GERIATRIC USE SECTION.

8.5 Geriatric Use Of the 393 patients with uHCC treated with IMJUDO in combination with durvalumab, 50% of patients were 65 years or older and 13% of patients were 75 years or older. No overall differences in safety or efficacy of IMJUDO have been observed between patients 65 years or older and younger adult patients.Of the 330 patients with metastatic NSCLC treated with IMJUDO in combination with durvalumab and platinum-based chemotherapy, 143 (43%) patients were 65 years or older and 35 (11%) patients were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

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)].. Most common adverse reactions (>= 20%) of patients with uHCC are rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain. Most common laboratory abnormalities (>= 40%) of patients with uHCC are AST increased, ALT increased, hemoglobin decreased, sodium decreased, bilirubin increased, alkaline phosphatase increased, and lymphocytes decreased. (6.1)Most common adverse reactions (>= 20%) of patients with metastatic NSCLC were nausea, fatigue, musculoskeletal pain, decreased appetite, rash, and diarrhea. (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. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 reflect exposure to IMJUDO 300 mg in combination with durvalumab 1,500 mg in 388 patients in HIMALAYA. In the HIMALAYA study patients received IMJUDO 300 mg administered as single intravenous infusion in combination with durvalumab 1,500 mg on the same day, followed by durvalumab every weeks. The data also reflects exposure to IMJUDO 75 mg in combination with durvalumab 1,500 mg and histology-based platinum chemotherapy regimens in the pooled safety population (N=596) of 330 patients in POSEIDON [see Clinical Studies (14.1)], and 266 patients in CASPIAN who received up to four cycles of platinum-etoposide plus durvalumab 1,500 mg with tremelimumab-actl 75 mg every weeks, followed by durvalumab 1,500 mg every weeks (an unapproved regimen for extensive-stage small cell lung cancer). Of these patients, 64% received the maximum of doses of IMJUDO and 79% received at least doses. In this pooled safety population, the most common (> 20%) adverse reactions were nausea (37%), decreased appetite (25%), and fatigue (22%). In this pooled safety population, the most common Grade or (> 10%) laboratory abnormalities were neutropenia (39%), leukopenia (21%), lymphocytopenia (20%), anemia (20%), hyponatremia (14%), lipase increased (12%), and thrombocytopenia (11%).The data described in this section reflect exposure to IMJUDO in patients with uHCC included in the HIMALAYA study and in patients with metastatic NSCLC enrolled in the POSEIDON study.Hepatocellular CarcinomaUnresectable HCC HIMALAYAThe safety of IMJUDO administered in combination with durvalumab was evaluated in total of 388 patients with uHCC in HIMALAYA, randomized, open-label, multicenter study [see Clinical Studies (14.1)]. Patients received IMJUDO 300 mg administered as single intravenous infusion in combination with durvalumab 1,500 mg on the same day, followed by durvalumab every weeks or sorafenib 400 mg given orally twice daily.Serious adverse reactions occurred in 41% of patients who received IMJUDO in combination with durvalumab. 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 IMJUDO in combination with durvalumab, 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 the 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 summarizes the adverse reactions that occurred in patients treated with IMJUDO in combination with durvalumab in the HIMALAYA study.Table 6. Adverse Reactions Occurring in >= 10% Patients in the HIMALAYA studyIMJUDO and Durvalumab(N=388)Sorafenib(N=374)Adverse ReactionAll Grades (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)Gastrointestinal disorders DiarrheaRepresents composite of multiple related terms. 276454.3Abdominal pain 201.8244Nausea120140Skin and subcutaneous tissue disordersRash 322.85712Pruritus23060.3Metabolism and nutrition disordersDecreased appetite171.3180.8General disorders and administration site conditionsFatigue 263.9306Pyrexia 130.390.3Psychiatric disordersInsomnia100.34.30Endocrine disordersHypothyroidism 14060Musculoskeletal and Connective Tissue DisordersMusculoskeletal pain 222.6170.8Table summarizes the laboratory abnormalities that occurred in patients treated with IMJUDO in combination with durvalumab in the HIMALAYA study.Table 7. Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients in the HIMALAYA studyIMJUDO and DurvalumabSorafenibLaboratory 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: IMJUDO with durvalumab (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 decreased200.8301.1Non-Small Cell Lung CancerMetastatic NSCLC POSEIDONThe safety of IMJUDO in combination with durvalumab and platinum-based chemotherapy in patients with metastatic NSCLC was evaluated in POSEIDON (NCT03164616), randomized, open-label, multicenter, active-controlled trial. total of 330 patients received IMJUDO (>= 30 kg body weight received 75 mg and <= 30kg body weight received 1mg/kg) in combination with durvalumab 1,500 mg and histology-based platinum chemotherapy regimens [see Clinical Studies (14.2)]. Of these patients, 66% received up to the maximum doses of IMJUDO and 79% received at least doses. Treatment was continued with durvalumab as single agent (or with durvalumab and histology-based pemetrexed for non-squamous patients, based on the investigators decision) until disease progression or unacceptable toxicity. The trial excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids or immunosuppressants [see Clinical Studies (14.2)]. The median age of patients who received IMJUDO in combination with durvalumab 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 IMJUDO in combination with durvalumab 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 IMJUDO in combination with durvalumab 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 (1 patient), dyspnea (1 patient), sudden death (1 patient), and ischemic stroke (1 patient).Permanent discontinuation of IMJUDO or durvalumab due to an adverse reaction occurred in 17% of the patients. Adverse reactions which resulted in permanent discontinuation of IMJUDO or durvalumab in 2% of patients included pneumonia. Dosage interruptions or delay of IMJUDO and durvalumab due to an adverse reaction occurred in 41% of patients. Adverse reactions which required dosage interruption or delay of IMJUDO and durvalumab 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 8. Adverse Reactions (>= 10%) in Patients with NSCLC Who Received IMJUDO in the POSEIDON StudyIMJUDO with durvalumab and platinum-based chemotherapy = 330Platinum-based chemotherapy = 333Adverse ReactionAll Grades (%)Grade or (%)All Grades (%)Grade or (%)Respiratory, thoracic and mediastinal disordersCough/Productive CoughIncludes cough and productive cough. 12080.3Gastrointestinal disordersNausea421.8372.1Diarrhea221.5151.5Constipation190240.6Vomiting181.2141.5StomatitisIncludes mucosal inflammation and stomatitis. 10060.3Endocrine disordersHypothyroidismIncludes blood thyroid stimulating hormone increased and hypothyroidism. 1302.10Skin and subcutaneous tissue disordersRashIncludes eczema, erythema, dermatitis, drug eruption, erythema multiforme, pemphigoid, rash, rash maculo-papular, rash papular, rash pruritic and rash pustular. 272.4100.6Alopecia10060Pruritus1104.50General 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, spinal pain. 290.6221.5Metabolism and nutrition disordersDecreased appetite281.5251.2Infections and InfestationsPneumoniaIncludes lower respiratory tract infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia aspiration, pneumonia bacterial. 178124.2Upper respiratory tract infectionsIncludes laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, tonsillitis, tracheobronchitis and upper respiratory tract infection. 150.690.9Nervous system disordersHeadacheIncludes headache, migraine. 11080.6Table summarizes the laboratory abnormalities in POSEIDON.Table 9: Select Laboratory Abnormalities (>= 10%) That Worsened from Baseline in Patients with NSCLC Who Received IMJUDO in the POSEIDON StudyLaboratory AbnormalityGraded according to NCI CTCAE version 4.03IMJUDO with Durvalumab 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(%)ChemistryLipase increased 3514255Hyponatremia55135011Hypernatremia150140Amylase increased419256Hypokalemia217172.8Hyperglycemia426373.1Increased ALT646564.7Increased AST635552.2Blood creatinine increased 894.0831.9Increased Alkaline Phosphatase333.4261.2Gamma Glutamyl Transferase increased382.2354.7Hyperkalemia492.2352.8Albumin decreased271.9180.9Hypocalcemia580.9490.9Hypomagnesemia124230Bilirubinemia160.980.3HematologyNeutropenia71376932Anemia84248425Leukopenia77218118Lymphocytopenia67206019Thrombocytopenia53115412.