract infection, lung abscess, paracancerous pneumonia, pneumonia, pneumonia aspiration, pneumonia bacterial, pneumonia chlamydial, pneumonia cryptococcal, pneumonia fungal, pneumonia pseudomonal, pneumonia streptococcal, pneumonia viral, and post-procedural pneumonia. Five Grade events in the IMFINZI arm and four Grade events in the Placebo arm. 113.5103COVID-19Includes COVID-19 and COVID-19 Pneumonia. Five Grade events in the IMFINZI arm and One Grade event in the placebo arm. 110.290.8Psychiatric DisordersInsomnia100120Table summarizes the laboratory abnormalities in patients treated with IMFINZI in combination with chemotherapy.Table 6. Select Laboratory Abnormalities (>=20%) That Worsened from Baseline in Patients with Disease Who Received IMFINZI with Chemotherapy in AEGEANLaboratory AbnormalityGraded per NCI CTCAE V5.IMFINZI with ChemotherapyThe denominator used to calculate the rate varied from 349 to 399 based on the number of patients with baseline value and at least one post-treatment value. Placebo with ChemotherapyThe denominator used to calculate the rate varied from 333 to 398 based on the number of patients with baseline value and at least one post-treatment value. All Grades(%)Grade or 4(%)AllGrades(%)Grade or 4(%)HematologyHemoglobin decreased 7810759Leukocytes decreased63126411Neutrophils decreased52245627Platelets decreased467448Lymphocytes decreased4111379ChemistryCalcium corrected, decreased 513.3524.5Alanine aminotransferase increased 496422Aspartate aminotransferase increased 473.5371.8Potassium increased 331.5292Sodium decreased 355336Gamma glutamyl transferase increased 364.7352.1Creatinine increased 322.3273.3Amylase increased 254.7243.6Magnesium decreased222.8203.6Lipase increased234.9247Neoadjuvant Phase of AEGEANA total of 401 patients received at least dose of IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment and 398 patients received at least dose of placebo in combination with platinum-containing chemotherapy as neoadjuvant treatment.Serious adverse reactions occurred in 21% of patients who received IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (>=1%) serious adverse reactions were pneumonia (2.7%), anemia (1.5%), myelosuppression (1.5%), vomiting (1.2%), neutropenia (1%), and acute kidney injury (1%). Fatal adverse reactions occurred in 2% of patients, including death due to COVID-19 pneumonia (0.5%), sepsis (0.5%), myocarditis (0.2%), decreased appetite (0.2%), hemoptysis (0.2%), and death not otherwise specified (0.2%).Permanent discontinuation of any study drug due to an adverse reaction occurred in 14% of patients who received IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (>0.5%) adverse reactions that led to permanent discontinuation of any study drug were anemia (1.5%), neutropenia (0.7%), myelosuppression (0.7%), and periphery sensory neuropathy (0.7%). Permanent discontinuation of IMFINZI due to an adverse reaction occurred in 6.7% of patients who received IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (>=0.5%) adverse reactions that led to permanent discontinuation of IMFINZI were peripheral sensory neuropathy (0.7%) and pneumonitis (0.5%).Of the 401 IMFINZI-treated patients and 398 placebo-treated patients who received neoadjuvant treatment, 1.7% (n=7) and 1% (n=4), respectively, did not receive surgery due to adverse reactions. Adverse reactions that led to cancellation of surgery in the IMFINZI arm were COVID-19 pneumonia, HIV infection, pneumonitis, prostate cancer, colon cancer, pruritus, and colitis.Of the 325 IMFINZI-treated patients who received surgery, 4% (n=15) experienced delay of surgery (a surgical delay is defined as on-study surgery occurring more than 40 days after the last dose of study treatment in the neoadjuvant period) due to adverse reactions. Of the 326 placebo-treated patients who received surgery, 4% (n=16) experienced delay of surgery due to adverse reactions.Of the 325 IMFINZI-treated patients who received surgery, 6.5% (n=21) did not receive adjuvant treatment due to adverse reactions. Of the 326 placebo-treated patients who received surgery, 5.8% (n=19) did not receive adjuvant treatment due to adverse reactions.Adjuvant Phase of AEGEANA total of 265 patients in the IMFINZI arm and 254 patients in the placebo arm received at least dose of adjuvant treatment.Of the patients who received single agent IMFINZI as adjuvant treatment, 13% experienced serious adverse reactions. The most frequent serious adverse reactions reported in >1% of patients were pneumonia (1.9%), pneumonitis (1.1%), and COVID-19 (1.1%). Four fatal adverse reactions occurred during the adjuvant phase of the study, including COVID-19 pneumonia, pneumonia aspiration, interstitial lung disease and aortic aneurysm. Permanent discontinuation of adjuvant IMFINZI due to an adverse reaction occurred in 8% of patients. The most frequent (>=0.5%) adverse reaction that led to permanent discontinuation of adjuvant IMFINZI was pneumonitis (1.1%) and rash (0.8%).Unresectable Stage III NSCLC PACIFICThe safety of IMFINZI in patients with Stage III NSCLC who completed concurrent platinum-based chemoradiotherapy within 42 days prior to initiation of study drug was evaluated in the PACIFIC study, multicenter, randomized, double-blind, placebo-controlled study. total of 475 patients received IMFINZI 10 mg/kg intravenously every weeks. The study excluded patients who had disease progression following chemoradiation, with active or prior autoimmune disease within years of initiation of the study or with medical conditions that required systemic immunosuppression [see Clinical Studies (14.1) ]. The study population characteristics were: median age of 64 years (range: 23 to 90), 45% age 65 years or older, 70% male, 69% White, 27% Asian, 75% former smoker, 16% current smoker, and 51% had WHO performance status (PS) of 1. All patients received definitive radiotherapy as per protocol, of which 92% received total radiation dose of 54 Gy to 66 Gy. The median duration of exposure to IMFINZI was 10 months (range: 0.2 to 12.6).IMFINZI was discontinued due to adverse reactions in 15% of patients. The most common adverse reactions leading to IMFINZI discontinuation were pneumonitis or radiation pneumonitis in 6% of patients. Serious adverse reactions occurred in 29% of patients receiving IMFINZI. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonitis or radiation pneumonitis (7%) and pneumonia (6%). Fatal pneumonitis or radiation pneumonitis and fatal pneumonia occurred in 2% of patients and were similar across arms. The most common adverse reactions (occurring in >= 20% of patients) were cough, fatigue, pneumonitis or radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash.Table summarizes the adverse reactions that occurred in at least 10% of patients treated with IMFINZI.Table 7. Adverse Reactions Occurring in >= 10% of Patients in the PACIFIC StudyIMFINZI = 475PlaceboN 234Adverse ReactionAll Grades(%)Grades 3-4 (%)All Grades(%)Grades 3-4 (%)Respiratory, Thoracic, and Mediastinal DisordersCough/Productive Cough400.6300.4PneumonitisIncludes acute interstitial pneumonitis, interstitial lung disease, pneumonitis, pulmonary fibrosis./Radiation Pneumonitis 343.4253DyspneaIncludes dyspnea, and exertional dyspnea. 251.5252.6General Disorders FatigueIncludes asthenia and fatigue. 340.8321.3Pyrexia150.290Infections Upper respiratory tract infectionsIncludes laryngitis, nasopharyngitis, peritonsillar abscess, pharyngitis, rhinitis, sinusitis, tonsillitis, tracheobronchitis, and upper respiratory tract infection. 260.4190PneumoniaIncludes lung infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia adenoviral, pneumonia bacterial, pneumonia cytomegaloviral, pneumonia haemophilus, pneumonia klebsiella, pneumonia necrotizing, pneumonia pneumococcal, and pneumonia streptococcal. 177126Skin and Subcutaneous Tissue DisordersRashIncludes rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, erythema, eczema, rash, and dermatitis. 230.6120PruritusIncludes pruritus generalized and pruritus. 12060Gastrointestinal DisordersDiarrhea180.6191.3Abdominal painIncludes abdominal pain, abdominal pain lower, abdominal pain upper, and flank pain. 100.460.4Endocrine DisordersHypothyroidismIncludes autoimmune hypothyroidism and hypothyroidism. 120.21.70Other adverse reactions occurring in less than 10% of patients treated with IMFINZI were dysphonia, dysuria, night sweats, peripheral edema, and increased susceptibility to infections.Table summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI.Table 8. Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients in the PACIFIC StudyIMFINZIPlaceboLaboratory AbnormalityAll GradesGraded according to NCI CTCAE version 4.0.(%)Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI (range: 464 to 470) and placebo (range: 224 to 228).Grade or 4(%)All Grades(%)Grade or 4(%)ChemistryHyperglycemia528518Hypocalcemia460.2410Increased ALT392.3220.4Increased AST362.8210.4Hyponatremia333.6303.1Hyperkalemia321.1291.8Increased GGT243.4221.7HematologyLymphopenia43 17 39 18 Metastatic NSCLC POSEIDONThe safety of IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy in patients with metastatic NSCLC was evaluated in POSEIDON (NCT03164616), randomized, open-label, multicenter, active-controlled study. total of 330 patients received IMFINZI 1,500 mg in combination with tremelimumab-actl (>= 30 kg body weight received 75 mg and 30 kg body weight received mg/kg) and histology-based platinum chemotherapy regimens [see Clinical Studies (14.1)]. Of these patients, 66% received the maximum doses of tremelimumab-actl and 79% received at least doses. Treatment was continued with IMFINZI as single agent (or with IMFINZI and histologically-based pemetrexed for non-squamous patients based on the investigators decision) until disease progression or unacceptable toxicity. The study excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids or immunosuppressants [see Clinical Studies (14.1)]. The median age of patients who received IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy was 63 years (range: 27 to 87); 80% male; 61% White, 29% Asian, 58% former smoker, 25% current smoker, and 68% ECOG performance of 1.Serious adverse reactions occurred in 44% of patients receiving IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (11%), anemia (5%), diarrhea (2.4%), thrombocytopenia (2.4%), pyrexia (2.4%), and febrile neutropenia (2.1%). Fatal adverse reactions occurred in total of 4.2% of patients receiving IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy. These include hepatitis, nephritis, myocarditis, pancreatitis (all in the same patient), death (2 patients), sepsis (2 patients), pneumonitis (2 patients), acute kidney injury (2 patients), febrile neutropenia (1 patient), chronic obstructive pulmonary disease (COPD) (1 patient), dyspnea (1 patient), sudden death (1 patient), and ischemic stroke (1 patient).Permanent discontinuation of IMFINZI or tremelimumab-actl due to an adverse reaction occurred in 17% of the patients. Adverse reactions which resulted in permanent discontinuation of IMFINZI or tremelimumab-actl in 2% of patients included pneumonia.Dosage interruption or delay of IMFINZI and tremelimumab-actl due to an adverse reaction occurred in 41% of patients. Adverse reactions which required dosage interruption or delay of IMFINZI and tremelimumab-actl in 1% of patients included anemia, leukopenia/white blood cell count decreased, pneumonia, pneumonitis, colitis, diarrhea, hepatitis, rash, asthenia, amylase increased, alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased, neutropenia/ neutrophil count decreased, and thrombocytopenia/platelet count decreased. The most common adverse reactions (occurring in >= 20% of patients) were nausea, fatigue, musculoskeletal pain, decreased appetite, rash, and diarrhea. Grade or laboratory abnormalities (>= 10%) were neutropenia, anemia, leukopenia, lymphocytopenia, lipase increased, hyponatremia and thrombocytopenia.Table summarizes the adverse reactions in POSEIDON.Table 9. Adverse Reactions (>= 10%) in Patients with NSCLC Who Received IMFINZI in the POSEIDON StudyIMFINZI with tremelimumab-actl and platinum-based chemotherapy = 330Platinum-based chemotherapyN 333Adverse ReactionAll Grades (%)Grade or (%)All Grades (%)Grade or (%)Gastrointestinal disordersNausea421.8372.1Diarrhea221.5151.5Constipation190240.6Vomiting181.2141.5StomatitisIncludes mucosal inflammation and stomatitis. 10060.3General disorders and administration site conditionsFatigue/AstheniaIncludes asthenia and fatigue. 365324.5PyrexiaIncludes body temperature increased, hyperpyrexia, hyperthermia, and pyrexia. 19080EdemaIncludes face edema, localized edema, and edema peripheral. 100100.6Musculoskeletal and connective tissue disordersMusculoskeletal PainIncludes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, and spinal pain. 290.6221.5Metabolism and nutrition disordersDecreased appetite281.5251.2Skin and subcutaneous tissue disordersRashIncludes eczema, erythema, dermatitis, drug eruption, erythema multiforme, pemphigoid, rash, rash maculo-papular, rash papular, rash pruritic, and rash pustular. 272.4100.6Pruritus1104.50Alopecia10060Infections and InfestationsPneumoniaIncludes lower respiratory tract infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia aspiration, and pneumonia bacterial. 178124.2Upper respiratory tract infectionsIncludes laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, tonsillitis, tracheobronchitis and upper respiratory tract infection. 150.690.9Endocrine disordersHypothyroidismIncludes blood thyroid stimulating hormone increased and hypothyroidism. 1302.10Respiratory, thoracic and mediastinal disordersCough/Productive CoughIncludes cough and productive cough. 12080.3Nervous system disordersHeadacheIncludes headache and migraine. 11080.6Table 10 summarizes the laboratory abnormalities in POSEIDON.Table 10. Select Laboratory Abnormalities (>= 10%) That Worsened from Baseline in Patients with NSCLC Who Received IMFINZI in the POSEIDON StudyLaboratory AbnormalityGraded according to NCI CTCAE version 4.03.IMFINZI with tremelimumab-actl and platinum-based chemotherapyThe denominator used to calculate the rate varied from 45 to 326 based on the number of patients with baseline value and at least one post-treatment value. Platinum-based chemotherapyThe denominator used to calculate the rate varied from 43 to 323 based on the number of patients with baseline value and at least one post-treatment value. All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)ChemistryBlood creatinine increased 894831.9Increased ALT646564.7Increased AST635552.2Hypocalcemia580.9490.9Hyponatremia55135011Hyperkalemia492.2352.8Hyperglycemia426373.1Amylase increased419256Gamma Glutamyl Transferase increased382.2354.7Lipase increased 3514255Increased Alkaline Phosphatase333.4261.2Albumin decreased271.9180.9Hypokalemia217172.8Bilirubinemia160.980.3Hypernatremia150140Hypomagnesemia124230HematologyAnemia84248425Leukopenia77218118Neutropenia71376932Lymphocytopenia67206019Thrombocytopenia53115412Small Cell Lung CancerLimited Stage Small Cell Lung Cancer ADRIATICThe safety of IMFINZI as single agent in patients with LS-SCLC without disease progression following completion of concurrent platinum-based chemoradiotherapy (60-66 Gy once daily over weeks or 45 Gy twice daily over weeks) within 42 days prior to initiation of study drug, was evaluated in the ADRIATIC study, multicenter, randomized, double-blind, placebo-controlled study [see Clinical Studies (14.2)]. total of 262 patients received IMFINZI 1,500 mg every weeks until disease progression or unacceptable toxicity or maximum of 24 months. The study excluded patients with Stage or II LS-SCLC who were considered medically operable and patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids or immunosuppressants.The study population characteristics were: median age of 62 years (range: 28 to 84); 39% age 65 years or older, 6% age 75 years or older; 69% male; 50% white, 48% Asian, 1.3% other races; 4.2% Hispanic or Latino; 68% former smoker, 22% current smoker; and 51% had WHO performance status of 1. Sixty-seven percent of patients received total radiation dose of 60 Gy to 66 Gy once daily and 27% of patients received total radiation dose of 45 Gy twice daily. The median duration of exposure to IMFINZI was 9.2 months (range: 0.92 to 25) in the IMFINZI arm.Serious adverse reactions occurred in 30% of patients receiving IMFINZI. The most frequent serious adverse reactions reported in >= 1% of patients receiving IMFINZI were pneumonitis or radiation pneumonitis (12%), and pneumonia (5%). Fatal adverse reactions occurred in 2.7% of patients who received IMFINZI including pneumonia (1.5%), cardiac failure, encephalopathy and pneumonitis (0.4% each). Permanent discontinuation of IMFINZI due to adverse reactions occurred in 16% of the patients. Adverse reactions which resulted in permanent discontinuation of IMFINZI in >= 1% of patients included pneumonitis or radiation pneumonitis (9%) and pneumonia (1.5%). Dosage interruptions of IMFINZI due to an adverse reaction occurred in 35% of patients. Adverse reactions which required dosage interruption in >= 5% of patients included pneumonitis or radiation pneumonitis (17%). The most common adverse reactions occurring in >= 20% of patients receiving IMFINZI were pneumonitis or radiation pneumonitis (38%), and fatigue (21%).Table 11 summarizes the adverse reactions that occurred in patients treated with IMFINZI in the ADRIATIC study. Table 11. Adverse Reactions (>= 10%) in Patients with LS-SCLC Who Received IMFINZI in the ADRIATIC StudyIMFINZI(N=262)Placebo(N=265)Adverse ReactionAll Grades (%)Grade or 4(%)All Grades (%)Grade or 4(%)Respiratory, thoracic and mediastinal disordersPneumonitis or Radiation pneumonitisIncludes pneumonitis, immune-mediated lung disease, interstitial lung disease, radiation pneumonitis, and lung radiation fibrosis 383.1302.6Cough/Productive cough170140DyspneaIncludes dyspnea and exertional dyspnea. 110.470General disordersFatigueIncludes fatigue and asthenia. 210.4202.3Skin and subcutaneous tissue disordersRashIncludes dermatitis, acneiform dermatitis, eczema, rash, maculo-papular rash, papular rash, pruritic rash, and skin exfoliation. 180.4110Pruritus13070Endocrine disordersHypothyroidismIncludes hypothyroidism, increased blood thyroid stimulating hormone, and decreased thyroxine free. 1704.90HyperthyroidismIncludes hyperthyroidism, decreased blood thyroid stimulating hormone, increased thyroxine free, increased thyroxine, increased tri-iodothyronine free, and increased tri-iodothyronine. 1201.90Metabolism and nutrition disordersDecreased appetite170130Nervous system disordersDizzinessIncludes dizziness, postural dizziness, vertigo, and positional vertigo. 14090Infections and infestationsPneumoniaIncludes pneumonia, atypical pneumonia, lower respiratory tract infection, bacterial pneumonia, pneumocystis jirovecii pneumonia, legionella pneumonia, and viral pneumonia. 133.194.2Gastrointestinal disordersNausea130110Diarrhea111.980Constipation100100Table 12 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI.Table 12. Select Laboratory Abnormalities (>= 20%) That Worsened from Baseline in Patients with LS-SCLC Who Received IMFINZI in the ADRIATIC StudyLaboratory AbnormalityGraded according to NCI CTCAE version 4.03, except creatinine increased which is graded according to NCI CTCAE version 5.0.IMFINZIThe denominator used to calculate the rate varied from 63 to 259 based on the number of patients with baseline value and at least one post-treatment value.PlaceboThe denominator used to calculate the rate varied from 65 to 262 based on the number of patients with baseline value and at least one post-treatment value. All Grades (%) Grade or (%)All Grades (%)Grade or 4(%)ChemistryHypocalcemia430430.8Hyperglycemia383.2451.5ALT increased362.3292.3AST increased332.3281.5Gamma Glutamyl Transferase increased327272.9Hyponatremia325296.2Hyperkalemia231.2170.8Creatinine increased 210170.8HematologyLymphocytes decreased34103310Leukocytes decreased260.4331.1Extensive Stage Small Cell Lung Cancer CASPIANThe safety of IMFINZI in combination with etoposide and either carboplatin or cisplatin in previously untreated ES-SCLC was evaluated in CASPIAN, randomized, open-label, multicenter, active-controlled study. total of 265 patients received IMFINZI 1,500 mg in combination with chemotherapy every weeks for cycles followed by IMFINZI 1,500 mg every weeks until disease progression or unacceptable toxicity. The study excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids or immunosuppressants [see Clinical Studies (14.2) ]. Among 265 patients receiving IMFINZI, 49% were exposed for months or longer and 19% were exposed for 12 months or longer.Among 266 patients receiving chemotherapy alone, 57% of the patients received cycles of chemotherapy and 8% of the patients received prophylactic cranial irradiation (PCI) after chemotherapy. IMFINZI was discontinued due to adverse reactions in 7% of the patients receiving IMFINZI plus chemotherapy. These include pneumonitis, hepatotoxicity, neurotoxicity, sepsis, diabetic ketoacidosis and pancytopenia (1 patient each). Serious adverse reactions occurred in 31% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 1% of patients were febrile neutropenia (4.5%), pneumonia (2.3%), anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%) and COPD (1.1%). Fatal adverse reactions occurred in 4.9% of patients receiving IMFINZI plus chemotherapy. These include pancytopenia, sepsis, septic shock, pulmonary artery thrombosis, pulmonary embolism, and hepatitis (1 patient each) and sudden death (2 patients). The most common adverse reactions (occurring in >= 20% of patients) were nausea, fatigue/asthenia and alopecia. Table 13 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy. Table 13. Adverse Reactions Occurring in >= 10% of Patients in the CASPIAN StudyIMFINZI with etoposide and either carboplatin or cisplatin = 265Etoposide and either carboplatin or cisplatin = 266Adverse ReactionAll Grades (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)Gastrointestinal disordersNausea340.4341.9Constipation170.8190Vomiting150171.1Diarrhea101.1111.1General disorders and administration site conditionsFatigue/Asthenia 323.4322.3Skin and subcutaneous tissue disordersAlopecia311.1340.8RashIncludes rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, erythema, eczema, rash and dermatitis. 11060Metabolism and nutrition disordersDecreased appetite180.8170.8Respiratory, thoracic and mediastinal disordersCough/Productive Cough150.890Endocrine disordersHyperthyroidismIncludes hyperthyroidism and Basedows disease. 