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic and genotoxic potential of tremelimumab-actl have not been evaluated.Animal fertility studies have not been conducted with tremelimumab-actl,.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action CTLA-4 is negative regulator of T-cell activity. Tremelimumab--actl is monoclonal antibody that binds to CTLA-4 and blocks the interaction with its ligands CD80 and CD86, releasing CTLA-4-mediated inhibition of T-cell activation. In synergistic mouse tumor models, blocking CTLA-4 activity resulted in decreased tumor growth and increased proliferation of cells in tumors.. 12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of tremelimumab-actl have not been fully characterized.. 12.3 Pharmacokinetics The pharmacokinetics of tremelimumab-actl was studied in patients with other solid tumors following administration of doses mg/kg, mg/kg, and 10 mg/kg (1- to 10-times the approved recommended dosage) administered once every weeks for doses. The pharmacokinetics of tremelimumab-actl as single dose of 300 mg were evaluated in patients with HCC.The AUC of tremelimumab-actl increased proportionally from mg/kg to 10 mg/kg every weeks (1 to 10-times the approved recommended dosage) and steady state was achieved at approximately 12 weeks.DistributionThe geometric mean (% coefficient of variation [CV%]) of tremelimumab-actl for central (V1) and peripheral (V2) volume of distribution was 3.45 (24%) and 2.66 (34%) L, respectively.EliminationThe geometric mean (CV%) terminal half-life of tremelimumab-actl was 16.9 days (19%) after single dose and 18.2 days (19%) during steady state. The geometric mean (CV%) clearance of tremelimumab-actl was 0.286 L/day (32%) after single dose and 0.263 L/day (32%) during steady state.Specific PopulationsThere were no clinically significant differences in the pharmacokinetics of tremelimumab-actl based on body weight (34 to149 kg), age (18 to 87 years), sex, race (White, Black, Asian, Native Hawaiian, Pacific Islander, or American Indian), serum albumin levels (0.3 to 396 g/L), lactate dehydrogenase levels (12 to 5570 U/L), soluble PD-L1 (67 to 349 pg/mL), tumor type (NSCLC, HCC), organ dysfunction including mild to moderate renal impairment (CLcr 30 to 89 mL/min), and mild to moderate hepatic impairment (bilirubin 3 ULN and any AST).The effect of severe renal impairment (CLcr 15 to 29 mL/min) or severe hepatic impairment (bilirubin 3 ULN and any AST) on the pharmacokinetics of tremelimumab-actl 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 comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of tremelimumab-actl.In the HIMALAYA study, of the 182 patients who were treated with single dose of tremelimumab-actl in combination with durvalumab once in every weeks therapy and evaluable for the presence of ADAs against tremelimumab-actl at predose week and week 4, 11% (20/182) of patients tested positive for anti-tremelimumab-actl antibodies. Among the 20 patients who tested positive for ADAs 40% (8/20) tested positive for neutralizing antibodies against tremelimumab-actl. There was no identified clinically significant effect of anti-tremelimumab antibodies on the pharmacokinetics or safety of tremelimumab-actl; however, the effect of ADAs and neutralizing antibodies on the effectiveness of tremelimumab-actl is unknown.In the POSEIDON study, of the 278 ADA-evaluable patients who were treated with IMJUDO 75 mg for up to five doses in combination with durvalumab 1,500 mg and platinum-based chemotherapy every weeks and evaluated for presence of ADAs against tremelimumab-actl at pre-dose week 0, week 3, and week 12, 14% (38/278) of patients tested positive for anti-tremelimumab-actl antibodies. Among the 38 patients who tested positive for ADAs, 82% (31/38) tested positive for neutralizing antibodies against tremelimumab-actl. There was no identified clinically significant effect of anti-tremelimumab-actl antibodies on pharmacokinetics or safety of tremelimumab-actl, however, the effect of ADAs on effectiveness of tremelimumab-actl is unknown.