1000.40Table 14 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI plus chemotherapy.Table 14. Laboratory Abnormalities Worsening from Baseline Occurring in >= 20%The frequency cut off is based on any grade change from baseline. of Patients in the CASPIAN StudyIMFINZI with Etoposide and either Carboplatin or Cisplatin Etoposide and either Carboplatin or Cisplatin Laboratory AbnormalityGradeGraded according to NCI CTCAE version 4.03. or (%)Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI (range: 258 to 263) and chemotherapy (range: 253 to 262) except magnesium IMFINZI with chemotherapy (18) and chemotherapy (16).Grade or (%)ChemistryHyponatremia1113Hypomagnesemia116Hyperglycemia55Increased Alkaline Phosphatase4.93.5Increased ALT4.92.7Increased AST4.61.2Hypocalcemia3.52.4Blood creatinine increased3.41.1Hyperkalemia1.53.1TSH decreased LLNLLN lower limit of normal. and >= LLN at baselineNANAHematologyNeutropenia 4148Lymphopenia1413Anemia1322Thrombocytopenia1215Biliary Tract CancerLocally Advanced or Metastatic BTC TOPAZ-1The safety of IMFINZI in combination with gemcitabine and cisplatin in locally advanced or metastatic BTC was evaluated in TOPAZ-1, randomized, double-blind, placebo-controlled, multicenter study. total of 338 patients received IMFINZI 1,500 mg in combination with gemcitabine and cisplatin every weeks up to cycles followed by IMFINZI 1,500 mg every weeks until disease progression or unacceptable toxicity.Patients with active or prior documented autoimmune or inflammatory disorders, HIV infection or other active infections, including tuberculosis or hepatitis were ineligible [see Clinical Studies (14.3)]. IMFINZI was discontinued due to adverse reactions in 6% of the patients receiving IMFINZI plus chemotherapy. The most frequently reported events resulting in discontinuation were sepsis (3 patients) and ischemic stroke (2 patients). The remaining events were dispersed across system organ classes and reported in patient each. Serious adverse reactions occurred in 47% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%) and acute kidney injury (2.4%). Fatal adverse reactions occurred in 3.6% of patients receiving IMFINZI plus chemotherapy. These include ischemic or hemorrhagic stroke (4 patients), sepsis (2 patients) and upper gastrointestinal hemorrhage (2 patients). The most common adverse reactions (occurring in >= 20% of patients) were fatigue, nausea, constipation, decreased appetite, abdominal pain, rash and pyrexia. Table 15 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy. Table 15. Adverse Reactions Occurring in >= 10% of Patients in the TOPAZ-1 StudyIMFINZI with Gemcitabine and Cisplatin = 338Placebo with Gemcitabine and Cisplatin = 342Adverse ReactionAll GradesGraded according to NCI CTCAE version 5.0. (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)General disorders and administration site conditionsFatigueIncludes fatigue, malaise, cancer fatigue and asthenia. 426436Pyrexia201.5160.6Gastrointestinal disordersNausea401.5341.8Constipation320.6290.3Abdominal painIncludes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain. 240.6232.9Vomiting181.5182.0Diarrhea171.2151.8Metabolism and nutrition disordersDecreased appetite262.1230.9Skin and subcutaneous tissue disordersRashIncludes rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, rash pustular, rash erythematous, dermatitis acneiform, dermatitis bullous, drug eruption, eczema, erythema, dermatitis and rash. 230.9140Pruritus11080Psychiatric disordersInsomnia100110Table 16 summarizes the laboratory abnormalities in patients treated with IMFINZI plus chemotherapy.Table 16. Laboratory Abnormalities Worsening from Baseline Occurring in >= 20%The frequency cut off is based on any grade change from baseline. of Patients in the TOPAZ-1 StudyIMFINZI with Gemcitabine and Cisplatin Placebo with Gemcitabine and Cisplatin Laboratory AbnormalityGradeGraded according to NCI CTCAE version 5.0. Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI with gemcitabine/cisplatin (range: 312 to 335) and Placebo with gemcitabine/cisplatin (range: 319 to 341). or (%)Grade or (%)ChemistryHyponatremia1813Gamma-glutamyltransferase increased1213Increased bilirubin1014Hypokalemia84.4Increased AST88Increased ALT76Blood creatinine increased52.1Hypomagnesemia4.52.2Hypoalbuminemia3.62.9Hyperkalemia2.12.1Increased Alkaline Phosphatase1.83.8Hypocalcemia1.82.4HematologyNeutropenia 4849Anemia3128Leukopenia2828Lymphopenia2315Thrombocytopenia1818Hepatocellular CarcinomaUnresectable HCC HIMALAYAThe safety of IMFINZI in combination with tremelimumab-actl was evaluated in total of 388 patients with uHCC in HIMALAYA, randomized, open-label, multicenter study [see Clinical Studies (14.1)]. Patients received IMFINZI 1,500 mg administered as single intravenous infusion in combination with tremelimumab-actl 300 mg on the same day, followed by IMFINZI every weeks or sorafenib 400 mg given orally twice daily.Serious adverse reactions occurred in 41% of patients who received IMFINZI in combination with tremelimumab-actl. Serious adverse reactions in 1% of patients included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%). Fatal adverse reactions occurred in 8% of patients who received IMFINZI in combination with tremelimumab-actl, including death (1%), hemorrhage intracranial (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and immune-mediated hepatitis (0.5%). The most common adverse reactions (occurring in >= 20% of patients) were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain.Permanent discontinuation of treatment regimen due to an adverse reaction occurred in 14% of patients; the most common adverse reactions leading to treatment discontinuation (>= 1%) were hemorrhage (1.8%), diarrhea (1.5%), AST increased (1%), and hepatitis (1%).Dosage interruptions or delay of the treatment regimen due to an adverse reaction occurred in 35% of patients. Adverse reactions which required dosage interruption or delay in >= 1% of patients included ALT increased (3.6%), diarrhea (3.6%), rash (3.6%), amylase increased (3.4%), AST increased (3.1%), lipase increased (2.8%), pneumonia (1.5%), hepatitis (1.5%), pyrexia (1.5%), anemia (1.3%), thrombocytopenia (1%), hyperthyroidism (1%), pneumonitis (1%), and blood creatinine increased (1%).Table 17 summarizes the adverse reactions that occurred in patients treated with IMFINZI in combination with tremelimumab-actl in the HIMALAYA study. Table 17. Adverse Reactions Occurring in >= 10% of Patients in the HIMALAYA StudyIMFINZI and Tremelimumab-actl(N 388)Sorafenib(N 374)Adverse ReactionAll Grades (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)Skin and subcutaneous tissue disordersRashRepresents composite of multiple related terms. 322.85712Pruritus23060.3Gastrointestinal disorders Diarrhea 276454.3Abdominal pain 201.8244Nausea120140General disorders and administration site conditionsFatigue 263.9306Pyrexia 130.390.3Musculoskeletal and Connective Tissue DisordersMusculoskeletal pain 222.6170.8Metabolism and nutrition disordersDecreased appetite171.3180.8Endocrine disordersHypothyroidism 14060Psychiatric disordersInsomnia100.34.30Table 18 summarizes the laboratory abnormalities that occurred in patients treated with IMFINZI in combination with tremelimumab-actl in the HIMALAYA study.Table 18. Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients in the HIMALAYA StudyIMFINZI and Tremelimumab-actlSorafenibLaboratory AbnormalityAny gradeGraded according to NCI CTCAE version 4.03. (%)Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI with tremelimumab-actl (range: 367-378) and sorafenib (range:344-352).Grade or (%)Any grade(%)Grade or (%)ChemistryAspartate Aminotransferase increased63275521Alanine Aminotransferase increased56185312Sodium decreased46154011Bilirubin increased4184711Alkaline Phosphatase increased418445Glucose increased3914294Calcium decreased34 0430.3Albumin decreased310.5371.7Potassium increased283.8212.6Creatinine increased211.3150.9HematologyHemoglobin decreased524.8406Lymphocytes decreased41113910Platelets decreased291.6353.1Leukocytes decreased200.8301.1Endometrial CancerAdvanced or Recurrent dMMR Endometrial Cancer DUO-EThe safety of IMFINZI in combination with carboplatin and paclitaxel followed by IMFINZI as single agent was evaluated in 44 patients with dMMR advanced or recurrent endometrial cancer in DUO-E, randomized, double-blind, placebo-controlled trial [See Clinical Studies (14.5)]. Patients received IMFINZI 1,120 mg with carboplatin and paclitaxel every weeks for up to six 21-day cycles followed by IMFINZI 1,500 mg every weeks or carboplatin and paclitaxel every weeks for up to six 21-day cycles alone. Treatment was continued until disease progression or unacceptable toxicity. The median duration of exposure to IMFINZI with carboplatin and paclitaxel was 14.8 months (range: 0.7 to 31.7). Serious adverse reactions occurred in 30% of patients who received IMFINZI with carboplatin and paclitaxel. The most common serious adverse reactions (>=4%) were constipation (4.5%) and rash (4.5%).Permanent discontinuation of IMFINZI due to adverse reactions occurred in 11% of patients. The adverse reaction which resulted in permanent discontinuation of IMFINZI (>=4%) was rash (4.5%). Dosage interruptions of IMFINZI due to adverse reactions occurred in 52% of patients. Adverse reactions which required dosage interruptions of IMFINZI (>= 4%) were anemia (11%), thrombocytopenia (9%), neutropenia (9%), COVID-19 (9%), increased ALT (4.5%), and pneumonitis (4.5%). The most common adverse reactions (> 20%), including laboratory abnormalities, were peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, decreased magnesium, increased ALT, increased AST, diarrhea, vomiting, cough, decreased potassium, dyspnea, headache, increased alkaline phosphatase, and decreased appetite.Tables 19 and 20 summarize adverse reactions and laboratory abnormalities in DUO-E, respectively.Table 19. Adverse Reactions Occurring in >= 10% of Patients with dMMR tumors in DUO-EAdverse ReactionsIMFINZI with Carboplatin and Paclitaxel(N=44)Carboplatin and Paclitaxel (N=46)All Grades(%)Grade 3-4(%)All Grades(%)Grade 3-4(%)Nervous system disordersPeripheral neuropathyIncludes neuropathy peripheral, peripheral sensory neuropathy, hypoasthesia, peripheral motor neuropathy, and parasthesia. 612.3614.3Headache230170Musculoskeletal and connective tissue disordersMusculoskeletal painIncludes arthralgia, pain in extremity, back pain, non-cardiac chest pain, myalgia, musculoskeletal pain, musculoskeletal chest pain, arthritis, bone pain, musculoskeletal stiffness, neck pain, musculoskeletal discomfort, and spinal pain. 592.3522.2Gastrointestinal disordersNausea590482.2Abdominal painIncludes abdominal pain, abdominal pain lower, flank pain, abdominal discomfort, and abdominal pain upper. 390242.2ConstipationIncludes constipation and fecaloma. 394.5352.2Diarrhea272.3242.2Vomiting270224.3Skin and subcutaneous tissue disordersAlopecia520410RashIncludes eczema, rash, rash erythematous, rash maculo-papular, dermatitis, rash pustular, skin exfoliation, and symmetrical drug-related intertriginous, and flexural exanthema. 392.3172.2Pruritus160110General disorders and administration site conditions FatigueIncludes asthenia and fatigue.414.55711Peripheral edemaIncludes peripheral edema, peripheral swelling, and edema. 160132.2Respiratory, thoracic and mediastinal disordersCough productive cough270200DyspneaIncludes dyspnea and exertional dyspnea. 252.390Metabolism and nutrition disordersDecreased appetite180180Infections and infestationsUpper respiratory tract infectionIncludes nasopharyngitis, pharyngitis, rhinitis, sinusitis, tracheobronchitis, and upper respiratory tract infection. 1404.30Endocrine disordersHypothyroidismIncludes blood thyroid stimulating hormone increased, and hypothyroidism. 1104.30Clinically relevant adverse reactions in 10% of patients who received IMFINZI with carboplatin and paclitaxel included autoimmune hemolytic anemia, colitis, immune-mediated thyroiditis, infusion related reaction, interstitial lung disease, myositis, pneumonitis, pulmonary embolism, and sepsis.Table 20 summarizes the laboratory abnormalities that occurred in patients treated with IMFINZI with carboplatin and paclitaxel followed by IMFINZI as single agent.Table 20. Select Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients with dMMR tumors in DUO-ELaboratory AbnormalityIMFINZI with Carboplatin and PaclitaxelEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI with carboplatin and paclitaxel (range: 40 to 44), and carboplatin and paclitaxel (range: 37 to 46)Carboplatin and PaclitaxelAll Grades(%)Grade 3-4(%)All Grades(%)Grade 3-4(%)ChemistryMagnesium decreased360302.5ALT increased322.3222.2AST increased302.3220Potassium decreased250242.2Alkaline phosphatase increased200160Non-Muscle-Invasive Bladder Cancer (NMIBC)BCG-Naive, High-Risk NMIBC POTOMACThe safety of IMFINZI in combination with intravesical BCG induction and maintenance treatment was evaluated in POTOMAC, randomized, open-label, multicenter study. Patients received IMFINZI in combination with BCG induction and maintenance treatment (n=336) or BCG induction and maintenance treatment alone (n=339) [see Clinical Studies (14.6) ]. Patients received IMFINZI 1,500 mg every weeks for up to 13 cycles, plus BCG induction every week for weeks, followed by BCG maintenance on weekly basis for weeks at 3, 6, 12, 18, and 24 months. The median duration of exposure to IMFINZI was 52 weeks (range: to 89 weeks). Serious adverse reactions occurred in 32% of patients who received IMFINZI with BCG. The most common (>= 1%) serious adverse reactions were urinary tract infection (4.5%), COVID (1.8%), hepatitis (1.5%), dysuria (1.2%), and prostate cancer (1.2%). Fatal adverse reactions occurred in 2.4% of patients who received IMFINZI with BCG, including congestive cardiac failure (0.6%), COVID (0.3%), cardiovascular disorder (0.3%), dementia with Lewy bodies (0.3%), and pancreatic cancer (0.3%).Permanent discontinuation of IMFINZI due to adverse reactions occurred in 18% of patients. The adverse reactions which resulted in permanent discontinuation of IMFINZI (>= 1%) were hepatitis (1.8%), acute kidney injury (1.2%), and diarrhea (1.2%).Dosage interruptions of IMFINZI due to adverse reactions occurred in 22% of patients. Adverse reactions which required dosage interruptions of IMFINZI (>= 1%) were increased lipase (3%), rash (1.8%), COVID (1.8%), hypothyroidism (1.5%), increased amylase (1.5%), diarrhea (1.2%), increased ALT (1.2%), and increased pancreatic enzymes (1.2%).The most common (>= 20%) adverse reactions, including laboratory abnormalities were increased glucose, increased AST, increased lipase, increased ALT, increased GGT, urinary tract infection, increased potassium, dysuria, decreased hemoglobin, hematuria, increased serum creatinine, musculoskeletal pain, decreased lymphocytes, urinary frequency, decreased sodium, fatigue, rash, and pyrexia.Table 21 summarizes the adverse reactions that occurred in patients treated with IMFINZI in combination with BCG induction and maintenance treatment.Table 21. Adverse Reactions Occurring in >= 10% of Patients with BCG-Naive, High-Risk NMIBC Who Received IMFINZI in the POTOMAC studyIMFINZI BCGBCG was administered as induction and maintenance treatment.(N 336)BCG(N 339)Adverse ReactionAll Grades (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)Infections and infestationsUrinary tract infectionIncludes other related terms 404.5341.5Renal and urinary disordersDysuria372.7361.2Hematuria 330.9312.4Urinary Frequency260250Musculoskeletal and connective tissue disordersMusculoskeletal pain 280.6150.3General disorders and administration site conditionsFatigue 210.6100.3Pyrexia 200.3250Skin and subcutaneous tissue disordersRash 200.660Endocrine disordersHypothyroidism 130.30.90Gastrointestinal disordersDiarrhea 131.570.3Constipation1104.70Abdominal pain 10060Clinically relevant adverse reactions in 10% of patients who received IMFINZI with BCG included hyperthyroidism, hepatitis, thyroiditis, adrenal insufficiency, pancreatitis, polymyalgia rheumatica, pneumonitis, nephritis, myositis, and type diabetes mellitus.Table 22 summarizes the laboratory abnormalities that occurred in patients treated with IMFINZI in combination with BCG induction and maintenance in the POTOMAC study.Table 22. Select Laboratory Abnormalities Worsening from Baseline Occurring in >= 20%The frequency cut off is based on any grade change from baseline. of Patients Who Received IMFINZI in the POTOMAC studyIMFINZI BCGBCG was administered as induction and maintenance treatment.BCGLaboratory AbnormalityAny gradeGraded according to NCI CTCAE version 4.03. (%)Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI with BCG (range: 289 to 335) and BCG (range: 284 to 333).Grade or (%)Any grade (%)Grade or (%)ChemistryIncreased glucose437344.5Increased AST436280Increased lipase4218298Increased ALT426260.3Increased GGT407322.2Increased potassium392.1332.4Increased creatinine301.2230.9Decreased sodium233.0110HematologyDecreased hemoglobin350.6240.6Decreased lymphocytes273.0131.2Muscle Invasive Bladder Cancer (MIBC)Neoadjuvant and adjuvant treatment of MIBC NIAGARAThe safety of IMFINZI in combination with neoadjuvant gemcitabine and cisplatin followed by surgery and continued IMFINZI treatment as adjuvant, single-agent therapy was evaluated in NIAGARA, randomized, open-label, multicenter trial. Patients received IMFINZI in combination with chemotherapy (n=530) or received chemotherapy alone (n=526) [see Clinical Studies (14.6)]. The median duration of exposure to IMFINZI 1,500 mg every weeks in the neoadjuvant phase was 12 weeks (range: 1.1 to 84 weeks). The median duration of exposure to IMFINZI 1,500 mg every weeks in the adjuvant phase was 32 weeks (range: 2.4 to 50 weeks).The most common adverse reactions, including laboratory abnormalities, in the overall study (occurring in >= 20% of patients) were decreased hemoglobin, decreased neutrophils, increased blood creatinine, decreased sodium, nausea, increased ALT, decreased calcium, decreased platelets, fatigue, increased potassium, decreased lymphocytes, increased AST, constipation, decreased magnesium, decreased appetite, increased alkaline phosphate, rash, pyrexia, diarrhea, vomiting, and abdominal pain.Table 23 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy.Table 23. Adverse Reactions Occurring in >= 10% of Patients in the NIAGARA StudyIMFINZI with gemcitabine and cisplatinN 530Gemcitabine and cisplatinN 526Adverse ReactionAll GradesGraded according to NCI CTCAE version 5.0.(%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)Gastrointestinal disordersNausea541.5481Constipation390.8390.8Diarrhea211.5140.4VomitingIncludes multiple similar terms. 200.9190.2Abdominal pain 200.9131General disorders and administration site conditionsFatigue 522.3493Pyrexia 220.4170Edema 130.4130Metabolism and nutrition disordersDecreased appetite270.6250.6Skin and subcutaneous tissue disordersRash 231.3120.6Pruritus15070Nervous system disordersPeripheral neuropathy 160.2140Headache 110110Dizziness 110100.2Endocrine disordersHypothyroidism 130.42.30Vascular disordersHypertension 124.592.9Hemorrhage 110.9102.1Table 24 summarizes the laboratory abnormalities in patients treated with IMFINZI plus chemotherapy.Table 24. Select Laboratory Abnormalities That Worsened from Baseline in >= 20% of Patients Who Received IMFINZI with Chemotherapy in the NIAGARA studyLaboratory AbnormalityIMFINZI with gemcitabine and cisplatinEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI plus chemotherapy (range: 482 to 528), and chemotherapy (range: 467 to 521).Gemcitabine and cisplatinAll GradesGraded per NCI CTCAE V5. (%)Grade or 4(%)AllGrades (%)Grade or 4(%)ChemistryIncreased blood creatinine 639587Decreased sodium 5495510Increased ALT 532.3544.0Decreased calcium 521.3431.2Increased potassium 514.2494.4Increased AST421.5392.1Decreased magnesium381.9372.3Increased alkaline phosphate260.8250.4HematologyDecreased hemoglobin88138713Decreased neutrophils76317434Decreased platelets526507Decreased lymphocytes4410408Neoadjuvant Phase of NIAGARA total of 530 patients received at least dose of IMFINZI in combination with chemotherapy as neoadjuvant treatment in the IMFINZI treatment arm, and 526 patients received at least dose of chemotherapy as neoadjuvant treatment in the chemotherapy treatment arm. In the neoadjuvant phase, serious adverse reactions occurred in 24% of patients who received IMFINZI in combination with chemotherapy; the most frequent (>=1%) serious adverse reactions were pulmonary embolism (1.9%), febrile neutropenia (1.5%), acute kidney injury (1.3%), thrombocytopenia (1.3%), urinary tract infection (1.3%) and pneumonia (1.3%). Fatal adverse reactions occurred in 1.1% of patients including sepsis (0.2%), myocardial infarction (0.2%), and pulmonary embolism (0.2%). One fatal adverse reaction of pneumonia was reported in (0.2%) patient in the post-surgery phase before adjuvant treatment started. Permanent discontinuation of IMFINZI due to an adverse reaction in the neoadjuvant phase occurred in 9% of patients while receiving IMFINZI in combination with chemotherapy. The most frequent (>= 0.5%) adverse reactions that led to permanent discontinuation of IMFINZI were blood creatinine increased (0.9%), neutropenia (0.6%), acute kidney injury (0.6%), asthenia (0.6%) and fatigue (0.6%). Of the 530 patients in the IMFINZI treatment arm and 526 patients in the chemotherapy treatment arm who received neoadjuvant treatment, (0.2%) patient in each treatment arm did not receive surgery due to adverse reactions. The adverse reaction that led to cancellation of surgery in the IMFINZI treatment arm was interstitial lung disease. Of the 469 patients in the IMFINZI treatment arm who underwent radical cystectomy, (0.8%) patients experienced delay of surgery (defined as occurring more than 56 days after the last dose of neoadjuvant treatment) due to adverse reactions.Adjuvant Phase of NIAGARA total of 383 patients (72%) in the IMFINZI treatment arm received at least dose of adjuvant treatment.Serious adverse reactions occurred in 26% of patients receiving IMFINZI as adjuvant treatment. The most frequent serious adverse reactions (occurring in >=1% of patients) were urinary tract infection (7%), acute kidney injury (3.7%), hydronephrosis (2.1%), pyelonephritis (2.1%), urosepsis (1.8%), and sepsis (1.6%). Fatal adverse reactions occurred in 1.8% of patients, including COVID-19 (0.3%), severe acute respiratory syndrome (0.3%), cardiopulmonary failure (0.3%), gastrointestinal haemorrhage (0.3%), and chronic hepatic failure (0.3%).Permanent discontinuation of adjuvant IMFINZI due to an adverse reaction occurred in 5% of patients. The most frequent (>=0.5%) adverse reactions that led to permanent discontinuation of adjuvant IMFINZI were nephritis (0.8%), fatigue (0.5%), diarrhea (0.5%), decreased appetite (0.5%) and pneumonitis (0.5%).Gastric or Gastroesophageal Junction Adenocarcinoma (GC/GEJC)Neoadjuvant and Adjuvant Treatment of Resectable GC/GEJC MATTERHORNThe safety of IMFINZI with FLOT as neoadjuvant and adjuvant treatment, followed by single-agent IMFINZI, was evaluated in MATTERHORN, randomized, double-blind, placebo-controlled, multicenter study of patients with resectable GC/GEJC (Stage II to Stage IVA [AJCC, 8th edition]) [see Clinical Studies (14.7)].Safety data are available for the 944 patients who received IMFINZI with FLOT (n=475) or placebo with FLOT (n=469).The median duration of exposure to IMFINZI 1,500 mg every weeks in the neoadjuvant phase was weeks (range: 1.4 to 8.7 weeks). The median duration of exposure to IMFINZI 1,500 mg every weeks in the adjuvant phase was 48 weeks (range: 1.9 to 50.1 weeks).The most common adverse reactions (occurring in >= 20% of patients) were diarrhea, nausea, peripheral neuropathy, fatigue, alopecia, decreased appetite, rash, abdominal pain, vomiting, musculoskeletal pain, pyrexia, and stomatitis.Table 25 summarizes the adverse reactions that occurred in >= 10% of patients treated with IMFINZI in combination with FLOT chemotherapy.Table 25: Adverse Reactions Occurring in >= 10% of Patients in the MATTERHORN studyAdverse ReactionIMFINZI with FLOT ChemotherapyN=475Placebo with FLOT ChemotherapyN=469All Grades (%)Grade or (%)All Grades (%)Grade or (%)Gastrointestinal disordersDiarrheaIncludes multiple similar terms. 648597Nausea512.5511.5Vomiting 262.1263Abdominal pain 272.3291.3Stomatitis 201.1150.6Constipation160170.9Dysphagia101.581.5Nervous system disordersPeripheral neuropathy 513.6472.3Dysgeusia 190150General disorders and administration site conditionsFatigue 475455Pyrexia 200.8161.3Skin and subcutaneous tissue disordersAlopecia310320Rash 301.5200.4Pruritus 11050Metabolism and nutrition disordersDecreased appetite 313.2302.1Musculoskeletal and connective tissue disordersMusculoskeletal pain 211.5190.6Infections and infestationsCOVID-19 191.7160.6Pneumonia 113.8104.3InvestigationsWeight decreased152.1193.4Vascular disordersHemorrhage 142.5152.8Respiratory, thoracic and mediastinal disordersCough 100100 Table 26 summarizes the laboratory abnormalities in patients treated with IMFINZI in combination with FLOT chemotherapy.Table 26: Laboratory Abnormalities (> 20%) That Worsened from Baseline in Patients with Disease Who Received IMFINZI with FLOT Chemotherapy in MATTERHORNLaboratory AbnormalityGraded per NCI CTCAE v5.0IMFINZI with FLOT ChemotherapyThe denominator used to calculate the rate varied from 444 to 472 based on the number of patients with baseline value and at least one post-treatment value. Placebo with FLOT ChemotherapyThe denominator used to calculate the rate varied from 443 to 468 based on the number of patients with baseline value and at least one post-treatment value. All Grades(%)Grade or 4(%)AllGrades(%)Grade or 4(%)HematologyDecreased leukocytes 75147917Decreased neutrophils70417444Decreased hemoglobin687738Decreased lymphocytes49134513Decreased platelets471.1461.9ChemistryIncreased AST726696Increased ALT707656Increased GGT5710516Increased lipase55165515Increased alkaline phosphatase533.2511.5Decreased calcium 450.8472.6Increased amylase426394.5Decreased potassium398408Decreased sodium334.4324.7Decreased albumin311.5310.2Increased potassium220.6261.3Adverse Reactions by Phase of TreatmentTable 27 summarizes safety profile by Phase of treatment. Table 27: Safety Profile by Phase of TreatmentIMFINZI with FLOT ChemotherapyPlacebo with FLOT ChemotherapyNeoadjuvant Phase Number of Patients475469 Serious Adverse Reactions21%18% Deaths during Treatment-emergent period1.9%1.7% Permanent discontinuation of IMFINZI or Placebo2.5%2.1% No surgery due to Adverse Reaction0.6%0.4% Delay in surgery due to Adverse Reaction2.3%2.6%Adjuvant Phase Number of Patients365351 Serious Adverse Reactions29%26% Deaths during Treatment-emergent period2.2%2.6% Permanent discontinuation of IMFINZI or Placebo7%4.6%Adjuvant Phase (IMFINZI as single-agent) Number of Patients345331 Serious Adverse Reactions14%15% Deaths during Treatment-emergent period1.7%2.4% Permanent discontinuation of IMFINZI or Placebo6%2.7%Serious adverse reactions (>=2%) in the IMFINZI arm were diarrhea (2.5%) during the neoadjuvant phase, and pneumonia (2.5%) in the adjuvant phase.Deaths (>=2 patients) in the IMFINZI arm were septic shock (0.6%) and acute coronary syndrome (0.4%) during the neoadjuvant phase; gastrointestinal perforation (0.5%) and COVID-19 (0.5%) during adjuvant phase; and gastrointestinal perforation (0.6%) and COVID-19 (0.6%) in the single-agent adjuvant phase.Permanent discontinuation of IMFINZI (>=2 patients) due an adverse reaction in the IMFINZI arm were nephritis (0.4%) during the neoadjuvant phase; hepatitis (1.1%), pneumonitis (1.1%), rash (0.8%), musculoskeletal pain (0.5%), and renal failure (0.5%) during adjuvant phase; and hepatitis (0.9%), pneumonitis (0.9%), musculoskeletal pain (0.6%), and renal failure (0.6%) during the single-agent adjuvant phase.. All Grades. (%). Grade or 4. (%). FatigueIncludes asthenia and fatigue.. Table 26 summarizes the laboratory abnormalities in patients treated with IMFINZI in combination with FLOT chemotherapy.. Permanent discontinuation of IMFINZI or Placebo. Permanent discontinuation of IMFINZI or Placebo. Permanent discontinuation of IMFINZI or Placebo.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 Non-Small Cell Lung Cancer (NSCLC) Neoadjuvant and Adjuvant Treatment of Resectable NSCLC AEGEAN StudyThe efficacy of IMFINZI in combination with neoadjuvant chemotherapy, followed by surgery and continued adjuvant treatment with IMFINZI as single agent was investigated in AEGEAN (NCT03800134), randomized, double-blind, placebo-controlled, multicenter trial conducted in 802 patients with previously untreated and resectable squamous or non-squamous NSCLC (Stage IIA to select Stage IIIB [AJCC, 8th edition]). Patients were enrolled regardless of tumor PD-L1 expression. Eligible patients had no prior exposure to immune-mediated therapy, WHO/ECOG Performance status of or 1, and at least one RECIST 1.1 target lesion.Patients with active or prior documented autoimmune disease, or use of any immunosuppressive medication within 14 days of the first dose of IMFINZI were ineligible. The population for efficacy analyses was modified intent-to-treat [mITT] which excluded patients with known EGFR mutations or ALK rearrangements. Crossover between the study arms was not permitted. Randomization was stratified by disease stage (Stage II vs. Stage III) and by PD-L1 expression (TC 1% vs. TC >= 1%) status. Patients were randomized 1:1 to one of the following treatment arms: oArm 1: Neoadjuvant IMFINZI 1,500 mg once every weeks for up to cycles in combination with:Squamous tumor histology: carboplatin AUC and paclitaxel 200 mg/m2 on Day1 of each 3-week cycle, OR cisplatin 75 mg/m2 on Day and gemcitabine 1250 mg/m2 on Day and Day of each 3-week cycle, for cycles Non-squamous tumor histology: pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on Day of each 3-week cycle, for cycles OR pemetrexed 500 mg/m2 and carboplatin AUC on Day of each 3-week cycle, for cycles. Followed by adjuvant IMFINZI 1,500 mg as single agent for up to 12 cycles post-surgery.oArm 2: Neoadjuvant placebo in combination with cycles of chemotherapy (see above) prior to surgery.oFollowed by placebo for up to 12 cycles post-surgery.All study medications were administered via intravenous infusion. In the event of unfavorable tolerability, patients who met the eligibility criteria were switched from cisplatin to carboplatin therapy at any point during the study. In patients with comorbidities or unable to tolerate cisplatin as per Investigators judgment, carboplatin AUC could be administered from cycle 1. Treatment with IMFINZI or placebo continued until completion of the treatment, disease progression that precluded definitive surgery, inability to complete definitive surgery, disease recurrence in the adjuvant phase, or unacceptable toxicity. RECIST 1.1 tumor assessment was performed at baseline, and upon completion of the neoadjuvant period (prior to surgery). Tumor assessments were conducted at weeks postoperatively, prior to the start of adjuvant therapy and every 12 weeks until week 48, every 24 weeks for approximately years, and then every 48 weeks thereafter until disease progression, consent withdrawal, or death. The trial was not designed to isolate the effect of IMFINZI in each phase (neoadjuvant or adjuvant) of treatment.The major efficacy outcome measures of the study were pathological complete response (pCR) by blinded central pathology review and event-free survival (EFS) by blinded independent central review (BICR) assessment. Additional efficacy outcome measures were major pathological response (MPR) by blinded central pathology review, DFS by BICR, and OS.The demographics and baseline disease characteristics were as follows: male (72%); median age 65 years (range: 30 to 88); age >= 65 years (52%); WHO/ECOG PS (68%), WHO/ECOG PS (32); White (54%), Asian (41%), Black or African American (0.9%), American Indian or Alaska Native (1.4%), Other Race (2.6%); Not Hispanic or Latino (84%); current or past smokers (86%); squamous histology (49%) and non-squamous histology (51%); Stage II (28%), Stage III (71%); PD-L1 expression status TC >= 1% (67%), PD-L1 expression status TC 1% (33%). In the mITT population, 78% of patients in Arm completed definitive surgery compared to 77% of patients in Arm 2. The trial demonstrated statistically significant improvements in EFS and pCR rate (see Table 28 and Figure 1) in the IMFINZI in combination with chemotherapy arm compared to the placebo in combination with chemotherapy arm.Table 28. Efficacy Results for the AEGEAN Study (mITT)IMFINZI 1,500 mg every weeks with chemotherapy/ IMFINZI(N 366)Placebo with Chemotherapy/ Placebo(N 374)EFSResults are based on planned EFS interim analysis and pCR final analysis (DCO: 10 November 2022) which occurred 46.3 months after study initiation. Number of events, (%)98 (27)138 (37) Median EFS (95% CI) (months) NR (31.9, NR)25.9 (18.9, NR) Hazard ratio (95% CI)0.68 (0.53, 0.88) 2-sided p-valueCompared to two-sided p-value boundary of 0.00989.The 2-sided p-value for pCR was calculated based on stratified CMH test. The 2-sided p-value for EFS was calculated based on based on stratified log-rank test. Stratification factors include PD-L1 and disease stage.0.0039pCR, Based on pre-specified pCR interim analysis (DCO: 14 January 2022) in = 402, the pCR rate was statistically significant (p 0.000036) compared to significance level of 0.0082%., Number of patients with response6316 pCR rate, (95% CI)17.2 (13.5, 21.5)4.3 (2.5, 6.8) p-value< 0.0001 Difference in proportions, (95% CI) Confidence interval for the difference in proportions was calculated based on stratified Miettinen and Nurminen method.13.0 (8.7, 17.6)Figure 1. Kaplan-Meier Curves of EFS in the AEGEAN StudyAt the interim analysis, the trial demonstrated statistically significant difference in MPR rate (34% vs. 14%; < 0.0001). At the time of the prespecified interim analyses, overall survival (OS) was not formally tested for statistical significance.Unresectable Stage III NSCLC PACIFICThe efficacy of IMFINZI was evaluated in the PACIFIC study (NCT02125461), multicenter, randomized, double-blind, placebo-controlled study in patients with unresectable Stage III NSCLC who completed at least cycles of concurrent platinum-based chemotherapy and definitive radiation within 42 days prior to initiation of the study drug and had WHO performance status of or 1. The study excluded patients who had progressed following concurrent chemoradiation, patients with active or prior documented autoimmune disease within years of initiation of the study or patients with medical conditions that required systemic immunosuppression. Randomization was stratified by sex, age (< 65 years vs. >= 65 years), and smoking history (smoker vs. non-smoker). Patients were randomized 2:1 to receive IMFINZI 10 mg/kg or placebo intravenously every weeks for up to 12 months or until unacceptable toxicity or confirmed RECIST v1.1-defined progression. Assessment of tumor status was performed every weeks. The major efficacy outcome measures were progression-free survival (PFS) as assessed by BICR RECIST v1.1, and overall survival (OS). Additional efficacy outcome measures included ORR and DoR assessed by BICR.A total of 713 patients were randomized: 476 patients to the IMFINZI arm and 237 to the placebo arm. The study population characteristics were: median age of 64 years (range: 23 to 90); 70% male; 69% White and 27% Asian; 16% current smokers, 75% former smokers, and 9% never smokers; 51% WHO performance status of 1; 53% with Stage IIIA and 45% were Stage IIIB; 46% with squamous and 54% with non-squamous histology. All patients received definitive radiotherapy as per protocol, of which 92% received total radiation dose of 54 Gy to 66 Gy; 99% of patients received concomitant platinum-based chemotherapy (55% cisplatin-based, 42% carboplatin-based chemotherapy, and 2% switched between cisplatin and carboplatin).At pre-specified interim analysis for OS based on 299 events (61% of total planned events), the study demonstrated statistically significant improvement in OS in patients randomized to IMFINZI compared to placebo. The pre-specified interim analysis of PFS based on 371 events (81% of total planned events) demonstrated statistically significant improvement in PFS in patients randomized to IMFINZI compared to placebo. Table 29 and Figure summarizes the efficacy results for PACIFIC.Table 29. Efficacy Results for the PACIFIC StudyEndpointIMFINZI (N 476)Among the ITT population, 7% in the IMFINZI arm and 10% in the placebo arm had non-measurable disease as assessed by BICR according to RECIST v1.1Placebo (N 237)Overall Survival (OS)OS results are based on the interim OS analysis conducted at 299 OS events which occurred 46 months after study initiation.Number of deaths183 (38%)116 (49%)Median in months (95% CI)NR(34.7, NR) 28.7(22.9, NR)Hazard Ratio (95% CI)Two-sided p-value based on log-rank test stratified by sex, age, and smoking history 0.68 (0.53, 0.87)p-value Compared with allocated of 0.00274 (Lan-DeMets spending function approximating OBrien Fleming boundary) for interim analysis 0.0025 Progression-Free Survival (PFS)As assessed by BICR RECIST v1.1PFS results are based on the interim PFS analysis conducted at 371 PFS events which occurred 33 months after study initiation. Number (%) of patients with event 214 (45%) 157 (66%) Median in months (95% CI) 16.8 (13.0, 18.1) 5.6 (4.6, 7.8) Hazard Ratio (95% CI)Pike estimator 0.52 (0.42, 0.65) p-valueCompared with allocated of 0.011035 (Lan-DeMets spending function approximating OBrien Fleming boundary) for interim analysis 0.0001Figure 2. Kaplan-Meier Curves of OS in the PACIFIC StudyMetastatic NSCLC POSEIDON The efficacy of IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy in previously untreated metastatic NSCLC patients with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations was investigated in POSEIDON, randomized, multicenter, active-controlled, open-label study (NCT03164616). Eligible patients had Eastern Cooperative Oncology Group (ECOG) Performance Status of or and must have had no prior chemotherapy or any other systemic therapy for metastatic NSCLC. Choice of platinum-based chemotherapy was at the investigators discretion, taking into consideration the calculated creatinine clearance. Patients with active and/or untreated brain metastases; history of active primary immunodeficiency; autoimmune disorders including active or prior documented autoimmune or inflammatory disorders; use of systemic immunosuppressants within 14 days before the first dose of the treatment except physiological dose of systemic corticosteroids were ineligible.Randomization was stratified by tumor cells (TC) PD-L1 expression (TC >= 50% vs. TC 50%), disease stage (Stage IVA vs. Stage IVB), and histology (non-squamous vs. squamous).Patients were randomized 1:1:1 to receive IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy according to the regimens listed below, IMFINZI and platinum-based chemotherapy (an unapproved regimen for metastatic NSCLC), or platinum-based chemotherapy. The evaluation of efficacy for metastatic NSCLC relied on comparison between:oIMFINZI 1,500 mg with tremelimumab-actl 75 mg (or mg/kg for patients 30 kg) and platinum-based chemotherapy every weeks for cycles, followed by IMFINZI 1,500 mg every weeks as single agent. fifth dose of tremelimumab-actl 75 mg (or mg/kg for patients 30 kg) was given at Week 16 in combination with IMFINZI dose 6.oPlatinum-based chemotherapy every weeks as monotherapy for cycles. Patients could receive an additional cycles (a total of cycles post-randomization), as clinically indicated, at investigators discretion.Patients received IMFINZI in combination with tremelimumab-actl with one of the following platinum-based chemotherapy regimens: oNon-squamous NSCLCPemetrexed 500 mg/m2 with carboplatin AUC 5-6 or cisplatin 75 mg/m2 every weeks for cycles. oSquamous NSCLCGemcitabine 1,000 or 1,250 mg/m2 on Days and with cisplatin 75 mg/m2 or carboplatin AUC 5-6 on Day every weeks for cycles.oNon-squamous and Squamous NSCLCNab-paclitaxel 100 mg/m2 on Days 1, 8, and 15 with carboplatin AUC 5-6 on Day every weeks for cycles.Tremelimumab-actl was given up to maximum of doses. IMFINZI and histology-based pemetrexed continued every weeks until disease progression or unacceptable toxicity. Administration of IMFINZI monotherapy was permitted beyond disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Patients with disease progression during IMFINZI monotherapy were given the option to be retreated with additional cycles of tremelimumab-actl in combination with IMFINZI. Tumor assessments were performed at Week 6, Week 12, and then every weeks thereafter.The major efficacy outcome measures were progression free survival (PFS) and overall survival (OS) of IMFINZI and tremelimumab-actl in combination with platinum-based chemotherapy compared to platinum-based chemotherapy alone. Additional efficacy outcome measures were overall response rate (ORR) and duration of response (DoR). PFS, ORR, and DoR were assessed using Blinded Independent Central Review (BICR) according to RECIST v1.1. total of 675 patients were randomized to receive either IMFINZI with tremelimumab-actl and platinum-based-chemotherapy (n 338) or platinum-based chemotherapy (n 337). The median age was 63 years (range: 27 to 87), 46% of patients age >= 65 years, 77% male, 57% White, 34% Asian, 0.3% Native Hawaiian or Other Pacific Islander, 3% American Indian or Alaska Native, 2% Black or African American, 4% Other Race, 79% former or current smoker, 34% ECOG PS 0, and 66% ECOG PS 1. Thirty-six percent had squamous histology, 63% non-squamous histology, 29% PD-L1 expression TC >= 50%, 71% PD-L1 expression TC 50%.Efficacy results are summarized in Table 30 and Figure 3.Table 30. Efficacy Results for the POSEIDON StudyIMFINZI with tremelimumab-actl and platinum-based chemotherapy (N 338) Platinum-based chemotherapy (N 337) OSPFS/OS results are based on planned analyses which occurred 25/45 months respectively after study initiation. Number of deaths (%) 251 (74)285 (85) Median OS (months) (95% CI) 14.0(11.7, 16.1)11.7(10.5, 13.1) HR (95% CI) 0.77 (0.65, 0.92) p-value2-sided p-values based on log-rank tests stratified by PD-L1, histology and disease stage and compared to boundary value of 0.00735 for PFS and 0.00797 for OS 0.00304PFS Number of events (%) 238 (70)258 (77) Median PFS (months) (95% CI) 6.2(5.0, 6.5)4.8(4.6, 5.8) HR (95% CI) 0.72 (0.60, 0.86) p-value0.00031ORR (95% CI)Confirmed responses with 95% Clopper-Pearson confidence interval. 39 (34, 44)24 (20, 29)Median DoR (months) (95% CI) 9.5(7.2, NR)5.1(4.4, 6.0)NR=Not Reached, CI=Confidence IntervalFigure 3. Kaplan-Meier Curves of OS in the POSEIDON Study. oArm 1: Neoadjuvant IMFINZI 1,500 mg once every weeks for up to cycles in combination with:. oArm 2: Neoadjuvant placebo in combination with cycles of chemotherapy (see above) prior to surgery.. oFollowed by placebo for up to 12 cycles post-surgery.. Number of events, (%). Median EFS (95% CI) (months) Hazard ratio (95% CI). 2-sided p-valueCompared to two-sided p-value boundary of 0.00989.The 2-sided p-value for pCR was calculated based on stratified CMH test. The 2-sided p-value for EFS was calculated based on based on stratified log-rank test. Stratification factors include PD-L1 and disease stage.. Number of patients with response. pCR rate, (95% CI). p-value. Difference in proportions, (95% CI) Confidence interval for the difference in proportions was calculated based on stratified Miettinen and Nurminen method.. Progression-Free Survival (PFS)As assessed by BICR RECIST v1.1PFS results are based on the interim PFS analysis conducted at 371 PFS events which occurred 33 months after study initiation.. Number (%) of patients with event. 214 (45%). 157 (66%). Median in months (95% CI). 16.8 (13.0, 18.1). 5.6 (4.6, 7.8). Hazard Ratio (95% CI)Pike estimator. 0.52 (0.42, 0.65). p-valueCompared with allocated of 0.011035 (Lan-DeMets spending function approximating OBrien Fleming boundary) for interim analysis. 0.0001. oIMFINZI 1,500 mg with tremelimumab-actl 75 mg (or mg/kg for patients 30 kg) and platinum-based chemotherapy every weeks for cycles, followed by IMFINZI 1,500 mg every weeks as single agent. fifth dose of tremelimumab-actl 75 mg (or mg/kg for patients 30 kg) was given at Week 16 in combination with IMFINZI dose 6.. oPlatinum-based chemotherapy every weeks as monotherapy for cycles. Patients could receive an additional cycles (a total of cycles post-randomization), as clinically indicated, at investigators discretion.. oNon-squamous NSCLCPemetrexed 500 mg/m2 with carboplatin AUC 5-6 or cisplatin 75 mg/m2 every weeks for cycles. Pemetrexed 500 mg/m2 with carboplatin AUC 5-6 or cisplatin 75 mg/m2 every weeks for cycles. oSquamous NSCLCGemcitabine 1,000 or 1,250 mg/m2 on Days and with cisplatin 75 mg/m2 or carboplatin AUC 5-6 on Day every weeks for cycles.. Gemcitabine 1,000 or 1,250 mg/m2 on Days and with cisplatin 75 mg/m2 or carboplatin AUC 5-6 on Day every weeks for cycles.. oNon-squamous and Squamous NSCLCNab-paclitaxel 100 mg/m2 on Days 1, 8, and 15 with carboplatin AUC 5-6 on Day every weeks for cycles.. Nab-paclitaxel 100 mg/m2 on Days 1, 8, and 15 with carboplatin AUC 5-6 on Day every weeks for cycles.. Number of deaths (%) Median OS (months) (95% CI) HR (95% CI) p-value2-sided p-values based on log-rank tests stratified by PD-L1, histology and disease stage and compared to boundary value of 0.00735 for PFS and 0.00797 for OS Number of events (%) Median PFS (months) (95% CI) HR (95% CI) p-value. (95% CI) figure1. figure2. figure3. 