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 Hepatocellular Carcinoma (HCC) The efficacy of IMJUDO in combination with durvalumab 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 (IMJUDO plus durvalumab or durvalumab) or sorafenib. Study treatment consisted of IMJUDO as one-time single intravenous infusion of 300 mg in combination with durvalumab 1,500 mg on the same day, followed by durvalumab every weeks; durvalumab 1,500 mg every weeks; or sorafenib 400 mg given orally twice daily, until disease progression or unacceptable toxicity. The efficacy assessment of IMJUDO is based on patients randomized to the IMJUDO plus durvalumab 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 was deriving clinical benefit as determined by the investigator.The major efficacy outcome measure was overall survival (OS) between the IMJUDO plus durvalumab 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 IMJUDO plus durvalumab 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%), uninfected (42%).Efficacy results are presented in Table 10 and Figure 1.Table 10. Efficacy Results for HIMALAYA StudyEndpointIMJUDO and Durvalumab(N=393)Sorafenib(N=389)OS Number 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 (IMJUDO and durvalumab 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 IMJUDO and durvalumab vs. sorafenib was 0.0398 (Lan and DeMets 1983).0.0035PFS Number of events (%)335 (85.2)327 (84.1) Median PFS (months) (95% CI)3.8 (3.7, 5.3)4.1 (3.7, 5.5) HR (95% CI) 0.90 (0.77, 1.05)ORR ORR (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)0 Partial Response (%)67 (17.0)20 (5.1)DoR Median 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 1. Kaplan-Meier curve of OS. Median OS (months). (95% CI). HR (95% CI)HR (IMJUDO and durvalumab vs. sorafenib) based on the stratified Cox proportional hazard model.. 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 IMJUDO and durvalumab vs. sorafenib was 0.0398 (Lan and DeMets 1983).. ORR (95% CI)Confirmed complete response or partial response.Based on Clopper-Pearson method.. Complete Response (%). Partial Response (%). Median DoR (months) (95% CI). with duration >= months. with duration >= 12 months. figure 1. Generic Section Metastic NSCLC POSEIDONThe efficacy of IMJUDO in combination with durvalumab 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 trial (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 IMJUDO in combination with durvalumab and platinum-based chemotherapy according to the regimens listed below, durvalumab 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:oIMJUDO 75 mg (or 1mg/kg for patients 30kg) with durvalumab 1,500 mg and platinum-based chemotherapy every weeks for cycles, followed by durvalumab 1,500 mg every weeks as single agent. fifth dose of IMJUDO 75 mg (or 1mg/kg for patients 30kg) was given at Week 16 in combination with durvalumab 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 IMJUDO and durvalumab in combination with one of the following platinum-based chemotherapy regimens: oNon-squamous NSCLCoPemetrexed 500 mg/m2 with carboplatin AUC 5-6 or cisplatin 75 mg/m2 every weeks for cyclesoSquamous NSCLCoGemcitabine 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 cyclesoNon-squamous and Squamous NSCLCoNab-paclitaxel 100 mg/m2 on Days 1, 8, and 15 with carboplatin AUC 5-6 on Day every weeks for cyclesIMJUDO was given up to maximum of doses. Durvalumab and histology-based pemetrexed continued every weeks until disease progression or unacceptable toxicity. Administration of durvalumab 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 durvalumab monotherapy were given the option to be retreated with additional cycles of IMJUDO in combination with durvalumab. 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 IMJUDO and durvalumab 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 IMJUDO with durvalumab 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 and Figure 2.Table 11. Efficacy Results for POSEIDONIMJUDO with durvalumab 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-value 0.00031ORR (95% CI)Confirmed responses with 95% Clopper-Pearson confidence intervals.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 2. Kaplan-Meier curves of OS in POSEIDON oIMJUDO 75 mg (or 1mg/kg for patients 30kg) with durvalumab 1,500 mg and platinum-based chemotherapy every weeks for cycles, followed by durvalumab 1,500 mg every weeks as single agent. fifth dose of IMJUDO 75 mg (or 1mg/kg for patients 30kg) was given at Week 16 in combination with durvalumab 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 NSCLCoPemetrexed 500 mg/m2 with carboplatin AUC 5-6 or cisplatin 75 mg/m2 every weeks for cycles. oPemetrexed 500 mg/m2 with carboplatin AUC 5-6 or cisplatin 75 mg/m2 every weeks for cycles. oSquamous NSCLCoGemcitabine 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. oGemcitabine 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 NSCLCoNab-paclitaxel 100 mg/m2 on Days 1, 8, and 15 with carboplatin AUC 5-6 on Day every weeks for cycles. oNab-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) Figure2.