14.2 Small Cell Lung Cancer (SCLC) Limited-stage SCLC ADRIATICThe efficacy of IMFINZI was evaluated in the ADRIATIC Study (NCT03703297), randomized, double-blind, placebo-controlled, multicenter study in 730 patients with histologically or cytologically confirmed LS-SCLC (Stage to III according to AJCC, 8th edition) whose disease had not progressed following concurrent chemoradiation therapy (cCRT). Patients who had Stage or II disease had to be medically inoperable as determined by the investigator. Eligible patients completed cCRT consisting of cycles of platinum-based chemotherapy and either 60-66 Gy once daily over weeks or 45 Gy twice daily over weeks radiation therapy within 42 days prior to the first dose of IMFINZI or placebo. Prophylactic cranial irradiation (PCI) could be delivered at the discretion of the investigator after cCRT and had to be completed within 42 days prior to the first dose of IMFINZI or placebo. Patients with active or prior documented autoimmune disease within years of initiation into the study; history of active primary immunodeficiency; history of Grade >= pneumonitis or active tuberculosis or hepatitis or or HIV infection; active interstitial lung disease were ineligible. Patients with mixed SCLC and NSCLC histology were also ineligible. Randomization was stratified by stage (I/II versus III) and receipt of PCI (yes versus no).Patients were randomized 1:1:1 to receive IMFINZI as single agent, IMFINZI in combination with another agent, or placebo. All study medications were administered intravenously. The evaluation of efficacy for LS-SCLC relied on comparison between:oArm 1: IMFINZI 1,500 mg in combination with placebo every weeks for cycles, followed by IMFINZI 1,500 mg every weeks. oArm 2: Placebo in combination with second placebo every weeks for cycles, followed by single placebo every weeks.A total of 530 patients were randomized between Arms and 2, 264 patients to the IMFINZI arm and 266 patients to the placebo arm. Treatment continued until disease progression, until unacceptable toxicity, or for maximum of 24 months. Tumor assessments were conducted every weeks for the first 72 weeks, then every 12 weeks up to 96 weeks and then every 24 weeks thereafter. The major efficacy outcome measures were OS and PFS assessed by BICR according to RECIST v1.1.The baseline demographics and disease characteristics for patients in the IMFINZI and placebo arms were as follows: male (69%); age >= 65 years (39%); White (50%), Black or African-American (0.8%), Asian (48%), other race (1.3%); Hispanic or Latino (4.2%); current smoker (22%), past-smoker (68%), never smoker (9%); WHO/ECOG PS (49%), WHO/ECOG PS (51%); and Stage (3.6%), Stage II (9%), Stage III (87%).Prior to randomization, all patients received platinum-based chemotherapy (66% cisplatin-etoposide, 34% carboplatin-etoposide) with 88% of patients receiving cycles; 72% of patients received once daily radiation (of which 92% received >= 60 <= 66 Gy QD); 28% received twice daily radiation (of which 97% received 45 Gy twice daily) and 54% of patients received PCI.Efficacy results are presented in Table 31 and Figure 4.Table 31. Efficacy Results for the ADRIATIC StudyIMFINZI(N=264)Placebo(N=266)OSNumber of deaths (%)115 (44)146 (55)Median OS (months) (95% CI)Calculated using the Kaplan Meier technique. CI for median derived based on Brookmeyer-Crowley method. 55.9 (37.3, NR)33.4 (25.5, 39.9)HR (95% CI)Based on Cox proportional hazards model stratified by receipt of PCI. 0.73 (0.57, 0.93)p-valueCompared with allocated alpha of 0.0168 for OS and 0.0280 for PFS (Lan-DeMets spending function approximating OBrien Fleming boundary) for interim analysis. 0.0104PFSAssessed by BICR according to RECIST v1.1.Number of events (%)139 (53)169 (64)Median PFS (months) (95% CI) 16.6 (10.2, 28.2)9.2 (7.4, 12.9)HR (95% CI)Based on Cox proportional hazards model stratified by TNM stage and receipt of PCI. 0.76 (0.61, 0.95)p-value 0.0161Figure 4. Kaplan-Meier Curves of OS in the ADRIATIC StudyExtensive-stage SCLC CASPIANThe efficacy of IMFINZI in combination with etoposide and either carboplatin or cisplatin in previously untreated ES-SCLC was investigated in CASPIAN, randomized, multicenter, active-controlled, open-label study (NCT03043872). Eligible patients had WHO Performance Status of or and were suitable to receive platinum-based chemotherapy regimen as first-line treatment for SCLC. Patients with asymptomatic or treated brain metastases were eligible. Choice of platinum agent was at the investigators discretion, taking into consideration the calculated creatinine clearance. Patients with history of chest radiation therapy; history of active primary immunodeficiency; autoimmune disorders including paraneoplastic syndrome; active or prior documented autoimmune or inflammatory disorders; use of systemic immunosuppressants within 14 days before the first dose of the treatment except physiological dose of systemic corticosteroids were ineligible.Randomization was stratified by the planned platinum-based therapy in cycle (carboplatin or cisplatin). The evaluation of efficacy for ES-SCLC relied on comparison between:IMFINZI 1,500 mg, and investigators choice of carboplatin (AUC or mg/mL/min) or cisplatin (75-80 mg/m2) on Day and etoposide (80-100 mg/m2) intravenously on Days 1, 2, and of each 21-day cycle for cycles, followed by IMFINZI 1,500 mg every weeks until disease progression or unacceptable toxicity, or Investigators choice of carboplatin (AUC or mg/mL/min) or cisplatin (75-80 mg/m2) on Day and etoposide (80-100 mg/m2) intravenously on Days 1, 2, and of each 21-day cycle, up to cycles. After completion of chemotherapy, PCI as administered per investigator discretion.Administration of IMFINZI as single agent was permitted beyond disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator.The major efficacy outcome measure was overall survival (OS) of IMFINZI plus chemotherapy vs. chemotherapy alone. Additional efficacy outcome measures were investigator-assessed progression-free survival (PFS) and objective response rate (ORR), per RECIST v1.1.The study population characteristics were: median age of 63 years (range: 28 to 82); 40% age 65 or older; 70% male; 84% White, 15% Asian, and 0.9% Black; 65% WHO/ECOG PS of 1; and 93% were former/current smokers. Ninety percent of patients had Stage IV disease and 10% had brain metastasis at baseline. total of 25% of the patients received cisplatin and 74% of the patients received carboplatin. In the chemotherapy alone arm, 57% of the patients received cycles of chemotherapy, and 8% of the patients received PCI.The OS results are summarized in Table 32 and Figure 5.Table 32. OS Results for the CASPIAN StudyEndpointIMFINZI with Etoposide and either Carboplatin or Cisplatin(N 268)Etoposide and either Carboplatin or Cisplatin(N 269)Overall Survival (OS)Number of deaths (%)At pre-specified interim analysis, 336 OS events (79% of total planned events) were observed, and the boundary for declaring efficacy (0.0178) was determined by Lan-Demets alpha spending function with OBrien Fleming type boundary 155 (58)181 (67)Median OS (months) (95% CI)13.0 (11.5, 14.8)10.3 (9.3, 11.2)Hazard Ratio (95% CI)The analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle (carboplatin or cisplatin) and using the rank tests of association approach. 0.73 (0.59, 0.91)p-value 0.0047Figure 5. Kaplan-Meier Curves of OS in the CASPIAN StudyInvestigator-assessed PFS (96% of total planned events) showed HR of 0.78 (95% CI: 0.65, 0.94), with median PFS of 5.1 months (95% CI: 4.7, 6.2) in the IMFINZI plus chemotherapy arm and 5.4 months (95% CI: 4.8, 6.2) in the chemotherapy alone arm. The investigator-assessed confirmed ORR was 68% (95% CI: 62%, 73%) in the IMFINZI plus chemotherapy arm and 58% (95% CI: 52%, 63%) in the chemotherapy alone arm.In the exploratory subgroup analyses of OS based on the planned platinum chemotherapy received at cycle 1, the HR was 0.70 (95% CI 0.55, 0.89) in patients who received carboplatin, and the HR was 0.88 (95% CI 0.55, 1.41) in patients who received cisplatin.. oArm 1: IMFINZI 1,500 mg in combination with placebo every weeks for cycles, followed by IMFINZI 1,500 mg every weeks. oArm 2: Placebo in combination with second placebo every weeks for cycles, followed by single placebo every weeks.. Figure4. figure4. 14.3 Biliary Tract Cancer (BTC) Locally Advanced or Metastatic BTC TOPAZ-1The efficacy of IMFINZI in combination with gemcitabine and cisplatin in patients with locally advanced or metastatic BTC was investigated in TOPAZ-1 (NCT03875235), randomized, double-blind, placebo-controlled, multicenter study that enrolled 685 patients with histologically confirmed locally advanced unresectable or metastatic BTC who have not previously received systemic therapy. Patients with recurrent disease 6 months after surgery and/or completion of adjuvant therapy were eligible. Patients had an ECOG Performance status of and and at least one target lesion by RECIST v1.1. Patients with ampullary carcinoma; active or prior documented autoimmune or inflammatory disorders; HIV infection or active infections, including tuberculosis or hepatitis C; current or prior use of immunosuppressive medication within 14 days before the first dose of IMFINZI were ineligible.Randomization was stratified by disease status (recurrent vs. initially unresectable) and primary tumor location (intrahepatic cholangiocarcinoma [ICCA] vs. extrahepatic cholangiocarcinoma [ECCA] vs. gallbladder cancer [GBC]). Patients were randomized 1:1 to receive:oIMFINZI 1,500 mg on Day 1+ gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on Days and of each 21-day cycle up to cycles, followed by IMFINZI 1,500 mg every weeks, oroPlacebo on Day 1+ gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on Days and of each 21-day cycle up to cycles, followed by placebo every weeks.Treatment with IMFINZI or placebo continued until disease progression, or unacceptable toxicity. Treatment beyond disease progression was permitted if the patient was clinically stable and deriving clinical benefit as determined by the investigator.The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures were investigator-assessed progression-free survival (PFS), objective response rate (ORR) and duration of response (DoR). Tumor assessments were conducted every weeks for the first 24 weeks after the date of randomization, and then every weeks until confirmed objective disease progression.The study population characteristics were: 50% male, median age of 64 years (range 20-85), 47% age 65 or older; 56% Asian, 37% White, 2% Black or African American, 0.1% American Indian or Alaskan Native, and 4% other; 51% had an ECOG PS of 1; primary tumor location was ICCA 56%, ECCA 18% and GBC 25%; 20% of patients had recurrent disease; 86% of patients had metastatic and 14% had locally advanced disease. At pre-specified interim analysis, the study demonstrated statistically significant improvement in OS and PFS in patients randomized to IMFINZI in combination with chemotherapy compared to placebo in combination with chemotherapy. Table 33 summarizes the efficacy results for TOPAZ-1.Table 33. Efficacy Results for the TOPAZ-1 StudyEndpointIMFINZI with Gemcitabine and Cisplatin(N 341)Placebo with Gemcitabine and Cisplatin(N 344)Overall Survival (OS) Number of deaths (%)198 (58)226 (66) Median OS (months) (95% CI)Kaplan-Meier estimated median with 95% CI derived using Brookmeyer-Crowley method12.8(11.1, 14)11.5(10.1, 12.5) Hazard Ratio (95% CI)Based on Cox proportional hazards model stratified by disease status and primary tumor location0.80 (0.66, 0.97) p-value2-sided p-value based on stratified log-rank test compared with alpha boundary of 0.0300.021Progression-Free Survival (PFS) Number of patients with event (%)276 (81)297 (86) Median in months (95% CI)7.2(6.7, 7.4)5.7(5.6, 6.7) Hazard Ratio (95% CI)0.75 (0.63, 0.89) p-value2-sided p-value based on stratified log-rank test compared with alpha boundary of 0.0480.001The investigator-assessed ORR was 27% (95% CI: 22% 32%) in the IMFINZI plus chemotherapy arm and 19% (95% CI: 15%-23%) in the chemotherapy alone arm.Figure 6. Kaplan-Meier Curves of OS in the TOPAZ-1 Study. oIMFINZI 1,500 mg on Day 1+ gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on Days and of each 21-day cycle up to cycles, followed by IMFINZI 1,500 mg every weeks, or. oPlacebo on Day 1+ gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on Days and of each 21-day cycle up to cycles, followed by placebo every weeks.. Number of deaths (%). Median OS (months) (95% CI)Kaplan-Meier estimated median with 95% CI derived using Brookmeyer-Crowley method. Hazard Ratio (95% CI)Based on Cox proportional hazards model stratified by disease status and primary tumor location. p-value2-sided p-value based on stratified log-rank test compared with alpha boundary of 0.030. Number of patients with event (%). Median in months (95% CI). Hazard Ratio (95% CI). p-value2-sided p-value based on stratified log-rank test compared with alpha boundary of 0.048. figure5. 14.4 Hepatocellular Carcinoma (HCC) Unresectable HCC HIMALAYAThe efficacy of IMFINZI in combination with tremelimumab-actl was evaluated in the HIMALAYA study (NCT03298451), randomized (1:1:1), open-label, multicenter study in patients with confirmed uHCC who had not received prior systemic treatment for HCC. Patients were randomized to one of two investigational arms (IMFINZI plus tremelimumab-actl or IMFINZI) or sorafenib. Study treatment consisted of IMFINZI 1,500 mg in combination with tremelimumab-actl as one-time single intravenous infusion of 300 mg on the same day, followed by IMFINZI every weeks; IMFINZI 1,500 mg every weeks; or sorafenib 400 mg given orally twice daily, until disease progression or unacceptable toxicity. The efficacy assessment of IMFINZI is based on patients randomized to the IMFINZI plus tremelimumab-actl arm versus the sorafenib arm. Randomization was stratified by macrovascular invasion (MVI) (yes or no), etiology of liver disease (hepatitis virus vs. hepatitis virus vs. others) and ECOG performance status (0 vs. 1).The study enrolled patients with BCLC Stage or (not eligible for locoregional therapy). The study excluded patients with co-infection of viral hepatitis and hepatitis C; active or prior documented gastrointestinal (GI) bleeding within 12 months; ascites requiring non-pharmacologic intervention within months; hepatic encephalopathy within 12 months before the start of treatment; active or prior documented autoimmune or inflammatory disorders. Esophagogastroduodenoscopy was not mandated prior to enrollment but adequate endoscopic therapy, according to institutional standards, was required for patients with history of esophageal variceal bleeding or those assessed as high risk for esophageal variceal bleeding by the treating physician. Study treatment was permitted beyond disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator.The major efficacy outcome measure was overall survival (OS) between the IMFINZI plus tremelimumab-actl arm versus the sorafenib arm. Additional efficacy outcomes were investigator-assessed progression-free survival (PFS), objective response rate (ORR) and duration of response (DoR) according to RECIST v1.1. Tumor assessments were conducted every weeks for the first 12 months and then every 12 weeks thereafter.The baseline demographics of the IMFINZI plus tremelimumab-actl and sorafenib arms were as follows: male (85%), age 65 years (50%), median age of 65 years (range: 18 to 88 years), White (46%), Asian (49%), Black or African American (2%), Native Hawaiian or other Pacific Islander (0.1%), race Unknown (2%), Hispanic or Latino (5%), Not Hispanic or Latino (94%), ethnicity Unknown (1%), ECOG PS (62%); Child-Pugh Class score (99%), macrovascular invasion (26%), extrahepatic spread (53%), viral etiology; hepatitis (31%), hepatitis (27%), and uninfected (42%).Efficacy results are presented in Table 34 and Figure 7.Table 34. Efficacy Results for the HIMALAYA StudyEndpointIMFINZI and Tremelimumab-actl(N 393)Sorafenib(N 389)OSNumber of deaths (%)262 (66.7)293 (75.3)Median OS (months)(95% CI)16.4(14.2, 19.6)13.8(12.3, 16.1)HR (95% CI)HR (IMFINZI and tremelimumab-actl vs. sorafenib) based on the stratified Cox proportional hazard model. 0.78 (0.66, 0.92)p-valueBased on stratified log-rank test. Based on Lan-DeMets alpha spending function with OBrien Fleming type boundary and the actual number of events observed, the boundary for declaring statistical significance for IMFINZI and tremelimumab-actl vs. sorafenib was 0.0398 (Lan and DeMets 1983). 0.0035PFSNumber of events (%)335 (85.2)327 (84.1)Median in (months) (95% CI)3.8(3.7, 5.3)4.1(3.7, 5.5)HR (95% CI) 0.90 (0.77, 1.05)ORRORR (95% CI)Confirmed complete response or partial response. Based on Clopper-Pearson method. 20.1 (16.3, 24.4)5.1 (3.2, 7.8)Complete Response (%)12 (3.1)0Partial Response (%)67 (17.0)20 (5.1)DoRMedian DoR (months) (95% CI)22.3 (13.7, NR)18.4 (6.5, 26.0)% with duration >= months82.378.9% with duration >= 12 months65.863.2CI=Confidence Interval, HR=Hazard Ratio, NR=Not ReachedFigure 7. Kaplan-Meier Curves of OS in the Himalaya Study. figure6. 14.5 Endometrial cancer Advanced or Recurrent dMMR Endometrial Cancer DUO-EIMFINZI was evaluated in combination with carboplatin and paclitaxel in DUO-E (NCT04269200), randomized, multicenter, double-blind, placebo-controlled study in patients with advanced or recurrent endometrial cancer. The trial enrolled patients with newly diagnosed Stage III disease (with measurable disease per RECIST v1.1), or newly diagnosed Stage IV disease. The trial also enrolled patients with recurrent disease with low potential for cure by radiation therapy or surgery. For patients with recurrent disease, prior chemotherapy was allowed only if it was administered in the adjuvant setting and at least 12 months had elapsed from the date of last dose of chemotherapy to the date of relapse. The trial included patients with epithelial endometrial carcinomas of all histologies, including carcinosarcomas. Patients with endometrial sarcoma were excluded, and patients who had active autoimmune disease or medical condition that required immunosuppression were ineligible.Randomization was stratified by tumor mismatch repair (MMR) status (proficient or deficient), disease status (recurrent or newly diagnosed), and geographic region (Asia or rest of the world). MMR status was assessed using an FDA-authorized test.Patients were randomized (1:1:1) to one of the following treatment arms:oIMFINZI 1,120 mg in combination with carboplatin and paclitaxel every weeks for maximum of cycles. Following completion of chemotherapy treatment, patients received IMFINZI 1,500 mg every weeks as maintenance treatment until disease progression.oPlacebo in combination with carboplatin and paclitaxel every weeks for maximum of cycles. Following completion of chemotherapy treatment, patients received placebo every weeks as maintenance treatment until disease progression.oAn additional investigational combination regimen. Treatment was continued until Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression of disease or unacceptable toxicity. Assessment of tumor status was performed every weeks for the first 18 weeks and every 12 weeks thereafter.The major efficacy outcome measure was progression-free survival (PFS), determined by investigator assessment using RECIST 1.1. Additional efficacy outcome measures included overall response rate (ORR), duration of response (DOR) and overall survival (OS).Among 95 patients with dMMR tumor, the baseline characteristics were median age of 63 years (range: 34 to 85); 47% age 65 or older; 62% White, 31% Asian, 2% Black or African American; 7% Hispanic or Latino, 1% American Indian or Alaska Native, and 4% other or not reported; ECOG PS of (55%) or (45%); 48% newly diagnosed (11% Stage III and 38% Stage IV) and 52% recurrent disease. The histologic subtypes were endometrioid (78%), mixed epithelial (6%), carcinosarcoma (5%), serous (4%), undifferentiated (1%), and other (5%).While statistically significant improvement in PFS was observed in the overall population for IMFINZI with carboplatin and paclitaxel compared to carboplatin and paclitaxel alone, based on an exploratory analysis by MMR status, the PFS improvement in the overall population was primarily attributed to patients with dMMR tumors.Efficacy results for DUO-E are summarized in Table 33 and Figure for patients with dMMR tumors. OS data in this subpopulation at the time of PFS analysis were immature with 26% of patients who died.Table 35. Efficacy Results for Patients with dMMR Tumors in the DUO-E StudyEndpointIMFINZI with Carboplatin and PaclitaxelN=46Carboplatin and PaclitaxelN=49 PFSInvestigator assessed. Number of events (%)15 (32.6)25 (51.0) Median in months (95% CI)Calculated using the Kaplan-Meier technique.NR (NR, NR)7.0 (6.7, 14.8) HR (95% CI)0.42 (0.22, 0.80) ORRN=42N=42 ORR (95% CI)71.4(55.4, 84.3)40.5(25.6, 56.7) Complete response %12 (28.6)4 (9.5) Partial response18 (42.9)13 (31.0) DOR Median in months (range)NR(2.4+, 26.9+)10.5(2.1+, 25.2+)CI=Confidence Interval, HR=Hazard Ratio, NR=Not Reached, = response ongoing at last assessment.Figure 8. Kaplan-Meier curves of PFS for Patients with dMMR Tumors in the DUO-E Study. oIMFINZI 1,120 mg in combination with carboplatin and paclitaxel every weeks for maximum of cycles. Following completion of chemotherapy treatment, patients received IMFINZI 1,500 mg every weeks as maintenance treatment until disease progression.. oPlacebo in combination with carboplatin and paclitaxel every weeks for maximum of cycles. Following completion of chemotherapy treatment, patients received placebo every weeks as maintenance treatment until disease progression.. oAn additional investigational combination regimen. Number of events (%). Median in months (95% CI)Calculated using the Kaplan-Meier technique.. HR (95% CI). ORR (95% CI). Complete response %. Partial response. figure7. 14.6 Bladder Cancer BCG Naive High-Risk Non-Muscle-Invasive Bladder Cancer (NMIBC) POTOMAC StudyThe efficacy of IMFINZI in combination with intravesical BCG induction and maintenance treatment was evaluated in the POTOMAC study (NCT03528694). POTOMAC was randomized, open-label, multicenter study in 1,018 patients with high-risk NMIBC following transurethral resection of bladder tumor. High-risk NMIBC was defined as having one of the following: T1 tumor, Grade 3/high-grade tumor, carcinoma in situ (CIS), or multiple and recurrent and large tumors. Patients had disease that was BCG-naive, defined as no prior receipt of intravesical BCG or prior receipt of intravesical BCG 3 years before study entry. Patients were randomized 1:1:1 to receive:oIMFINZI: 1500 mg (patients >= 30 kg) or 20 mg/kg (patients <30 kg) every weeks for 13 cycles plus BCG Induction and Maintenance (N 339) oBCG Induction and Maintenance (N 340)oAn additional investigational combination regimen (N= 339)Randomization was stratified by the presence of CIS and by the presence of papillary disease with the following characteristics: Grade 3/high-grade T1, or multiple and recurrent and large (with diameter of largest tumor >= cm) tumors. Tumor status was assessed every months from the date of randomization until 36 months, and then every months thereafter. Patients with CIS were discontinued from treatment if they did not have complete response after re-induction.The major efficacy outcome was investigator-assessed disease-free survival (DFS) for IMFINZI in combination with BCG induction and maintenance treatment compared to BCG induction and maintenance treatment alone. DFS was defined as the time from the date of randomization until the date of first recurrence of high-risk NMIBC, persistent CIS, MIBC and/or metastatic disease, or death. The study demographics were median age of 67 years (range: 24 to 90), 81% male, 79% White, 18% Asian, 0.1% Black or African American, 1.6% other race, 1.6% unknown race, 4.0% patients were of Hispanic or Latino ethnicity; 96% non-Hispanic or Latino ethnicity; 9% of patients had CIS only, 64% papillary tumor only, 27% CIS and papillary tumor, 28% recurrent NMIBC, 31% tumor stage Ta, 60% tumor stage T1 and 46% papillary tumor Grade 3. Per American Urological Association (AUA) NMIBC risk classification, 81% of patients had high-risk disease, 16% had intermediate-risk disease, and 3.7% had risk-undetermined disease. Twenty-four percent of patients received TICE BCG and 76% received other BCG products.The study demonstrated statistically significant improvement in DFS for IMFINZI in combination with BCG induction and maintenance treatment compared to BCG induction and maintenance treatment alone. Table 36 and Figure summarize the efficacy results for POTOMAC.Table 36. Efficacy Results for the POTOMAC StudyEndpointIMFINZI BCG(N 339) BCG(N 340) DFS Numbere of events %67 (20)98 (29) Recurrence of high-risk 36 (11)52 (15) Persistent CIS1 (0.3)2 (0.6) MIBC and/or metastatic disease16 (4.7)15 (4.4) Death14 (4.1)29 (9) Median DFS (months) (95% CI)NR (NR, NR)NR (74.0, NR) HR (95% CI)Based on stratified Cox proportional hazard model. 0.68 (0.50, 0.93) 2-sided p-valueBased on stratified log-rank test, as compared to an allocated alpha of 0.0317. 0.0154CI Confidence interval; HR Hazard ratio; NR Not reached.Figure 9. Kaplan-Meier Curves of DFS in the POTOMAC StudyMuscle-invasive bladder cancer (MIBC) NIAGARA Study The efficacy of neoadjuvant IMFINZI in combination with gemcitabine and cisplatin followed by adjuvant IMFINZI as single agent in patients with MIBC was evaluated in NIAGARA (NCT03732677), randomized, open-label, multicenter study. The study randomized (1:1) 1,063 patients who were candidates for radical cystectomy and who had not received prior systemic chemotherapy or immune-mediated therapy for the treatment of NMIBC or MIBC. The study excluded patients with pure non-urothelial histology, any small cell histology and primary non-bladder (i.e., ureter, urethral, or renal pelvis) cancer of the urothelium.Randomization was stratified by clinical tumor stage T2N0 vs. T2N0 (including T2N1, T3, and T4a), renal function (creatinine clearance [CrCl] >= 60 mL/min vs. CrCl >= 40 mL/min to 60 mL/min), and PD-L1 expression (high vs. low/negative). Patients received:oNeoadjuvant IMFINZI 1,500 mg plus gemcitabine 1,000 mg/m2 and cisplatin 70 mg/m2 every weeks for cycles prior to surgery, followed by IMFINZI 1,500 mg every weeks as single agent adjuvant treatment for up to cycles after surgery, oroNeoadjuvant gemcitabine 1,000 mg/m2 and cisplatin 70 mg/m2 every weeks for cycles prior to surgery, without adjuvant treatment.Patients with CrCl >= 40 mL/min to 60 mL/min in both arms received split-dose cisplatin of 35 mg/m2 on days and of each cycle. RECIST 1.1 tumor assessment was performed at baseline and upon completion of neoadjuvant therapy (prior to surgery). After surgery, tumor assessments were performed every 12 weeks for the first 24 months, then every 24 weeks for 36 months, and then every 52 weeks thereafter until progression, the end of study, or death.The major efficacy outcome measure was EFS by BICR assessment. OS was an additional efficacy outcome measure. Baseline demographics were: male (82%), median age 65 years (range: 32 to 84), age >=65 years (53%), White (67%), Asian (28%), Black or African American (0.9%), other (0.8%), Hispanic or Latino (8%), and ECOG PS (78%) vs. PS (22%). Disease characteristics were: tumor stage T2N0 (40%) and >T2N0 (60%), regional lymph nodes N0 (95%) and N1 (5%), adequate renal function (81%) and borderline renal function (19%). The histologic subtypes included urothelial carcinoma (85%) and urothelial carcinoma with variant histology (15%). In the overall population, 469 (88%) patients in the IMFINZI plus gemcitabine and cisplatin arm and 441 (83%) patients in the gemcitabine and cisplatin arm underwent radical cystectomy.At pre-specified interim analysis, the study demonstrated statistically significant improvement in EFS and OS in the IMFINZI plus gemcitabine and cisplatin arm compared to the gemcitabine and cisplatin arm. The trial was not designed to isolate the effect of IMFINZI in each phase (neoadjuvant or adjuvant) of treatment. See Table 37 and Figures 10 and 11.Table 37. Efficacy Results for the NIAGARA StudyIMFINZI plus gemcitabine and cisplatin(N=533)Gemcitabine and cisplatin(N 530)EFSEFS is defined as the time from randomization to the first recurrence of disease after radical cystectomy, the time of first documented progression in patients who are medically precluded from radical cystectomy, or time of expected surgery in patients who refuse to undergo radical cystectomy or failure to undergo radical cystectomy in participants with residual disease, or the time of death due to any cause, whichever occurs first. Number of events (%)187. (35.1)246 (46.4) Median EFS (months) (95% CI)NR (NR, NR)46.1 (32.2, NR) HR (95% CI)Based on stratified Cox proportional hazard model. 0.68 (0.56, 0.82) 2-sided p-valueBased on stratified log-rank test. Alpha allocated at the interim analysis was 0.0412 for EFS and 0.0154 for OS. <0.0001Overall Survival (OS) Number of events (%)136.(25.5)169 (31.9 Median OS (months) (95% CI)NR (NR, NR)NR (NR, NR) HR (95% CI) 0.75 (0.59, 0.93) 2-sided p-value 0.0106CI Confidence Interval, HR Hazard Ratio, NR Not ReachedFigure 10. Kaplan-Meier Curve of EFSFigure 11. Kaplan-Meier Curve of OS. oIMFINZI: 1500 mg (patients >= 30 kg) or 20 mg/kg (patients <30 kg) every weeks for 13 cycles plus BCG Induction and Maintenance (N 339) oBCG Induction and Maintenance (N 340). oAn additional investigational combination regimen (N= 339). oNeoadjuvant IMFINZI 1,500 mg plus gemcitabine 1,000 mg/m2 and cisplatin 70 mg/m2 every weeks for cycles prior to surgery, followed by IMFINZI 1,500 mg every weeks as single agent adjuvant treatment for up to cycles after surgery, or. oNeoadjuvant gemcitabine 1,000 mg/m2 and cisplatin 70 mg/m2 every weeks for cycles prior to surgery, without adjuvant treatment.. figure9. Figure9. Figure10. 14.7 Gastric or gastroesophageal junction adenocarcinoma (GC/GEJC) Neoadjuvant and Adjuvant Treatment of Resectable GC/GEJC MATTERHORN StudyThe efficacy of IMFINZI with FLOT as neoadjuvant and adjuvant treatment, followed by IMFINZI as single agent, was investigated in MATTERHORN (NCT04592913), randomized, double-blind, placebo-controlled, multicenter study conducted in 948 patients with previously untreated and resectable GC/GEJC (Stage II to Stage IVA [AJCC, 8th edition]). Eligible patients had no prior exposure to immune-mediated therapy and WHO/ECOG performance status of or 1. Patients with active or prior documented autoimmune or inflammatory disorders, or use of immunosuppressive medication within 14 days of the first dose of durvalumab were ineligible.Randomization was stratified by geographic region (Asia vs. non-Asia), clinical lymph node status (positive vs. negative), and PD-L1 expression status (TAP 1% vs. TAP >= 1%).Patients were randomized in 1:1 ratio to one of the following treatment arms. Crossover between the study arms was not permitted.oIMFINZI 1,500 mg on Day + FLOT on Days and 15 of every 4-week cycle for cycles in the neoadjuvant phase and cycles in the adjuvant phase followed by IMFINZI 1,500 mg on Day every weeks for up to 10 additional cycles for total of 12 cycles (1 dose per cycle)oPlacebo on Day + FLOT on Days and 15 of every 4-week cycle for cycles in the neoadjuvant phase and cycles in the adjuvant phase followed by placebo on Day every weeks for up to 10 additional cycles for total of 12 cycles (1 dose per cycle)Tumor assessment per RECIST was performed prior to the start of neoadjuvant therapy, prior to surgery, before starting adjuvant treatment and then every 12 weeks for years and every 24 weeks until RECIST 1.1 defined radiological progression, consent withdrawal, or death.The major efficacy outcome measure of the study was EFS by BICR assessment. EFS was defined as the earliest of one of the following: disease progression according to RECIST 1.1 that precluded surgery or that required non-protocol therapy during the neoadjuvant treatment period; progression (after R1/R2 resection) or recurrence (after R0 resection), according to RECIST 1.1, during the adjuvant treatment period; non-RECIST progression (according to investigator assessment or confirmed by local pathology testing) that precluded surgery or that required non-protocol therapy during the neoadjuvant treatment period, or that was discovered during surgery; progression or recurrence confirmed by local pathology testing after surgery; or death.Additional efficacy outcome measures were OS and pCR rate by blinded central pathology review. The trial was not designed to isolate the effect of IMFINZI in each phase (neoadjuvant or adjuvant) of treatment.The demographics were as follows: median age 62 years (range: 26 to 84), age >=65 years (41%), male (72%), White (68%), Asian (20%), American Indian or Alaska Native (4%), Black or African American (1.1%), other race (1.7%), Hispanic or Latino (20%), and WHO/ECOG PS (74%). Disease characteristics were as follows: Stage II (29%), Stage III (62%), Stage IVA (9%), gastric (68%), gastroesophageal junction (32%), Siewert type (10%), Siewert type (15%), Siewert type (7%), intestinal type (51%), diffuse type (26%), indeterminate type (23%), clinical lymph node status positive (70%), clinical lymph node status negative (29%), PD-L1 expression status TAP >=1% (90%), and PD-L1 expression status TAP <1% (10%).There were 412 (87%) patients in the IMFINZI arm who completed curative intent surgery compared to 400 (84%) patients in the placebo arm. Surgery was delayed (defined as surgery attempt >8 weeks from last dose of neoadjuvant therapy) in 48 (10%) patients in the IMFINZI arm and 51 (11%) patients in the placebo arm. In the IMFINZI arm, 248 (52%) and 291 (61%) patients completed the two cycles of adjuvant IMFINZI and two cycles of adjuvant FLOT, respectively. In the placebo arm, 245 (52%) and 303 (64%) patients completed the two cycles of adjuvant placebo and two cycles of adjuvant FLOT, respectively. There were 344 (73%) patients in the IMFINZI arm who initiated adjuvant IMFINZI monotherapy compared to 332 (70%) patients in the placebo arm.The study demonstrated statistically significant improvement in EFS in the IMFINZI arm compared to the placebo arm. See Table 38, Figure 12, and Figure 13.Table 38. Efficacy Results for the MATTERHORN StudyIMFINZI FLOT chemotherapy(N 474)Placebo FLOT chemotherapy(N 474)Event Free Survival (EFS)Results for EFS are based on pre-specified interim analysis (DCO: 20 December 2024), results for OS are based on pre-specified final analysis (DCO: 01 September 2025), and results for pCR are based on pre-specified final analysis (DCO: 01 February 2023).Number of events, (%)167 (35)218 (46)Median EFS (months) (95% CI)Calculated using the Kaplan-Meier method. NR (40.7, NE)32.8 (27.9, NE)HR (95% CI)Based on stratified Cox proportional hazards model stratified by geographic region, clinical lymph node status and PD-L1 expression status at randomization. CI calculated using the profile likelihood approach. 0.71 (0.58, 0.86)p-valueBased on stratified log-rank test adjusting for geographic region, clinical lymph node status, and PD-L1 expression status using an OBrien-Fleming boundary of 0.0239 (2-sided). <0.001Overall Survival (OS)Number of events (%)160 (33.8)192 (40.5)Median OS (months) (95% CI) NR (NE, NE)NR (NE, NE)HR (95% CI) 0.78 (0.63, 0.96)p-valueBased on stratified log-rank test adjusting for geographic region, clinical lymph node status, and PD-L1 expression status using pre-specified boundary of 0.0499 (2-sided). 0.021pCRNumber of patients with response9134Response rate, (%) (95% CI)CI was calculated using the Clopper Pearson method. 19.2 (15.7, 23.0)7.2 (5.0, 9.9)p-valueBased on stratified Cochran-Mantel-Haenszel test adjusting for geographic region, clinical lymph node status, and PD-L1 expression status using pre-specified boundary of 0.001 (2-sided). <0.001CI=Confidence Interval, HR=Hazard Ratio, NE=Not estimable, NR=Not reachedFigure 12. Kaplan-Meier Curve of EFSFigure 13. Kaplan-Meier Curve of OS. oIMFINZI 1,500 mg on Day + FLOT on Days and 15 of every 4-week cycle for cycles in the neoadjuvant phase and cycles in the adjuvant phase followed by IMFINZI 1,500 mg on Day every weeks for up to 10 additional cycles for total of 12 cycles (1 dose per cycle). oPlacebo on Day + FLOT on Days and 15 of every 4-week cycle for cycles in the neoadjuvant phase and cycles in the adjuvant phase followed by placebo on Day every weeks for up to 10 additional cycles for total of 12 cycles (1 dose per cycle). Figure11. Figure12.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oAdminister IMFINZI as an intravenous infusion over 60 minutes after dilution. (2.4)oNeoadjuvant and Adjuvant Treatment of Resectable NSCLC:Weight >= 30 kg: Neoadjuvant: IMFINZI 1,500 mg in combination with chemotherapy every weeks for up to cycles prior to surgery. Adjuvant: IMFINZI 1,500 mg as single agent every weeks for up to 12 cycles after surgery. (2.2) Weight 30 kg Neoadjuvant: IMFINZI 20 mg/kg every weeks in combination with chemotherapy for up to cycles prior to surgery.Adjuvant: IMFINZI 20 mg/kg every weeks as single agent for up to 12 cycles after surgery. (2.2)oUnresectable Stage III NSCLC, following concurrent platinum-based chemotherapy and radiation therapy:Weight >= 30 kg: IMFINZI 10 mg/kg every weeks or 1,500 mg every weeks. (2.2)Weight 30 kg: IMFINZI 10 mg/kg every weeks. (2.2)oMetastatic NSCLC: Weight >= 30 kg: IMFINZI 1,500 mg every weeks in combination with tremelimumab-actl 75 mg and platinum-based chemotherapy for cycles, and then administer IMFINZI 1,500 mg every weeks as single agent with histology-based pemetrexed maintenance therapy every weeks, and fifth dose of tremelimumab-actl 75 mg in combination with IMFINZI dose at week 16. (2.2)Weight 30 kg: IMFINZI 20 mg/kg every weeks in combination with tremelimumab-actl mg/kg and platinum-based chemotherapy, and then administer IMFINZI 20 mg/kg every weeks as single agent with histology-based pemetrexed therapy every weeks, and fifth dose of tremelimumab-actl mg/kg in combination with IMFINZI dose at week 16. (2.2)oLS-SCLC, following concurrent platinum-based chemotherapy and radiation therapy:Weight >= 30 kg: 1,500 mg every weeks. (2.2)Weight 30 kg: 20 mg/kg every weeks. (2.2)oES-SCLC: Weight >= 30 kg: With etoposide and either carboplatin or cisplatin, administer IMFINZI 1,500 mg every weeks in combination with chemotherapy, and then 1,500 mg every weeks as single agent. (2.2)Weight 30 kg: With etoposide and either carboplatin or cisplatin, administer IMFINZI 20 mg/kg every weeks in combination with chemotherapy, and then 10 mg/kg every weeks as single agent. (2.2)oBTC:Weight >= 30 kg: administer IMFINZI 1,500 mg every weeks in combination with chemotherapy, and then 1,500 mg every weeks as single agent. (2.2)Weight 30 kg: administer IMFINZI 20 mg/kg every weeks in combination with chemotherapy, and then 20 mg/kg every weeks as single agent. (2.2)ouHCC:Weight >= 30 kg: IMFINZI 1,500 mg in combination with tremelimumab-actl 300 mg as single dose at Cycle 1/Day 1, followed by IMFINZI as single agent every weeks. (2.2)Weight 30 kg: IMFINZI 20 mg/kg in combination with tremelimumab-actl mg/kg as single dose at Cycle 1/Day 1, followed by IMFINZI as single agent every weeks. (2.2)odMMR endometrial cancer:Weight >= 30 kg: IMFINZI 1,120 mg in combination with carboplatin and paclitaxel every weeks for cycles, followed by IMFINZI 1,500 mg every weeks as single agent. (2.1, 2.2)Weight 30 kg: IMFINZI 15 mg/kg in combination with carboplatin and paclitaxel every weeks for cycles, followed by IMFINZI 20 mg/kg every weeks as single agent. (2.1, 2.2)oNMIBCWeight >= 30 kg: IMFINZI 1,500 mg every weeks for 13 cycles in combination with BCG induction and maintenance. (2.2).Weight 30 kg: IMFINZI 20 mg/kg every weeks for 13 cycles in combination with BCG induction and maintenance. (2.2)oMIBC:Weight >= 30 kg:Neoadjuvant: IMFINZI 1,500 mg in combination with gemcitabine and cisplatin every weeks for cycles prior to surgery.Adjuvant: IMFINZI 1,500 mg every weeks as single agent for up to cycles after surgery. (2.2) Weight 30 kg: Neoadjuvant: IMFINZI 20 mg/kg in combination with gemcitabine and cisplatin every weeks for cycles prior to surgery.Adjuvant: IMFINZI 20 mg/kg every weeks as single agent for up to cycles after surgery. (2.2)oResectable GC/GEJCWeight >= 30 kg:Neoadjuvant: IMFINZI 1,500 mg in combination with FLOT chemotherapy every weeks for up to cycles prior to surgery.Adjuvant: IMFINZI 1,500 mg in combination with FLOT chemotherapy, every weeks for up to cycles and then 1,500 mg as single agent every weeks for up to 10 cycles, for total of up to 12 cycles after surgery. (2.2) oWeight 30 kg:Neoadjuvant: IMFINZI 20 mg/kg in combination with FLOT chemotherapy every weeks for up to cycles prior to surgery.Adjuvant: IMFINZI 20 mg/kg in combination with FLOT chemotherapy, every weeks for up to cycles and then 20 mg/kg as single agent every weeks for up to 10 cycles, for total of up to 12 cycles after surgery. (2.2)oSee full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions.. oAdminister IMFINZI as an intravenous infusion over 60 minutes after dilution. (2.4). oNeoadjuvant and Adjuvant Treatment of Resectable NSCLC:Weight >= 30 kg: Weight >= 30 kg: Weight 30 kg Weight 30 kg oUnresectable Stage III NSCLC, following concurrent platinum-based chemotherapy and radiation therapy:Weight >= 30 kg: IMFINZI 10 mg/kg every weeks or 1,500 mg every weeks. (2.2)Weight 30 kg: IMFINZI 10 mg/kg every weeks. (2.2). Weight >= 30 kg: IMFINZI 10 mg/kg every weeks or 1,500 mg every weeks. (2.2). Weight 30 kg: IMFINZI 10 mg/kg every weeks. (2.2). oMetastatic NSCLC: Weight >= 30 kg: IMFINZI 1,500 mg every weeks in combination with tremelimumab-actl 75 mg and platinum-based chemotherapy for cycles, and then administer IMFINZI 1,500 mg every weeks as single agent with histology-based pemetrexed maintenance therapy every weeks, and fifth dose of tremelimumab-actl 75 mg in combination with IMFINZI dose at week 16. (2.2)Weight 30 kg: IMFINZI 20 mg/kg every weeks in combination with tremelimumab-actl mg/kg and platinum-based chemotherapy, and then administer IMFINZI 20 mg/kg every weeks as single agent with histology-based pemetrexed therapy every weeks, and fifth dose of tremelimumab-actl mg/kg in combination with IMFINZI dose at week 16. (2.2). Weight >= 30 kg: IMFINZI 1,500 mg every weeks in combination with tremelimumab-actl 75 mg and platinum-based chemotherapy for cycles, and then administer IMFINZI 1,500 mg every weeks as single agent with histology-based pemetrexed maintenance therapy every weeks, and fifth dose of tremelimumab-actl 75 mg in combination with IMFINZI dose at week 16. (2.2). Weight 30 kg: IMFINZI 20 mg/kg every weeks in combination with tremelimumab-actl mg/kg and platinum-based chemotherapy, and then administer IMFINZI 20 mg/kg every weeks as single agent with histology-based pemetrexed therapy every weeks, and fifth dose of tremelimumab-actl mg/kg in combination with IMFINZI dose at week 16. (2.2). oLS-SCLC, following concurrent platinum-based chemotherapy and radiation therapy:Weight >= 30 kg: 1,500 mg every weeks. (2.2)Weight 30 kg: 20 mg/kg every weeks. (2.2). Weight >= 30 kg: 1,500 mg every weeks. (2.2). Weight 30 kg: 20 mg/kg every weeks. (2.2). oES-SCLC: Weight >= 30 kg: With etoposide and either carboplatin or cisplatin, administer IMFINZI 1,500 mg every weeks in combination with chemotherapy, and then 1,500 mg every weeks as single agent. (2.2)Weight 30 kg: With etoposide and either carboplatin or cisplatin, administer IMFINZI 20 mg/kg every weeks in combination with chemotherapy, and then 10 mg/kg every weeks as single agent. (2.2). Weight >= 30 kg: With etoposide and either carboplatin or cisplatin, administer IMFINZI 1,500 mg every weeks in combination with chemotherapy, and then 1,500 mg every weeks as single agent. (2.2). Weight 30 kg: With etoposide and either carboplatin or cisplatin, administer IMFINZI 20 mg/kg every weeks in combination with chemotherapy, and then 10 mg/kg every weeks as single agent. (2.2). oBTC:Weight >= 30 kg: administer IMFINZI 1,500 mg every weeks in combination with chemotherapy, and then 1,500 mg every weeks as single agent. (2.2)Weight 30 kg: administer IMFINZI 20 mg/kg every weeks in combination with chemotherapy, and then 20 mg/kg every weeks as single agent. (2.2). Weight >= 30 kg: administer IMFINZI 1,500 mg every weeks in combination with chemotherapy, and then 1,500 mg every weeks as single agent. (2.2). Weight 30 kg: administer IMFINZI 20 mg/kg every weeks in combination with chemotherapy, and then 20 mg/kg every weeks as single agent. (2.2). ouHCC:Weight >= 30 kg: IMFINZI 1,500 mg in combination with tremelimumab-actl 300 mg as single dose at Cycle 1/Day 1, followed by IMFINZI as single agent every weeks. (2.2)Weight 30 kg: IMFINZI 20 mg/kg in combination with tremelimumab-actl mg/kg as single dose at Cycle 1/Day 1, followed by IMFINZI as single agent every weeks. (2.2). Weight >= 30 kg: IMFINZI 1,500 mg in combination with tremelimumab-actl 300 mg as single dose at Cycle 1/Day 1, followed by IMFINZI as single agent every weeks. (2.2). Weight 30 kg: IMFINZI 20 mg/kg in combination with tremelimumab-actl mg/kg as single dose at Cycle 1/Day 1, followed by IMFINZI as single agent every weeks. (2.2). odMMR endometrial cancer:Weight >= 30 kg: IMFINZI 1,120 mg in combination with carboplatin and paclitaxel every weeks for cycles, followed by IMFINZI 1,500 mg every weeks as single agent. (2.1, 2.2)Weight 30 kg: IMFINZI 15 mg/kg in combination with carboplatin and paclitaxel every weeks for cycles, followed by IMFINZI 20 mg/kg every weeks as single agent. (2.1, 2.2). Weight >= 30 kg: IMFINZI 1,120 mg in combination with carboplatin and paclitaxel every weeks for cycles, followed by IMFINZI 1,500 mg every weeks as single agent. (2.1, 2.2). Weight 30 kg: IMFINZI 15 mg/kg in combination with carboplatin and paclitaxel every weeks for cycles, followed by IMFINZI 20 mg/kg every weeks as single agent. (2.1, 2.2). oNMIBCWeight >= 30 kg: IMFINZI 1,500 mg every weeks for 13 cycles in combination with BCG induction and maintenance. (2.2).Weight 30 kg: IMFINZI 20 mg/kg every weeks for 13 cycles in combination with BCG induction and maintenance. (2.2). Weight >= 30 kg: IMFINZI 1,500 mg every weeks for 13 cycles in combination with BCG induction and maintenance. (2.2).. Weight 30 kg: IMFINZI 20 mg/kg every weeks for 13 cycles in combination with BCG induction and maintenance. (2.2). oMIBC:Weight >= 30 kg:. Weight >= 30 kg:. Weight 30 kg: Weight 30 kg: oResectable GC/GEJCWeight >= 30 kg:. Weight >= 30 kg:. oWeight 30 kg:. oSee full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions.. 2.1 Patient Selection Advanced or Recurrent dMMR Endometrial CancerSelect patients for treatment based on the presence of dMMR in tumor specimens [see Clinical Studies (14.5)]. Information on FDA-approved tests for the detection of dMMR status in endometrial cancer is available at https://www.fda.gov/companiondiagnostics . 