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS None. (4). None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION Tremelimumab-actl, cytotoxic T-lymphocyte-associated antigen (CTLA-4) blocking human IgG2 monoclonal antibody, is produced by recombinant DNA technology in NS0 cell suspension culture and has molecular weight of 149 kDa.IMJUDO (tremelimumab-actl) injection is sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution, in single-dose vial for intravenous infusion after dilution. IMJUDO contains tremelimumab-actl at concentration of 20 mg/mL in either 25 mg/1.25 mL or 300 mg/15 mL single-dose vial.Each mL contains 20 mg of tremelimumab-actl, and edetate disodium (0.09 mg), histidine (0.68 mg), histidine hydrochloride monohydrate (3.3 mg), polysorbate 80 (0.2 mg), trehalose (76 mg), and Water for Injection, USP. The pH is approximately 5.5.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oAdminister IMJUDO as an intravenous infusion over 60 minutes after dilution. (2.3)ouHCC: oWeight 30 kg and more: IMJUDO 300 mg as single dose in combination with durvalumab 1,500 mg at Cycle 1/Day 1, followed by durvalumab as single agent every weeks (2.1)oWeight less than 30 kg: IMJUDO mg/kg as single dose in combination with durvalumab 20 mg/kg at Cycle 1/Day 1, followed by durvalumab as single agent every weeks (2.1)oMetastatic NSCLC: oWeight 30 kg and more: 75 mg every weeks in combination with durvalumab 1,500 mg and platinum-based chemotherapy for cycles, and then administer durvalumab 1,500 mg every weeks as single agent with histology-based pemetrexed therapy every weeks, and fifth dose of IMJUDO 75 mg in combination with durvalumab dose at week 16 (2.1)oWeight less than 30 kg: mg/kg every weeks in combination with durvalumab 20 mg/kg and platinum-based chemotherapy for cycles, and then administer durvalumab 20 mg/kg every weeks as single agent with histology-based pemetrexed therapy every weeks, and fifth dose of IMJUDO mg/kg in combination with durvalumab dose at week 16 (2.1)oSee full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions.. oAdminister IMJUDO as an intravenous infusion over 60 minutes after dilution. (2.3). ouHCC: oWeight 30 kg and more: IMJUDO 300 mg as single dose in combination with durvalumab 1,500 mg at Cycle 1/Day 1, followed by durvalumab as single agent every weeks (2.1)oWeight less than 30 kg: IMJUDO mg/kg as single dose in combination with durvalumab 20 mg/kg at Cycle 1/Day 1, followed by durvalumab as single agent every weeks (2.1). oWeight 30 kg and more: IMJUDO 300 mg as single dose in combination with durvalumab 1,500 mg at Cycle 1/Day 1, followed by durvalumab as single agent every weeks (2.1). oWeight less than 30 kg: IMJUDO mg/kg as single dose in combination with durvalumab 20 mg/kg at Cycle 1/Day 1, followed by durvalumab as single agent every weeks (2.1). oMetastatic NSCLC: oWeight 30 kg and more: 75 mg every weeks in combination with durvalumab 1,500 mg and platinum-based chemotherapy for cycles, and then administer durvalumab 1,500 mg every weeks as single agent with histology-based pemetrexed therapy every weeks, and fifth dose of IMJUDO 75 mg in combination with durvalumab dose at week 16 (2.1)oWeight less than 30 kg: mg/kg every weeks in combination with durvalumab 20 mg/kg and platinum-based chemotherapy for cycles, and then administer durvalumab 20 mg/kg every weeks as single agent with histology-based pemetrexed therapy every weeks, and fifth dose of IMJUDO mg/kg in combination with durvalumab dose at week 16 (2.1). oWeight 30 kg and more: 75 mg every weeks in combination with durvalumab 1,500 mg and platinum-based chemotherapy for cycles, and then administer durvalumab 1,500 mg every weeks as single agent with histology-based pemetrexed therapy every weeks, and fifth dose of IMJUDO 75 mg in combination with durvalumab dose at week 16 (2.1). oWeight less than 30 kg: mg/kg every weeks in combination with durvalumab 20 mg/kg and platinum-based chemotherapy for cycles, and then administer durvalumab 20 mg/kg every weeks as single agent with histology-based pemetrexed therapy every weeks, and fifth dose of IMJUDO mg/kg in combination with durvalumab dose at week 