2.2 Recommended Dosage The recommended dosages for IMFINZI as single agent and IMFINZI in combination with other therapeutic agents are presented in Table 1. The recommended dosage schedule and regimens for IMFINZI for the treatment of metastatic NSCLC are provided in Tables and [see Indications and Usage (1.1)]. Administer IMFINZI as 60 minute intravenous infusion after dilution [see Dosage and Administration (2.3)]. Table 1. Recommended Dosages of IMFINZIIndicationRecommended IMFINZI DosageDuration of TherapyNeoadjuvant and Adjuvant Treatment of Resectable NSCLCPatients with body weight of >= 30 kg:oNeoadjuvant: IMFINZI 1,500 mg in combination with chemotherapyAdminister IMFINZI prior to chemotherapy on the same day. Refer to the Prescribing Information for the agent administered in combination with IMFINZI for recommended dosage information, as appropriate. every weeks for up to cycles prior to surgery oAdjuvant: IMFINZI 1,500 mg as single agent every weeks for up to 12 cycles after surgery.Patients with body weight of 30 kg:oNeoadjuvant: IMFINZI 20 mg/kg every weeks in combination with chemotherapy for up to cycles prior to surgery.oAdjuvant: IMFINZI 20 mg/kg every weeks for up to 12 cycles as single agent after surgery.Until disease progression that precludes definitive surgery, recurrence, unacceptable toxicity, or maximum of 12 cycles after surgeryUnresectable Stage III NSCLCFollowing concurrent platinum-based chemotherapy and radiation therapy:Patients with body weight of >= 30 kg:o10 mg/kg every weeks or o1,500 mg every weeksPatients with body weight of 30 kg:o10 mg/kg every weeksUntil disease progression, unacceptable toxicity, or maximum of 12 monthsLimited Stage SCLCFollowing concurrent platinum-based chemotherapy and radiation therapy: Patients with body weight of >= 30 kg:o1,500 mg every weeksPatients with body weight of 30 kg:o20 mg/kg every weeksUntil disease progression, unacceptable toxicity, or maximum of 24 monthsExtensive Stage SCLCPatients with body weight of >= 30 kg:o1,500 mg in combination with chemotherapy every weeks (21 days) for cycles, followed by 1,500 mg every weeks as single agentPatients with body weight of 30 kg:o20 mg/kg in combination with chemotherapy every weeks (21 days) for cycles, followed by 10 mg/kg every weeks as single agentUntil disease progression or until unacceptable toxicityBTCPatients with body weight of >= 30 kg:o1,500 mg in combination with chemotherapy every weeks (21 days) up to cycles followed by 1,500 mg every weeks as single agentPatients with body weight of 30 kg:o20 mg/kg in combination with chemotherapy every weeks (21 days) up to cycles, followed by 20 mg/kg every weeks as single agentUntil disease progression or until unacceptable toxicityuHCCPatients with body weight of >= 30 kg:oIMFINZI 1,500 mg following single dose of tremelimumab-actlAdminister tremelimumab-actl prior to IMFINZI on the same day. When tremelimumab-actl is administered in combination with IMFINZI, refer to the Prescribing Information for tremelimumab-actl dosing information. 300 mg at Day of Cycle 1;oContinue IMFINZI 1,500 mg as single agent every weeksPatients with body weight of 30 kg:oIMFINZI 20 mg/kg following single dose of tremelimumab-actl mg/kg at Day of Cycle 1;oContinue IMFINZI 20 mg/kg as single agent every weeksAfter Cycle of combination therapy, administer IMFINZI as single agent every weeks until disease progression or unacceptable toxicitydMMR endometrial cancerPatients with body weight of >= 30 kg:oIMFINZI 1,120 mg in combination with carboplatin and paclitaxel every weeks (21 days) for cycles, followed by IMFINZI 1,500 mg every weeks as single agentPatients with body weight of 30 kg:oIMFINZI 15 mg/kg in combination with carboplatin and paclitaxel every weeks (21 days) for cycles, followed by IMFINZI 20 mg/kg every weeks as single agentUntil disease progression or unacceptable toxicityBCG-Naive, High-Risk NMIBCPatients with body weight of >= 30 kg:oIMFINZI 1,500 mg every weeks (28 days) for 13 cycles in combination with BCGAdminister IMFINZI prior to BCG if given on the same day. Refer to the Prescribing Information for BCG dosing information. induction and maintenance Patients with body weight of 30 kg: oIMFINZI 20 mg/kg every weeks (28 days) for 13 cycles in combination with BCG induction and maintenanceUntil recurrence of high-risk disease, disease progression, unacceptable toxicity, or maximum of 13 cyclesNeoadjuvant and Adjuvant Treatment of MIBCPatients with body weight of >=30 kg:oNeoadjuvant: 1,500 mg in combination with gemcitabine and cisplatin every weeks for cycles prior to surgeryoAdjuvant: IMFINZI 1,500 mg as single agent every weeks for up to cycles after surgeryPatients with body weight of 30 kg:oNeoadjuvant: 20 mg/kg in combination with gemcitabine and cisplatin every weeks for cycles prior to surgeryoAdjuvant: IMFINZI 20 mg/kg as single agent every weeks for up to cycles after surgeryUntil disease progression that precludes definitive surgery, recurrence, or unacceptable toxicity or maximum of cycles after surgeryNeoadjuvant and Adjuvant Treatment of Resectable GC/GEJCPatients with body weight of >= 30 kg: oNeoadjuvant: IMFINZI 1,500 mg every weeks with FLOTFLOT chemotherapy is administered on days and 15 of each week cycle [See Clinical Studies (14.7)]. for up to cycles prior to surgeryoAdjuvant: IMFINZI 1,500 mg every weeks with FLOT for up to cycles, followed by IMFINZI 1,500 mg as single agent every weeks for up to 10 cyclesPatients with body weight of 30 kg:oNeoadjuvant: IMFINZI 20 mg/kg every weeks with FLOT for up to cycles prior to surgeryoAdjuvant: IMFINZI 20 mg/kg every weeks with FLOT for up to cycles, followed by IMFINZI 20 mg/kg as single agent every weeks for up to 10 cyclesNeoadjuvant: Until disease progression that precludes definitive surgery or unacceptable toxicityIMFINZI in Combination with Tremelimumab-actl and Platinum-Based ChemotherapyThe recommended dosage schedule and regimens for IMFINZI for the treatment of metastatic NSCLC are provided in Tables and 3.Weigh patients prior to each infusion.Calculate the appropriate dose using Table below based on the patients weight and tumor histology.Table 2. Recommended Dosage Schedule for Metastatic NSCLCWeekcontinue IMFINZI until disease progression or intolerable toxicity.note the dosing interval change from every weeks to every weeks starting at cycle 5.0123456789101112131415161718192021222324Cycle:12345678IMFINZI intravenous infusion over 60 minutes [see Dosage and Administration (2.4) ]. XXXXXXXXTremelimumab-actl if patients receive fewer than cycles of platinum-based chemotherapy, the remaining cycles of tremelimumab-actl (up to total of 5) should be given after the platinum-based chemotherapy phase, in combination with IMFINZI, every weeks. XXXXXChemotherapyXXXXXoptional pemetrexed therapy from week 12 until disease progression or intolerable toxicity for patients with non-squamous disease who received treatment with pemetrexed and carboplatin/cisplatin. X Table 3. Recommended Regimen and Dosage for Metastatic NSCLCTumor HistologyPatient WeightIMFINZI DosageTremelimumab-actl DosageRefer to the Prescribing Information for dosing information. Platinum-based Chemotherapy Regimen Non-Squamous>= 30 kg1,500 mg75 mgocarboplatin nab-paclitaxel ORocarboplatin or cisplatin pemetrexed< 30 kg20 mg/kg1 mg/kgSquamous>= 30 kg1,500 mg75 mgocarboplatin nab-paclitaxelORocarboplatin or cisplatin gemcitabine< 30 kg20 mg/kg1 mg/kg. oNeoadjuvant: IMFINZI 1,500 mg in combination with chemotherapyAdminister IMFINZI prior to chemotherapy on the same day. Refer to the Prescribing Information for the agent administered in combination with IMFINZI for recommended dosage information, as appropriate. every weeks for up to cycles prior to surgery oAdjuvant: IMFINZI 1,500 mg as single agent every weeks for up to 12 cycles after surgery.. oNeoadjuvant: IMFINZI 20 mg/kg every weeks in combination with chemotherapy for up to cycles prior to surgery.. oAdjuvant: IMFINZI 20 mg/kg every weeks for up to 12 cycles as single agent after surgery.. o10 mg/kg every weeks o1,500 mg every weeks. o10 mg/kg every weeks. o1,500 mg every weeks. o20 mg/kg every weeks. o1,500 mg in combination with chemotherapy every weeks (21 days) for cycles, followed by 1,500 mg every weeks as single agent. o20 mg/kg in combination with chemotherapy every weeks (21 days) for cycles, followed by 10 mg/kg every weeks as single agent. o1,500 mg in combination with chemotherapy every weeks (21 days) up to cycles followed by 1,500 mg every weeks as single agent. o20 mg/kg in combination with chemotherapy every weeks (21 days) up to cycles, followed by 20 mg/kg every weeks as single agent. oIMFINZI 1,500 mg following single dose of tremelimumab-actlAdminister tremelimumab-actl prior to IMFINZI on the same day. When tremelimumab-actl is administered in combination with IMFINZI, refer to the Prescribing Information for tremelimumab-actl dosing information. 300 mg at Day of Cycle 1;. oContinue IMFINZI 1,500 mg as single agent every weeks. oIMFINZI 20 mg/kg following single dose of tremelimumab-actl mg/kg at Day of Cycle 1;. oContinue IMFINZI 20 mg/kg as single agent every weeks. oIMFINZI 1,120 mg in combination with carboplatin and paclitaxel every weeks (21 days) for cycles, followed by IMFINZI 1,500 mg every weeks as single agent. oIMFINZI 15 mg/kg in combination with carboplatin and paclitaxel every weeks (21 days) for cycles, followed by IMFINZI 20 mg/kg every weeks as single agent. oIMFINZI 1,500 mg every weeks (28 days) for 13 cycles in combination with BCGAdminister IMFINZI prior to BCG if given on the same day. Refer to the Prescribing Information for BCG dosing information. induction and maintenance oIMFINZI 20 mg/kg every weeks (28 days) for 13 cycles in combination with BCG induction and maintenance. oNeoadjuvant: 1,500 mg in combination with gemcitabine and cisplatin every weeks for cycles prior to surgery. oAdjuvant: IMFINZI 1,500 mg as single agent every weeks for up to cycles after surgery. oNeoadjuvant: 20 mg/kg in combination with gemcitabine and cisplatin every weeks for cycles prior to surgery. oAdjuvant: IMFINZI 20 mg/kg as single agent every weeks for up to cycles after surgery. oNeoadjuvant: IMFINZI 1,500 mg every weeks with FLOTFLOT chemotherapy is administered on days and 15 of each week cycle [See Clinical Studies (14.7)]. for up to cycles prior to surgery. oAdjuvant: IMFINZI 1,500 mg every weeks with FLOT for up to cycles, followed by IMFINZI 1,500 mg as single agent every weeks for up to 10 cycles. oNeoadjuvant: IMFINZI 20 mg/kg every weeks with FLOT for up to cycles prior to surgery. oAdjuvant: IMFINZI 20 mg/kg every weeks with FLOT for up to cycles, followed by IMFINZI 20 mg/kg as single agent every weeks for up to 10 cycles. ocarboplatin nab-paclitaxel ocarboplatin or cisplatin pemetrexed. ocarboplatin nab-paclitaxel. ocarboplatin or cisplatin gemcitabine. 2.3 Dosage Modifications for Adverse Reactions No dose reduction for IMFINZI is recommended. In general, withhold IMFINZI for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue IMFINZI for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids.Dosage modifications for IMFINZI or IMFINZI in combination with tremelimumab-actl or chemotherapy for adverse reactions that require management different from these general guidelines are summarized in Table 4. Table 4. Recommended Dosage Modifications for Adverse ReactionsAdverse ReactionSeverityBased on National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.Dosage ModificationImmune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] Pneumonitis Grade 2WithholdResume in patients with complete or partial resolution (Grade to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating corticosteroids or an inability to reduce corticosteroid dose to 10 mg of prednisone or less per day (or equivalent) within 12 weeks of initiating corticosteroids. Grade or 4Permanently discontinue ColitisGrade 2Withhold Grade 3Withhold or permanently discontinuePermanently discontinue IMFINZI for Grade colitis when administered as part of tremelimumab-actl containing regimen. Grade 4Permanently discontinue Intestinal perforationAny gradePermanently discontinue Hepatitis with no tumor involvement of the liverALT or AST increases to more than and up to times the ULNortotal bilirubin increases to more than 1.5 and up to times ULNWithhold ALT or AST increases to more than times ULNortotal bilirubin increases to more than times the ULNPermanently discontinue Hepatitis with tumor involvement of the liverIf AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue IMFINZI based on recommendations for hepatitis with no liver involvement.AST or ALT is more than and up to times ULN at baseline and increases to more than and up to 10 times ULN orAST or ALT is more than and up to times ULN at baseline and increases to more than and up to 10 times ULNWithhold AST or ALT increases to more than 10 times ULNortotal bilirubin increases to more than times ULNPermanently discontinue EndocrinopathiesGrade or 4Withhold until clinically stable or permanently discontinue depending on severity Nephritis with Renal DysfunctionGrade or increased blood creatinineWithhold Grade increased blood creatininePermanently discontinue Exfoliative Dermatologic ConditionsSuspected SJS, TEN, or DRESSWithhold Confirmed SJS, TEN, or DRESSPermanently discontinue MyocarditisGrade 2, 3, or 4Permanently discontinue Neurological ToxicitiesGrade 2Withhold Grade or 4Permanently discontinueOther Adverse Reactions Infusion-related reactions [see Warnings and Precautions (5.2)]Grade or 2Interrupt or slow the rate of infusionGrade or 4Permanently discontinueALT alanine aminotransferase, AST aspartate aminotransferase, DRESS Drug Rash with Eosinophilia and Systemic Symptoms, SJS Stevens Johnson Syndrome, TEN toxic epidermal necrolysis, ULN upper limit normal.. Pneumonitis Colitis. Intestinal perforation. Hepatitis with no tumor involvement of the liver. Hepatitis with tumor involvement of the liverIf AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue IMFINZI based on recommendations for hepatitis with no liver involvement.. Endocrinopathies. Nephritis with Renal Dysfunction. Exfoliative Dermatologic Conditions. Myocarditis. Neurological Toxicities. Infusion-related reactions [see Warnings and Precautions (5.2)]. 2.4 Preparation and Administration PreparationoVisually inspect drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or visible particles are observed.oDo not shake the vial.oWithdraw the required volume from the vial(s) of IMFINZI and transfer into an intravenous bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. Do not shake the solution. The final concentration of the diluted solution should be between mg/mL and 15 mg/mL.oDiscard partially used or empty vials of IMFINZI.Storage of Infusion SolutionoIMFINZI does not contain preservative.oAdminister infusion solution immediately once prepared. If the infusion solution is not administered immediately and needs to be stored, the time from preparation until the completion of the infusion should not exceed:28 days in refrigerator at 2C to 8C (36F to 46F)8 hours at room temperature up to 25C (77F)oDo not freeze.oDo not shake.AdministrationoAdminister infusion solution intravenously over 60 minutes through an intravenous line containing sterile, low-protein binding 0.2 or 0.22 micron in-line filter.oUse separate infusion bags and filters for each drug product.IMFINZI in Combination with Other ProductsoAdminister all intravenous drug products as separate infusions.oDo not co-administer other intravenous drugs through the same infusion line. oFor platinum-based chemotherapy, refer to Prescribing Information for administration information.oFor pemetrexed therapy, refer to Prescribing Information for administration information.oFor BCG therapy, refer to BCG Prescribing Information for administration information.Combination Regimens: Order of AdministrationsIMFINZI in Combination with Tremelimumab-actloInfuse tremelimumab-actl first, followed by IMFINZI on the same day of dosing.IMFINZI in Combination with Tremelimumab-actl and Platinum-Based ChemotherapyoInfuse tremelimumab-actl first, followed by IMFINZI and then platinum-based chemotherapy on the day of dosing.IMFINZI in Combination with Tremelimumab-actl and Pemetrexed TherapyoInfuse tremelimumab-actl first, followed by IMFINZI and then pemetrexed therapy on the day of dosing.IMFINZI in Combination with Carboplatin and PaclitaxeloInfuse IMFINZI first and then carboplatin and paclitaxel on the same day of dosing.IMFINZI in Combination with ChemotherapyoInfuse IMFINZI first and then chemotherapy on the same day of dosing.IMFINZI in combination with BCGoIf IMFINZI is given on the same day as BCG, infuse IMFINZI first, then administer BCG as an intravesical instillation.Combination Regimens: Infusion InstructionsIMFINZI in Combination with Tremelimumab-actloAdminister tremelimumab-actl over 60 minutes followed by 60 minute observation period. Then administer IMFINZI as separate intravenous infusion over 60 minutes. IMFINZI in Combination with Tremelimumab-actl and Platinum-Based Chemotherapy/ Pemetrexed TherapyCycle 1oInfuse tremelimumab-actl over 60 minutes. One to two hours after completion of tremelimumab-actl infusion, infuse IMFINZI over 60 minutes. One to two hours after completion of IMFINZI infusion, administer platinum-based chemotherapy.Subsequent CyclesoIf there are no infusion reactions during cycle 1, subsequent cycles of IMFINZI can be given immediately after tremelimumab-actl. The time between the end of the IMFINZI infusion and the start of chemotherapy can be reduced to 30 minutes.. oVisually inspect drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or visible particles are observed.. oDo not shake the vial.. oWithdraw the required volume from the vial(s) of IMFINZI and transfer into an intravenous bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. Do not shake the solution. The final concentration of the diluted solution should be between mg/mL and 15 mg/mL.. oDiscard partially used or empty vials of IMFINZI.. oIMFINZI does not contain preservative.. oAdminister infusion solution immediately once prepared. If the infusion solution is not administered immediately and needs to be stored, the time from preparation until the completion of the infusion should not exceed:28 days in refrigerator at 2C to 8C (36F to 46F)8 hours at room temperature up to 25C (77F). 28 days in refrigerator at 2C to 8C (36F to 46F). hours at room temperature up to 25C (77F). oDo not freeze.. oDo not shake.. oAdminister infusion solution intravenously over 60 minutes through an intravenous line containing sterile, low-protein binding 0.2 or 0.22 micron in-line filter.. oUse separate infusion bags and filters for each drug product.. oAdminister all intravenous drug products as separate infusions.. oDo not co-administer other intravenous drugs through the same infusion line. oFor platinum-based chemotherapy, refer to Prescribing Information for administration information.. oFor pemetrexed therapy, refer to Prescribing Information for administration information.. oFor BCG therapy, refer to BCG Prescribing Information for administration information.. oInfuse tremelimumab-actl first, followed by IMFINZI on the same day of dosing.. oInfuse tremelimumab-actl first, followed by IMFINZI and then platinum-based chemotherapy on the day of dosing.. oInfuse tremelimumab-actl first, followed by IMFINZI and then pemetrexed therapy on the day of dosing.. oInfuse IMFINZI first and then carboplatin and paclitaxel on the same day of dosing.. oInfuse IMFINZI first and then chemotherapy on the same day of dosing.. oIf IMFINZI is given on the same day as BCG, infuse IMFINZI first, then administer BCG as an intravesical instillation.. oAdminister tremelimumab-actl over 60 minutes followed by 60 minute observation period. Then administer IMFINZI as separate intravenous infusion over 60 minutes. oInfuse tremelimumab-actl over 60 minutes. One to two hours after completion of tremelimumab-actl infusion, infuse IMFINZI over 60 minutes. One to two hours after completion of IMFINZI infusion, administer platinum-based chemotherapy.. oIf there are no infusion reactions during cycle 1, subsequent cycles of IMFINZI can be given immediately after tremelimumab-actl. The time between the end of the IMFINZI infusion and the start of chemotherapy can be reduced to 30 minutes.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. Mycobacterium tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 blockade using primate anti-PD-1 antibody was also shown to exacerbate M. tuberculosis infection in rhesus macaques. PD-L1 and PD-1 knockout mice and mice receiving PD-L1 blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic and genotoxic potential of durvalumab have not been evaluated.Animal fertility studies have not been conducted with durvalumab. In repeat-dose toxicology studies with durvalumab in sexually mature cynomolgus monkeys of up to months duration, there were no notable effects on the male and female reproductive organs.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Expression of programmed cell death ligand-1 (PD-L1) can be induced by inflammatory signals (e.g., IFN-gamma) and can be expressed on both tumor cells and tumor-associated immune cells in the tumor microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation, and cytokine production.Durvalumab is human immunoglobulin G1 kappa (IgG1) monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, without inducing antibody dependent cell-mediated cytotoxicity (ADCC).PD-L1 blockade with durvalumab led to increased T-cell activation in vitro and decreased tumor size in co-engrafted human tumor and immune cell xenograft mouse models.. 12.2 Pharmacodynamics The steady state AUC, Ctrough, and Cmax in patients administered with 1,500 mg every weeks are 6% higher, 19% lower, and 55% higher than those administered with 10 mg/kg every weeks, respectively. Based on the modeling of pharmacokinetic data and exposure relationships for safety, there are no anticipated clinically meaningful differences in efficacy and safety for the doses of 1,500 mg every weeks compared to 10 mg/kg every weeks in patients weighing 30 kg with NSCLC.. 12.3 Pharmacokinetics The pharmacokinetics of durvalumab as single agent was studied in patients with doses ranging from 0.1 mg/kg (0.01 times the approved recommended dosage) to 20 mg/kg (2 times the approved recommended dosage) administered once every two, three, or four weeks.PK exposure increased more than dose-proportionally at doses 3 mg/kg (0.3 times the approved recommended dosage) and dose proportionally at doses >= mg/kg every weeks. Steady state was achieved at approximately 16 weeks.The pharmacokinetics of durvalumab is similar when assessed as single agent, when in combination with chemotherapy, when in combination with tremelimumab-actl and when in combination with tremelimumab-actl and platinum-based chemotherapy.DistributionThe geometric mean (% coefficient of variation [CV%]) steady state volume of distribution (Vss) was 5.4 (13.1%) L.EliminationDurvalumab clearance decreases over time, with mean maximal reduction (CV%) from baseline values of approximately 23% (57%) resulting in geometric mean (CV%) steady state clearance (CLss) of mL/h (39%) at day 365; the decrease in CLss is not considered clinically relevant. The geometric mean (CV%) terminal half-life, based on baseline CL was approximately 21 (26%) days.Specific PopulationsThere were no clinically significant differences in the pharmacokinetics of durvalumab based on body weight (31 to 175 kg), age (18 to 96 years), sex, race (White, Black, Asian, Native Hawaiian, Pacific Islander, or Native American), albumin levels (4 to 57 g/L), lactate dehydrogenase levels (18 to 15,800 U/L), soluble PD-L1 (67 to 3,470 pg/mL), tumor type (NSCLC, SCLC, BTC and HCC), mild or moderate renal impairment (CLcr 30 to 89 mL/min), and mild or moderate hepatic impairment (bilirubin <= 3x ULN and any AST). The effect of severe renal impairment (CLcr 15 to 29 mL/min) or severe hepatic impairment (bilirubin 3x ULN and any AST) on the pharmacokinetics of durvalumab is unknown.. 