16 (2.1). oSee full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions.. 2.1 Recommended Dosing for Unresectable Hepatocellular Carcinoma The recommended dosage of IMJUDO is presented in Tables 1, and 3. Administer IMJUDO as an intravenous infusion after dilution as recommended [see Dosage and Administration (2.3)]. IMJUDO in Combination with DurvalumabTable 1. Recommended dosage of IMJUDOIndicationRecommended IMJUDO dosageDuration of TherapyuHCCPatients with body weight of 30 kg and more:oA single dose of IMJUDOAdminister IMJUDO prior to durvalumab on the same day. 300 mg followed by durvalumabRefer to the Prescribing Information for durvalumab dosing information. 1,500 mg at Day of Cycle 1oContinue durvalumab 1,500 mg as single agent every weeksPatients with body weight of less than 30 kg:oA single dose of IMJUDO mg/kg followed by durvalumab 20 mg/kg at Day of Cycle 1;oContinue durvalumab 20 mg/kg as single agent every weeksAfter Cycle of combination therapy, administer durvalumab as single agent every weeks until disease progression or unacceptable toxicityIMJUDO in Combination with Durvalumab and Platinum-Based ChemotherapyThe recommended dosage schedule and regimens for IMJUDO for the treatment of metastatic non-small cell lung cancer (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 ScheduleWeekcontinue durvalumab until disease progression or intolerable toxicity.dosing interval change from every weeks to every weeks starting at cycle 5.0123456789101112131415161718192021222324Cycle:12345678IMJUDOintravenous infusion over 60 minutes [see Dosage and Administration (2.3)]. if patients receive fewer than cycles of platinum-based chemotherapy, the remaining cycles of IMJUDO (up to total of 5) should be given after the platinum-based chemotherapy phase, in combination with durvalumab, every weeks. XXXXXDurvalumab XXXXXXXXChemotherapyXXXXXoptional 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.XXXTable 3: Recommended Regimen and DosageTumor HistologyPatient WeightIMJUDODosageDurvalumabRefer to the Prescribing Information for dosing information.DosagePlatinum-basedChemotherapy RegimeNon-Squamous>= 30 kg75 mg1,500 mgocarboplatin nabpaclitaxlORocarboplatin or cisplatin pemetrexed< 30 kg1 mg/kg20 mg/kgSquamous>= 30 kg75 mg1,500 mgocarboplatin nabpaclitaxlORocarboplatin or cisplatin gemcitabine< 30 kg1 mg/kg20 mg/kg. oA single dose of IMJUDOAdminister IMJUDO prior to durvalumab on the same day. 300 mg followed by durvalumabRefer to the Prescribing Information for durvalumab dosing information. 1,500 mg at Day of Cycle 1. oContinue durvalumab 1,500 mg as single agent every weeks. oA single dose of IMJUDO mg/kg followed by durvalumab 20 mg/kg at Day of Cycle 1;. oContinue durvalumab 20 mg/kg as single agent every weeks. ocarboplatin nabpaclitaxl. ocarboplatin or cisplatin pemetrexed. ocarboplatin nabpaclitaxl. ocarboplatin or cisplatin gemcitabine. 2.2 Dosage Modifications for Adverse Reactions No dose reduction for treatment is recommended. In general, withhold treatment regimen for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue treatment regimen 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.Recommended treatment modifications are presented in Table 2.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 steroids 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 discontinueColitis Grade 2Withhold Grade or 4Permanently discontinueIntestinal perforationAny gradePermanently discontinueHepatitis with no tumor involvement of the liver ALT 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 ULN or total bilirubin increases to more than times the ULN Permanently discontinueHepatitis 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 durvalumab 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 ULN orTotal bilirubin increases to more than times ULNPermanently discontinueEndocrinopathies Grade or 4Withhold until clinically stable or permanently discontinue depending on severityNephritis with Renal Dysfunction Grade or increased blood creatinine Withhold Grade increased blood creatinine Permanently discontinueExfoliative Dermatologic ConditionsSuspected SJS, TEN, or DRESS Withhold Confirmed SJS, TEN, or DRESSPermanently discontinueMyocarditisGrade 2, 3, or 4Permanently discontinueNeurological ToxicitiesGrade Withhold Grade or 4Permanently discontinueOther Adverse ReactionsInfusion-related reactions [see Warnings and Precautions (5.2)] Grade or Interrupt or slow the rate of infusion Grade or Permanently 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. 