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 comparison of the incidence of ADAs in the studies described below with the incidence of ADAs in other studies including those of IMFINZI or of other durvalumab products.In clinical trials of patients who received IMFINZI for 10 to 48 weeks at dosages of 1,500 mg every weeks, 10 mg/kg every weeks, 20 mg/kg every weeks as single agent or 1,120 mg every weeks, or 1,500 mg every weeks in the combination therapies, 3.6% (199/5562) of evaluable patients tested positive for treatment-emergent anti-durvalumab antibodies, and 8.5% (17/199) of treatment-emergent ADA positive patients had neutralizing antibodies against durvalumab. There were no identified clinically significant effects of ADAs on durvalumab pharmacokinetics or safety; however, the effect of these ADAs on the effectiveness of IMFINZI is unknown.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION Durvalumab is programmed cell death ligand (PD-L1) blocking antibody. Durvalumab is human immunoglobulin G1 kappa (IgG1) monoclonal antibody that is produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cell suspension culture.IMFINZI (durvalumab) Injection for intravenous use is sterile, preservative-free, clear to opalescent, colorless to slightly yellow solution, free from visible particles.Each 500 mg vial of IMFINZI contains 500 mg of durvalumab in 10 mL solution. Each mL contains durvalumab, 50 mg, L-histidine (2 mg), L-histidine hydrochloride monohydrate (2.7 mg), ,-trehalose dihydrate (104 mg), Polysorbate 80 (0.2 mg), and Water for Injection, USP.Each 120 mg vial of IMFINZI contains 120 mg of durvalumab in 2.4 mL solution. Each mL contains durvalumab, 50 mg, L-histidine (2 mg), L-histidine hydrochloride monohydrate (2.7 mg), ,-trehalose dihydrate (104 mg), Polysorbate 80 (0.2 mg), and Water for Injection, USP.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Injection: 120 mg/2.4 mL (50 mg/mL) and 500 mg/10 mL (50 mg/mL) clear to opalescent, colorless to slightly yellow solution in single-dose vial.. oInjection: 500 mg/10 mL (50 mg/mL) solution in single-dose vial. (3)oInjection: 120 mg/2.4 mL (50 mg/mL) solution in single-dose vial. (3). oInjection: 500 mg/10 mL (50 mg/mL) solution in single-dose vial. (3). oInjection: 120 mg/2.4 mL (50 mg/mL) solution in single-dose vial. (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use Of the 401 patients with resectable NSCLC treated with IMFINZI in combination with chemotherapy in the AEGEAN study, 209 (52%) patients were 65 years or older and 49 (12%) patients were 75 years or older. There were no overall clinically meaningful differences in safety or efficacy between patients >= 65 years of age and younger patients.Of the 476 patients with unresectable, Stage III NSCLC treated with IMFINZI in the PACIFIC study, 45% were 65 years or older, while 7.6% were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients. The PACIFIC study did not include sufficient numbers of patients aged 75 years and over to determine whether they respond differently from younger patients.Of the 330 patients with metastatic NSCLC treated with IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy, 143 (43%) patients were 65 years or older and 35 (11%) patients were 75 years or older. There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients.Of the 262 patients with LS-SCLC treated with IMFINZI, 103 (39%) patients were 65 years or older and 15 (6%) patients were 75 years or older. There were no clinically meaningful differences in safety and efficacy between patients 65 years or older and younger patients.Of the 265 patients with ES-SCLC treated with IMFINZI in combination with chemotherapy 101 (38%) patients were 65 years or older and 19 (7.2%) patients were 75 years or older. There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients.Of the 338 patients with BTC treated with IMFINZI in combination with chemotherapy in the TOPAZ-1 study, 158 (47%) patients were 65 years or older and 38 (11%) patients were 75 years or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients.Of the 393 patients with uHCC treated with IMFINZI in combination with tremelimumab-actl, 50% of patients were 65 years of age or older and 13% of patients were 75 years of age or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients.Of the 235 patients with endometrial cancer treated with IMFINZI with carboplatin and paclitaxel, 49% of patients were 65 years of age or older and 12% of patients were 75 years of age or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients.Of the 530 patients with MIBC treated with IMFINZI in combination with gemcitabine and cisplatin in the NIAGARA study, 272 (51%) patients were 65 years or older, and 57 (11%) patients were 75 years or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients.Of the 336 patients with NMIBC treated with IMFINZI in combination with BCG induction and maintenance in the POTOMAC study, 215 (64%) patients were 65 years of age and 72 (21%) patients were >75 years of age or older. No overall differences in safety or effectiveness of IMFINZI were observed between patients >65 years of age and younger adult patients.Of the 475 patients with resectable GC/GEJC treated with IMFINZI in combination with FLOT chemotherapy in the MATTERHORN study, 184 (39%) patients were 65 years or older and 37 (8%) patients were 75 years or older. No overall differences in safety or effectiveness were observed between patients >= 65 years of age and younger adult patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING IMFINZI (durvalumab) Injection is clear to opalescent, colorless to slightly yellow solution supplied in carton containing one single-dose vial either as:o500 mg/10 mL (50 mg/mL) (NDC 0310-4611-50)o120 mg/2.4 mL (50 mg/mL) (NDC 0310-4500-12)Store in refrigerator at 2C to 8C (36F to 46F) in original carton to protect from light.Do not freeze. Do not shake.. o500 mg/10 mL (50 mg/mL) (NDC 0310-4611-50). o120 mg/2.4 mL (50 mg/mL) (NDC 0310-4500-12).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE IMFINZI is programmed death-ligand (PD-L1) blocking antibody indicated:oin combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by IMFINZI continued as single agent as adjuvant treatment after surgery, for the treatment of adult patients with resectable (tumors >= cm and/or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements. (1.1)oas single agent, for the treatment of adult patients with unresectable, Stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. (1.1)oin combination with tremelimumab-actl and platinum-based chemotherapy, for the treatment of adult patients with metastatic NSCLC with no sensitizing EGFR mutations or ALK genomic tumor aberrations. (1.1)oas single agent, for the treatment of adult patients with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. (1.2)oin combination with etoposide and either carboplatin or cisplatin, as first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). (1.2)oin combination with gemcitabine and cisplatin, as treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC). (1.3)oin combination with tremelimumab-actl, for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC). (1.4)oin combination with carboplatin and paclitaxel followed by IMFINZI as single agent, for the treatment of adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) as determined by an FDA-authorized test. (1.5, 2.1)oin combination with Bacillus Calmette-Guerin (BCG) for the treatment of adult patients with BCG-naive, high-risk non-muscle-invasive bladder cancer (NMIBC). (1.6)oin combination with gemcitabine and cisplatin as neoadjuvant treatment, followed by single agent IMFINZI as adjuvant treatment following radical cystectomy, for the treatment of adult patients with muscle invasive bladder cancer (MIBC). (1.6)oin combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy as neoadjuvant and adjuvant treatment, followed by single agent IMFINZI, for the treatment of adult patients with resectable gastric or gastroesophageal junction adenocarcinoma (GC/GEJC). (1.7). IMFINZI is programmed death-ligand (PD-L1) blocking antibody indicated:. oin combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by IMFINZI continued as single agent as adjuvant treatment after surgery, for the treatment of adult patients with resectable (tumors >= cm and/or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements. (1.1). oas single agent, for the treatment of adult patients with unresectable, Stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. (1.1). oin combination with tremelimumab-actl and platinum-based chemotherapy, for the treatment of adult patients with metastatic NSCLC with no sensitizing EGFR mutations or ALK genomic tumor aberrations. (1.1). oas single agent, for the treatment of adult patients with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. (1.2). oin combination with etoposide and either carboplatin or cisplatin, as first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). (1.2). oin combination with gemcitabine and cisplatin, as treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC). (1.3). oin combination with tremelimumab-actl, for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC). (1.4). oin combination with carboplatin and paclitaxel followed by IMFINZI as single agent, for the treatment of adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) as determined by an FDA-authorized test. (1.5, 2.1). oin combination with Bacillus Calmette-Guerin (BCG) for the treatment of adult patients with BCG-naive, high-risk non-muscle-invasive bladder cancer (NMIBC). (1.6). oin combination with gemcitabine and cisplatin as neoadjuvant treatment, followed by single agent IMFINZI as adjuvant treatment following radical cystectomy, for the treatment of adult patients with muscle invasive bladder cancer (MIBC). (1.6). oin combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy as neoadjuvant and adjuvant treatment, followed by single agent IMFINZI, for the treatment of adult patients with resectable gastric or gastroesophageal junction adenocarcinoma (GC/GEJC). (1.7). 1.1 Non-Small Cell Lung Cancer oIMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by IMFINZI continued as single agent as adjuvant treatment after surgery, is indicated for the treatment of adult patients with resectable (tumors >= cm and/or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements.oIMFINZI, as single agent, is indicated for the treatment of adult patients with unresectable Stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT).oIMFINZI, in combination with tremelimumab-actl and platinum-based chemotherapy, is indicated for the treatment of adult patients with metastatic NSCLC with no sensitizing EGFR mutations or ALK genomic tumor aberrations.. oIMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by IMFINZI continued as single agent as adjuvant treatment after surgery, is indicated for the treatment of adult patients with resectable (tumors >= cm and/or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements.. oIMFINZI, as single agent, is indicated for the treatment of adult patients with unresectable Stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT).. oIMFINZI, in combination with tremelimumab-actl and platinum-based chemotherapy, is indicated for the treatment of adult patients with metastatic NSCLC with no sensitizing EGFR mutations or ALK genomic tumor aberrations.. 1.2 Small Cell Lung Cancer oIMFINZI, as single agent, is indicated for the treatment of adult patients with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT).oIMFINZI, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).. oIMFINZI, as single agent, is indicated for the treatment of adult patients with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT).. oIMFINZI, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).. 1.3 Biliary Tract Cancers IMFINZI, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC).. 1.4 Hepatocellular Carcinoma IMFINZI, in combination with tremelimumab-actl, is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC).. 1.5 Endometrial Cancer IMFINZI, in combination with carboplatin and paclitaxel followed by IMFINZI as single agent, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) as determined by an FDA-approved test [see Dosage and Administration (2.1)].. 1.6 Bladder Cancer. oIMFINZI in combination with Bacillus Calmette-Guerin (BCG) is indicated for the treatment of adult patients with BCG-naive, high-risk non-muscle-invasive bladder cancer (NMIBC).oIMFINZI in combination with gemcitabine and cisplatin as neoadjuvant treatment, followed by single agent IMFINZI as adjuvant treatment following radical cystectomy, is indicated for the treatment of adult patients with muscle invasive bladder cancer (MIBC).. oIMFINZI in combination with Bacillus Calmette-Guerin (BCG) is indicated for the treatment of adult patients with BCG-naive, high-risk non-muscle-invasive bladder cancer (NMIBC).. oIMFINZI in combination with gemcitabine and cisplatin as neoadjuvant treatment, followed by single agent IMFINZI as adjuvant treatment following radical cystectomy, is indicated for the treatment of adult patients with muscle invasive bladder cancer (MIBC).. 1.7 Gastric or gastroesophageal junction adenocarcinoma IMFINZI in combination with fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) as neoadjuvant and adjuvant treatment, followed by single-agent IMFINZI, is indicated for the treatment of adult patients with resectable gastric or gastroesophageal junction adenocarcinoma (GC/GEJC).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).Immune-Mediated Adverse ReactionsInform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of IMFINZI [see Warnings and Precautions (5.1)], including:oPneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath.oHepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding.oColitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain.oEndocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, type diabetes mellitus, or hypophysitis.oNephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.oDermatological Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of severe dermatological reactions.oPancreatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of pancreatitis.oOther Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of pancreatitis, aseptic meningitis, encephalitis, immune thrombocytopenia, myocarditis, hemolytic anemia, myositis, uveitis, keratitis, and myasthenia gravis.Infusion-Related Reactions: oAdvise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2)].Complications of Allogeneic HSCT: oAdvise patients of potential risk of post-transplant complications [see Warnings and Precautions (5.3)].Embryo-Fetal Toxicity: oAdvise females of reproductive potential that IMFINZI can cause harm to fetus and to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1, 8.3)].oAdvise females of reproductive potential to use effective contraception during treatment and for months after the last dose of IMFINZI [see Use in Specific Populations (8.3)].Lactation: oAdvise female patients not to breastfeed while taking IMFINZI and for months after the last dose [see Warnings and Precautions (5.4) and Use in Specific Populations (8.2)].Manufactured for:AstraZeneca Pharmaceuticals LPWilmington, DE 19850. oPneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath.. oHepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding.. oColitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain.. oEndocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, type diabetes mellitus, or hypophysitis.. oNephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.. oDermatological Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of severe dermatological reactions.. oPancreatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of pancreatitis.. oOther Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of pancreatitis, aseptic meningitis, encephalitis, immune thrombocytopenia, myocarditis, hemolytic anemia, myositis, uveitis, keratitis, and myasthenia gravis.. oAdvise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2)].. oAdvise patients of potential risk of post-transplant complications [see Warnings and Precautions (5.3)].. oAdvise females of reproductive potential that IMFINZI can cause harm to fetus and to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1, 8.3)].. oAdvise females of reproductive potential to use effective contraception during treatment and for months after the last dose of IMFINZI [see Use in Specific Populations (8.3)].. oAdvise female patients not to breastfeed while taking IMFINZI and for months after the last dose [see Warnings and Precautions (5.4) and Use in Specific Populations (8.2)].

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Expression of programmed cell death ligand-1 (PD-L1) can be induced by inflammatory signals (e.g., IFN-gamma) and can be expressed on both tumor cells and tumor-associated immune cells in the tumor microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation, and cytokine production.Durvalumab is human immunoglobulin G1 kappa (IgG1) monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, without inducing antibody dependent cell-mediated cytotoxicity (ADCC).PD-L1 blockade with durvalumab led to increased T-cell activation in vitro and decreased tumor size in co-engrafted human tumor and immune cell xenograft mouse models.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic and genotoxic potential of durvalumab have not been evaluated.Animal fertility studies have not been conducted with durvalumab. In repeat-dose toxicology studies with durvalumab in sexually mature cynomolgus monkeys of up to months duration, there were no notable effects on the male and female reproductive organs.. 13.2 Animal Toxicology and/or Pharmacology In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. Mycobacterium tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 blockade using primate anti-PD-1 antibody was also shown to exacerbate M. tuberculosis infection in rhesus macaques. PD-L1 and PD-1 knockout mice and mice receiving PD-L1 blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0310-4500-12Rx onlyIMFINZI(TM)(durvalumab)Injection120 mg/2.4 mL(50 mg/mL)For Intravenous Infusion After DilutionSingle-dose vial. Discard unused portion.Store at to 8C (36 to 46F).Do not freeze or shake.Keep vial in original carton to protect from light.Attention Pharmacist: Dispense the accompanying Medication Guide to each patient.Do not use if vial seal is broken or missing.Must dilute before use.See prescribing information.AstraZeneca. 0310450012.

PEDIATRIC USE SECTION.

8.4 Pediatric Use The safety and effectiveness of IMFINZI have not been established in pediatric patients. Safety and efficacy were assessed but not established in multi-center, open-label study (NCT03837899) in 45 pediatric patients aged to 17 years with advanced solid tumors. All 45 patients received at least single dose of IMFINZI, and 41 patients received IMFINZI in combination with tremelimumab-actl. No new safety signals were observed in pediatric patients in this study. Durvalumab systemic exposure in pediatric patients weighing >= 35 kg was within the range of values previously observed in adults given the same weight-based dose, whereas the systemic exposure in pediatric patients weighing 35 kg was lower than that observed in adults.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics The steady state AUC, Ctrough, and Cmax in patients administered with 1,500 mg every weeks are 6% higher, 19% lower, and 55% higher than those administered with 10 mg/kg every weeks, respectively. Based on the modeling of pharmacokinetic data and exposure relationships for safety, there are no anticipated clinically meaningful differences in efficacy and safety for the doses of 1,500 mg every weeks compared to 10 mg/kg every weeks in patients weighing 30 kg with NSCLC.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics The pharmacokinetics of durvalumab as single agent was studied in patients with doses ranging from 0.1 mg/kg (0.01 times the approved recommended dosage) to 20 mg/kg (2 times the approved recommended dosage) administered once every two, three, or four weeks.PK exposure increased more than dose-proportionally at doses 3 mg/kg (0.3 times the approved recommended dosage) and dose proportionally at doses >= mg/kg every weeks. Steady state was achieved at approximately 16 weeks.The pharmacokinetics of durvalumab is similar when assessed as single agent, when in combination with chemotherapy, when in combination with tremelimumab-actl and when in combination with tremelimumab-actl and platinum-based chemotherapy.DistributionThe geometric mean (% coefficient of variation [CV%]) steady state volume of distribution (Vss) was 5.4 (13.1%) L.EliminationDurvalumab clearance decreases over time, with mean maximal reduction (CV%) from baseline values of approximately 23% (57%) resulting in geometric mean (CV%) steady state clearance (CLss) of mL/h (39%) at day 365; the decrease in CLss is not considered clinically relevant. The geometric mean (CV%) terminal half-life, based on baseline CL was approximately 21 (26%) days.Specific PopulationsThere were no clinically significant differences in the pharmacokinetics of durvalumab based on body weight (31 to 175 kg), age (18 to 96 years), sex, race (White, Black, Asian, Native Hawaiian, Pacific Islander, or Native American), albumin levels (4 to 57 g/L), lactate dehydrogenase levels (18 to 15,800 U/L), soluble PD-L1 (67 to 3,470 pg/mL), tumor type (NSCLC, SCLC, BTC and HCC), mild or moderate renal impairment (CLcr 30 to 89 mL/min), and mild or moderate hepatic impairment (bilirubin <= 3x ULN and any AST). The effect of severe renal impairment (CLcr 15 to 29 mL/min) or severe hepatic impairment (bilirubin 3x ULN and any AST) on the pharmacokinetics of durvalumab is unknown.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryBased on findings from animal studies and its mechanism of action, IMFINZI can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of IMFINZI in pregnant women.In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery at exposure levels approximately to 20 times higher than those observed at the clinical dose of 10 mg/kg based on area under the curve (AUC), resulted in an increase in premature delivery, fetal loss, and premature neonatal death (see Data). Human immunoglobulin G1 (IgG1) is known to cross the placental barrier; therefore, durvalumab has the potential to be transmitted from the mother to the developing fetus. Apprise pregnant women of the potential risk to fetus.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.DataAnimal DataAs reported in the literature, the PD-1/PD-L1 pathway plays central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. In mouse allogeneic pregnancy models, disruption of PD-L1 signaling was shown to result in an increase in fetal loss. The effects of durvalumab on prenatal and postnatal development were evaluated in reproduction studies in cynomolgus monkeys. Durvalumab was administered from the confirmation of pregnancy through delivery at exposure levels approximately to 20 times higher than those observed at clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature delivery, fetal loss (abortion and stillbirth), and increase in neonatal deaths. Durvalumab was detected in infant serum on postpartum Day 1, indicating the presence of placental transfer of durvalumab. Based on its mechanism of action, fetal exposure to durvalumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1.6) 05/2026Indications and Usage (1.7) 11/2025Dosage and Administration 2.2) 05/2026.

SPL UNCLASSIFIED SECTION.

1.1 Non-Small Cell Lung Cancer oIMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by IMFINZI continued as single agent as adjuvant treatment after surgery, is indicated for the treatment of adult patients with resectable (tumors >= cm and/or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements.oIMFINZI, as single agent, is indicated for the treatment of adult patients with unresectable Stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT).oIMFINZI, in combination with tremelimumab-actl and platinum-based chemotherapy, is indicated for the treatment of adult patients with metastatic NSCLC with no sensitizing EGFR mutations or ALK genomic tumor aberrations.. oIMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by IMFINZI continued as single agent as adjuvant treatment after surgery, is indicated for the treatment of adult patients with resectable (tumors >= cm and/or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements.. oIMFINZI, as single agent, is indicated for the treatment of adult patients with unresectable Stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT).. oIMFINZI, in combination with tremelimumab-actl and platinum-based chemotherapy, is indicated for the treatment of adult patients with metastatic NSCLC with no sensitizing EGFR mutations or ALK genomic tumor aberrations.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy Risk SummaryBased on findings from animal studies and its mechanism of action, IMFINZI can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of IMFINZI in pregnant women.In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery at exposure levels approximately to 20 times higher than those observed at the clinical dose of 10 mg/kg based on area under the curve (AUC), resulted in an increase in premature delivery, fetal loss, and premature neonatal death (see Data). Human immunoglobulin G1 (IgG1) is known to cross the placental barrier; therefore, durvalumab has the potential to be transmitted from the mother to the developing fetus. Apprise pregnant women of the potential risk to fetus.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.DataAnimal DataAs reported in the literature, the PD-1/PD-L1 pathway plays central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. In mouse allogeneic pregnancy models, disruption of PD-L1 signaling was shown to result in an increase in fetal loss. The effects of durvalumab on prenatal and postnatal development were evaluated in reproduction studies in cynomolgus monkeys. Durvalumab was administered from the confirmation of pregnancy through delivery at exposure levels approximately to 20 times higher than those observed at clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature delivery, fetal loss (abortion and stillbirth), and increase in neonatal deaths. Durvalumab was detected in infant serum on postpartum Day 1, indicating the presence of placental transfer of durvalumab. Based on its mechanism of action, fetal exposure to durvalumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice.. 8.2 Lactation Risk SummaryThere are no data on the presence of durvalumab in human milk, its effects on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to IMFINZI are unknown. Durvalumab was present in the milk of lactating cynomolgus monkeys and was associated with premature neonatal death (see Data). Because of the potential for adverse reactions in breastfed child, advise women not to breastfeed during treatment with IMFINZI and for months after the last dose. Refer to the Prescribing Information for the agents administered in combination with IMFINZI for recommended duration to not breastfeed, as appropriate.DataIn lactating cynomolgus monkeys, durvalumab was present in breast milk at about 0.15% of maternal serum concentrations after administration of durvalumab from the confirmation of pregnancy through delivery at exposure levels approximately to 20 times higher than those observed at the recommended clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature neonatal death. 8.3 Females and Males of Reproductive Potential Pregnancy testingVerify pregnancy status of females of reproductive potential prior to initiating treatment with IMFINZI.ContraceptionFemalesIMFINZI 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 IMFINZI and for months following the last dose of IMFINZI. Refer to the Prescribing Information for the agents administered in combination with IMFINZI for recommended contraception duration, as appropriate.. 8.4 Pediatric Use The safety and effectiveness of IMFINZI have not been established in pediatric patients. Safety and efficacy were assessed but not established in multi-center, open-label study (NCT03837899) in 45 pediatric patients aged to 17 years with advanced solid tumors. All 45 patients received at least single dose of IMFINZI, and 41 patients received IMFINZI in combination with tremelimumab-actl. No new safety signals were observed in pediatric patients in this study. Durvalumab systemic exposure in pediatric patients weighing >= 35 kg was within the range of values previously observed in adults given the same weight-based dose, whereas the systemic exposure in pediatric patients weighing 35 kg was lower than that observed in adults.. 8.5 Geriatric Use Of the 401 patients with resectable NSCLC treated with IMFINZI in combination with chemotherapy in the AEGEAN study, 209 (52%) patients were 65 years or older and 49 (12%) patients were 75 years or older. There were no overall clinically meaningful differences in safety or efficacy between patients >= 65 years of age and younger patients.Of the 476 patients with unresectable, Stage III NSCLC treated with IMFINZI in the PACIFIC study, 45% were 65 years or older, while 7.6% were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients. The PACIFIC study did not include sufficient numbers of patients aged 75 years and over to determine whether they respond differently from younger patients.Of the 330 patients with metastatic NSCLC treated with IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy, 143 (43%) patients were 65 years or older and 35 (11%) patients were 75 years or older. There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients.Of the 262 patients with LS-SCLC treated with IMFINZI, 103 (39%) patients were 65 years or older and 15 (6%) patients were 75 years or older. There were no clinically meaningful differences in safety and efficacy between patients 65 years or older and younger patients.Of the 265 patients with ES-SCLC treated with IMFINZI in combination with chemotherapy 101 (38%) patients were 65 years or older and 19 (7.2%) patients were 75 years or older. There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients.Of the 338 patients with BTC treated with IMFINZI in combination with chemotherapy in the TOPAZ-1 study, 158 (47%) patients were 65 years or older and 38 (11%) patients were 75 years or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients.Of the 393 patients with uHCC treated with IMFINZI in combination with tremelimumab-actl, 50% of patients were 65 years of age or older and 13% of patients were 75 years of age or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients.Of the 235 patients with endometrial cancer treated with IMFINZI with carboplatin and paclitaxel, 49% of patients were 65 years of age or older and 12% of patients were 75 years of age or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients.Of the 530 patients with MIBC treated with IMFINZI in combination with gemcitabine and cisplatin in the NIAGARA study, 272 (51%) patients were 65 years or older, and 57 (11%) patients were 75 years or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients.Of the 336 patients with NMIBC treated with IMFINZI in combination with BCG induction and maintenance in the POTOMAC study, 215 (64%) patients were 65 years of age and 72 (21%) patients were >75 years of age or older. No overall differences in safety or effectiveness of IMFINZI were observed between patients >65 years of age and younger adult patients.Of the 475 patients with resectable GC/GEJC treated with IMFINZI in combination with FLOT chemotherapy in the MATTERHORN study, 184 (39%) patients were 65 years or older and 37 (8%) patients were 75 years or older. No overall differences in safety or effectiveness were observed between patients >= 65 years of age and younger adult patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oImmune-Mediated Adverse Reactions (5.1)Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, immune-mediated nephritis and renal dysfunction, solid organ transplant rejection, and immune-mediated pancreatitis.oMonitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. oWithhold or permanently discontinue based on severity and type of reaction.oInfusion-Related Reactions: Interrupt, slow the rate of infusion, or permanently discontinue IMFINZI based on the severity of the reaction. (5.2)oComplications of Allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with PD-1/PD-L1 blocking antibody. (5.3)oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and use of effective contraception. (5.4, 8.1, 8.3). oImmune-Mediated Adverse Reactions (5.1)Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, immune-mediated nephritis and renal dysfunction, solid organ transplant rejection, and immune-mediated pancreatitis.oMonitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. oWithhold or permanently discontinue based on severity and type of reaction.. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, immune-mediated nephritis and renal dysfunction, solid organ transplant rejection, and immune-mediated pancreatitis.oMonitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. oWithhold or permanently discontinue based on severity and type of reaction.. oMonitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. oWithhold or permanently discontinue based on severity and type of reaction.. oInfusion-Related Reactions: Interrupt, slow the rate of infusion, or permanently discontinue IMFINZI based on the severity of the reaction. (5.2). oComplications of Allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with PD-1/PD-L1 blocking antibody. (5.3). oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and use of effective contraception. (5.4, 8.1, 8.3). 5.1 Immune-Mediated Adverse Reactions. IMFINZI is monoclonal antibody that belongs to class of drugs that bind to either the programmed death-receptor (PD-1) or the PD-ligand (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions.The incidence and severity of immune-mediated adverse reactions were similar when IMFINZI was administered as single agent or in combination with chemotherapy, tremelimumab-actl and platinum-based chemotherapy, or BCG, unless otherwise noted.Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with PD 1/PD L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.Withhold or permanently discontinue IMFINZI depending on severity [see Dosage and Administration (2.3) ]. In general, if IMFINZI requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to mg/kg/day prednisone or equivalent) until improvement to Grade or less. Upon improvement to Grade or less, initiate corticosteroid taper and continue to taper over at least month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.Immune-Mediated PneumonitisIMFINZI can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation.IMFINZI as Single AgentIn Patients Who Did Not Receive Recent Prior RadiationIn patients who received IMFINZI on clinical studies in which radiation therapy was generally not administered immediately prior to initiation of IMFINZI, the incidence of immune-mediated pneumonitis was 2.4% (34/1414), including fatal (< 0.1%), and Grade 3-4 (0.4%) adverse reactions. Events resolved in 19 of the 34 patients and resulted in permanent discontinuation in patients. Systemic corticosteroids were required in 19 patients (19/34) with pneumonitis who did not receive chemoradiation prior to initiation of IMFINZI.The frequency and severity of immune-mediated pneumonitis in patients who did not receive definitive chemoradiation prior to IMFINZI were similar whether IMFINZI was given as single agent in patients with various cancers in pooled data set or in patients with ES-SCLC or BTC when given in combination with chemotherapy.In Patients Who Received Recent Prior RadiationThe incidence of pneumonitis (including radiation pneumonitis) in patients with unresectable Stage III NSCLC following definitive chemoradiation within 42 days prior to initiation of IMFINZI in PACIFIC was 18.3% (87/475) in patients receiving IMFINZI and 12.8% (30/234) in patients receiving placebo. Of the patients who received IMFINZI (475), 1.1% had fatal adverse reaction and 2.7% had Grade adverse reactions. Events resolved in 50 of the 87 (57%) patients and resulted in permanent discontinuation in 27 of the 87 (31%) patients. Systemic corticosteroids were required in 64 patients (64/87) with pneumonitis who had received chemoradiation prior to initiation of IMFINZI, while patients required use of infliximab with high-dose steroids.The incidence of pneumonitis (including radiation pneumonitis) in patients with LS-SCLC following chemoradiation within 42 days prior to initiation of IMFINZI in ADRIATIC was 14% (37/262) in patients receiving IMFINZI and 6% (16/265) in patients receiving placebo. Of the patients who received IMFINZI (262), 0.4% had fatal adverse reaction and 2.7% had Grade adverse reactions. Events resolved in 19 of the 37 (51%) patients and resulted in permanent discontinuation in 18 of the 37 (49%) patients. Systemic corticosteroids were required in all patients, while patient required use of infliximab with high-dose steroids.IMFINZI with Tremelimumab-actlImmune-mediated pneumonitis occurred in 1.3% (5/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including fatal (0.3%) and Grade (0.2%) adverse reactions. Events resolved in of the patients and resulted in permanent discontinuation in patient. Systemic corticosteroids were required in all patients; of these, patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient (1/5) required other immunosuppressants.IMFINZI with Tremelimumab-actl and Platinum-Based ChemotherapyImmune-mediated pneumonitis occurred in 3.5% (21/596) of patients receiving IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy, including fatal (0.5%), and Grade (1%) adverse reactions. Events resolved in 11 of the 21 patients and resulted in permanent discontinuation in patients. Systemic corticosteroids were required in all patients with immune-mediated pneumonitis, while patient (1/21) required other immunosuppressants.Immune-Mediated ColitisIMFINZI can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.IMFINZI as Single AgentImmune-mediated colitis occurred in 2% (37/1889) of patients receiving IMFINZI, including Grade (< 0.1%) and Grade (0.4%) adverse reactions. Events resolved in 27 of the 37 patients and resulted in permanent discontinuation in patients. Systemic corticosteroids were required in all patients with immune-mediated colitis, while patients (2/37) required other immunosuppressants (e.g., infliximab, mycophenolate).IMFINZI with Tremelimumab-actlImmune-mediated colitis or diarrhea occurred in 6% (23/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade (3.6%) adverse reactions. Events resolved in 22 of the 23 patients and resulted in permanent discontinuation in patients. All patients received systemic corticosteroids, and 20 of the 23 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Three patients also received other immunosuppressants.Intestinal perforation has been observed in other studies of IMFINZI in combination with tremelimumab-actl.IMFINZI with Tremelimumab-actl and Platinum-Based ChemotherapyImmune-mediated colitis occurred in 6.5% (39/596) of patients receiving IMFINZI in combination with tremelimumab-actl including fatal (0.2%) and Grade (2.5%) adverse reactions. Events resolved in 33 of 39 patients and resulted in permanent discontinuation in 11 patients. Systemic corticosteroids were required in all patients with immune-mediated colitis, while patients (4/39) required other corticosteroids.Intestinal perforation and large intestine perforation were reported in 0.1% of patients receiving IMFINZI in combination with tremelimumab-actl.Immune-Mediated HepatitisIMFINZI can cause immune-mediated hepatitis.IMFINZI as Single AgentImmune-mediated hepatitis occurred in 2.8% (52/1889) of patients receiving IMFINZI, including fatal (0.2%), Grade (0.3%) and Grade (1.4%) adverse reactions. Events resolved in 21 of the 52 patients and resulted in permanent discontinuation of IMFINZI in patients. Systemic corticosteroids were required in all patients with immune-mediated hepatitis, while patients (2/52) required use of mycophenolate with high-dose steroids.IMFINZI with Tremelimumab-actlImmune-mediated hepatitis occurred in 7.5% (29/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including fatal (0.8%), Grade (0.3%), and Grade (4.1%) adverse reactions. Events resolved in 12 of the 29 patients and resulted in permanent discontinuation in patients. Systemic corticosteroids were required in all 29 patients and all 29 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Eight patients (8/29) required other immunosuppressants.IMFINZI with Tremelimumab-actl and Platinum-Based ChemotherapyImmune-mediated hepatitis occurred in 3.9% (23/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including fatal (0.3%), Grade (0.5%), and Grade (2.0%) adverse reactions. Events resolved in 12 of the 23 patients and resulted in permanent discontinuation in 10 patients. Systemic corticosteroids were required in all patients with immune-mediated hepatitis, while patients (2/23) required use of other immunosuppressants.Immune-Mediated EndocrinopathiesAdrenal Insufficiency IMFINZI can cause primary or secondary adrenal insufficiency. For Grade or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold or permanently discontinue IMFINZI based on the severity [see Dosage and Administration (2.3) ].IMFINZI as Single AgentImmune-mediated adrenal insufficiency occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade (< 0.1%) adverse reactions. Events resolved in of the patients and did not lead to permanent discontinuation of IMFINZI in any patients. Systemic corticosteroids were required in all patients with adrenal insufficiency; of these, the majority remained on systemic corticosteroids.IMFINZI with Tremelimumab-actlImmune-mediated adrenal insufficiency occurred in 1.5% (6/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade (0.3%) adverse reactions. Events resolved in of the patients. Systemic corticosteroids were required in all patients, and of these, patient required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).IMFINZI with Tremelimumab-actl and Platinum-Based ChemotherapyImmune-mediated adrenal insufficiency occurred in 2.2% (13/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade (0.8%) adverse reactions. Events resolved in of the 13 patients and resulted in permanent discontinuation in patient. Systemic corticosteroids were required in all patients with adrenal insufficiency. One patient also required endocrine therapy.HypophysitisIMFINZI can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. Withhold or permanently discontinue IMFINZI depending on severity [see Dosage and Administration (2.3) ].IMFINZI as Single AgentGrade hypophysitis/hypopituitarism occurred in 0.1% (1/1889) of patients who received IMFINZI. Treatment with systemic corticosteroids was administered in this patient. The event did not lead to permanent discontinuation of IMFINZI.IMFINZI with Tremelimumab-actlImmune-mediated hypophysitis/hypopituitarism occurred in 1% (4/388) of patients receiving IMFINZI in combination with tremelimumab-actl. Events resolved in of the patients. Systemic corticosteroids were required in patients, and of these, patient received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Two patients also required endocrine therapy.IMFINZI with Tremelimumab-actl and Platinum-Based ChemotherapyImmune-mediated hypophysitis occurred in 1.3% (8/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade (0.5%) adverse reactions. Events resulted in permanent discontinuation in patient. Systemic corticosteroids were required in patients with immune-mediated hypophysitis; of these, of the patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Four patients also required endocrine therapy.Thyroid DisordersIMFINZI can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or discontinue IMFINZI based on the severity [see Dosage and Administration (2.3) ]. ThyroiditisIMFINZI as Single AgentImmune-mediated thyroiditis occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade (< 0.1%) adverse reactions. Events resolved in of the patients and resulted in permanent discontinuation in patient. Systemic corticosteroids were required in patients (3/9) with immune-mediated thyroiditis, while patients (8/9) required endocrine therapy.IMFINZI with Tremelimumab-actlImmune-mediated thyroiditis occurred in 1.5% (6/388) of patients receiving IMFINZI in combination with tremelimumab-actl. Events resolved in of the patients. Systemic corticosteroids were required in patients (2/6) with immune-mediated thyroiditis; of these, patient required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy including hormone replacement therapy, thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker.IMFINZI with Tremelimumab-actl and Platinum-Based ChemotherapyImmune-mediated thyroiditis occurred in 1.2% (7/596) of patients receiving IMFINZI in combination with tremelimumab-actl. Events resolved in of the patients and one resulted in permanent discontinuation. Systemic corticosteroids were required in patients (2/7) with immune-mediated thyroiditis, while all patients required endocrine therapy.HyperthyroidismIMFINZI as Single AgentImmune-mediated hyperthyroidism occurred in 2.1% (39/1889) of patients receiving IMFINZI. Events resolved in 30 of the 39 patients and did not lead to permanent discontinuation of IMFINZI in any patients. Systemic corticosteroids were required in patients (9/39) with immune-mediated hyperthyroidism, while 35 patients (35/39) required endocrine therapy.IMFINZI with Tremelimumab-actlImmune-mediated hyperthyroidism occurred in 4.6% (18/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade (0.3%) adverse reactions. Events resolved in 15 of the 18 patients. Two patients (2/18) required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Seventeen patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker).IMFINZI with Tremelimumab-actl and Platinum-Based ChemotherapyImmune-mediated hyperthyroidism occurred in 5% (30/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade (0.2%) adverse reactions. Events resolved in 21 of the 30 patients. Systemic corticosteroids were required in patients (5/30) with immune-mediated hyperthyroidism, while 28 patients (28/30) required endocrine therapy.HypothyroidismIMFINZI as Single Agent Immune-mediated hypothyroidism occurred in 8.3% (156/1889) of patients receiving IMFINZI, including Grade (<0.1%) adverse reactions. Events resolved in 31 of the 156 patients and did not lead to permanent discontinuation of IMFINZI in any patients. Systemic corticosteroids were required in 11 patients (11/156) and the majority of patients (152/156) required long-term thyroid hormone replacement.IMFINZI with Tremelimumab-actlImmune-mediated hypothyroidism occurred in 11% (42/388) of patients receiving IMFINZI in combination with tremelimumab-actl. Events resolved in of the 42 patients. One patient received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker).IMFINZI with Tremelimumab-actl and Platinum-Based ChemotherapyImmune-mediated hypothyroidism occurred in 8.6% (51/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade (0.5%) adverse reactions. Systemic corticosteroids were required in patients (2/51) and all patients required endocrine therapy.IMFINZI with Carboplatin and PaclitaxelImmune-mediated hypothyroidism occurred in 14% (34/235) of patients receiving IMFINZI in combination with carboplatin and paclitaxel. Events resolved in of the 34 patients. Endocrine therapy was required in 34 of the 34 patients. Type Diabetes Mellitus, which can present with diabetic ketoacidosisMonitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue IMFINZI based on the severity [see Dosage and Administration (2.3) ]. IMFINZI as Single AgentGrade immune-mediated type diabetes mellitus occurred in 0.1% (1/1889) of patients receiving IMFINZI. This patient required long-term insulin therapy and IMFINZI was permanently discontinued. Two additional patients (0.1%, 2/1889) had events of hyperglycemia requiring insulin therapy that did not resolve at the time of reporting.IMFINZI with Tremelimumab-actlTwo patients (0.5%, 2/388) had events of hyperglycemia requiring insulin therapy that had not resolved at last follow-up.IMFINZI with Tremelimumab-actl and Platinum-Based ChemotherapyImmune-mediated Type diabetes mellitus occurred in 0.5% (3/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade (0.3%) adverse reactions. All patients required endocrine therapy.Immune-Mediated Nephritis with Renal DysfunctionIMFINZI can cause immune-mediated nephritis.IMFINZI as Single AgentImmune-mediated nephritis occurred in 0.5% (10/1889) of patients receiving IMFINZI, including Grade (< 0.1%) adverse reactions. Events resolved in of the 10 patients and resulted in permanent discontinuation in patients. Systemic corticosteroids were required in all patients with immune-mediated nephritis.IMFINZI with Tremelimumab-actlImmune-mediated nephritis occurred in 1% (4/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade (0.5%) adverse reactions. Events resolved in of the patients and resulted in permanent discontinuation in patients. Systemic corticosteroids were required in all patients with immune-mediated nephritis; of these, patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).IMFINZI with Tremelimumab-actl and Platinum-Based ChemotherapyImmune-mediated nephritis occurred in 0.7% (4/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade (0.2%) adverse reactions. Events resolved in of the patients and resulted in permanent discontinuation in patients. Systemic corticosteroids were required in all patients with immune-mediated nephritis.Immune-Mediated Dermatology Reactions IMFINZI can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue IMFINZI depending on severity [see Dosage and Administration (2.3)]. IMFINZI as Single AgentImmune-mediated rash or dermatitis occurred in 1.8% (34/1889) of patients receiving IMFINZI, including Grade (0.4%) adverse reactions. Events resolved in 19 of the 34 patients and resulted in permanent discontinuation in patients. Systemic corticosteroids were required in all patients with immune-mediated rash or dermatitis.IMFINZI with Tremelimumab-actlImmune-mediated rash or dermatitis occurred in 4.9% (19/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade (0.3%) and Grade (1.5%) adverse reactions. Events resolved in 13 of the 19 patients and resulted in permanent discontinuation in patients. Systemic corticosteroids were required in all patients with immune-mediated rash or dermatitis; of these, 12 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient received other immunosuppressants.IMFINZI with Tremelimumab-actl and Platinum-Based ChemotherapyImmune-mediated rash or dermatitis occurred in 7.2% (43/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade (0.3%) adverse reactions. Events resolved in 32 of the 43 patients and resulted in permanent discontinuation in patients. Systemic corticosteroids were required in all patients with immune-mediated rash or dermatitis.Immune-Mediated PancreatitisIMFINZI in combination with tremelimumab-actl can cause immune-mediated pancreatitis.IMFINZI with Tremelimumab-actlImmune-mediated pancreatitis occurred in 2.3% (9/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade (0.3%) and Grade (1.5%) adverse reactions. Events resolved in of the patients. Systemic corticosteroids were required in all patients, and of these patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).Other Immune-Mediated Adverse ReactionsThe following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI or IMFINZI in combination with tremelimumab-actl, or were reported with the use of other PD-1/PD-L1 blocking antibodies.Cardiac/vascular: Myocarditis, pericarditis, vasculitis.Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy.Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis.Musculoskeletal and connective tissue disorders: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic.Endocrine: Hypoparathyroidism.Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection, other transplant (including corneal graft) rejection.. 5.2 Infusion-Related Reactions IMFINZI can cause severe or life-threatening infusion-related reactions.Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue IMFINZI based on the severity [see Dosage and Administration (2.3) ]. For Grade or infusion-related reactions, consider using pre-medications with subsequent doses.IMFINZI as Single AgentInfusion-related reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade (0.3%) adverse reactions.IMFINZI in Combination with Tremelimumab-actlInfusion-related reactions occurred in 2.6% (10/388) of patients receiving IMFINZI in combination with tremelimumab-actl.IMFINZI with Tremelimumab-actl and Platinum-Based ChemotherapyInfusion-related reactions occurred in 2.9% (17/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade (0.3%) adverse reactions.. 5.3 Complications of Allogeneic HSCT after IMFINZI Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with PD-1/L-1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/L-1 blockade and allogeneic HSCT.Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT.. 5.4 Embryo-Fetal Toxicity Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to pregnant woman. In animal reproduction studies, administration of durvalumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased premature delivery, fetal loss and premature neonatal death. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI and for months after the last dose of IMFINZI [see Use in Specific Populations (8.1, 8.3)].