2.3 Preparation and Administration PreparationoVisually inspect drug product for particulate matter and discoloration. Discard 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 IMJUDO 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 maximum final concentration of the diluted solution should not exceed 10 mg/mL. The total volume of diluent for use with each dose and patient weight is presented in Table 5.oDiscard partially used or empty vials of IMJUDO. Table 5. IMJUDO Infusion ConditionsDosePatient WeightMaximum diluent volume300 mg>= 30 kg150 mL4 mg/kg< 30 kg80 mL75 mg>= 30 kg150 mL1 mg/kg< 30 kg80 mLStorage of Infusion SolutionoIMJUDO does not contain preservative. Administer infusion solution immediately once prepared. If infusion solution is not administered immediately and needs to be stored, the total time from preparation to the start of administration should not exceed:o24 hours in refrigerator at 2C to 8C (36F to 46F)o24 hours at room temperature up to 30C (86F)oDo not freeze.oDo not shake.AdministrationoAdminister IMJUDO infusion solution intravenously over 60 minutes through an intravenous line containing sterile, low-protein binding 0.2 or 0.22 micron filter.oUse separate infusion bags and filters for each drug product.IMJUDO In Combination with Other ProductsoAdminister all drug products as separate intravenous infusions. oDo not co-administer other drugs through the same infusion line.oFor platinum-based chemotherapy, refer to Prescribing Information for administration information. oFor pemetrexed treatment, refer to Prescribing Information for administration information.Combination Regimens: Order of InfusionsIMJUDO in Combination with DurvalumaboInfuse IMJUDO, followed by durvalumab on the same day of dosing.IMJUDO in Combination with Durvalumab and Platinum-based ChemotherapyoInfuse IMJUDO first, followed by durvalumab and then platinum-based chemotherapy on the day of dosing. IMJUDO in Combination with Durvalumab and Pemetrexed Therapy oInfuse IMJUDO first, followed by durvalumab and then pemetrexed treatment on the day of dosing.Combination Regimens: Infusion InstructionsIMJUDO in Combination with DurvalumaboObserve patient for 60 minutes following completion of IMJUDO infusion [see Warnings and Precautions (5.2)]. Then administer durvalumab as separate intravenous infusion over 60 minutes IMJUDO in Combination with Durvalumab and Platinum-based Chemotherapy/ Pemetrexed TherapyCycle 1:oInfuse IMJUDO over one hour. One to two hours after completion of IMJUDO infusion, infuse durvalumab over one hour. One to two hours after completion of durvalumab infusion, administer platinum-based chemotherapy.Subsequent Cycles:If there are no infusion reactions during cycle 1, subsequent cycles of durvalumab can be given immediately after IMJUDO. The time between the end of the durvalumab infusion and the start of chemotherapy can be reduced to 30 minutes. oVisually inspect drug product for particulate matter and discoloration. Discard 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 IMJUDO 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 maximum final concentration of the diluted solution should not exceed 10 mg/mL. The total volume of diluent for use with each dose and patient weight is presented in Table 5.. oDiscard partially used or empty vials of IMJUDO. oIMJUDO does not contain preservative. Administer infusion solution immediately once prepared. If infusion solution is not administered immediately and needs to be stored, the total time from preparation to the start of administration should not exceed:o24 hours in refrigerator at 2C to 8C (36F to 46F)o24 hours at room temperature up to 30C (86F). o24 hours in refrigerator at 2C to 8C (36F to 46F). o24 hours at room temperature up to 30C (86F). oDo not freeze.. oDo not shake.. oAdminister IMJUDO infusion solution intravenously over 60 minutes through an intravenous line containing sterile, low-protein binding 0.2 or 0.22 micron filter.. oUse separate infusion bags and filters for each drug product.. oAdminister all drug products as separate intravenous infusions. oDo not co-administer other drugs through the same infusion line.. oFor platinum-based chemotherapy, refer to Prescribing Information for administration information. oFor pemetrexed treatment, refer to Prescribing Information for administration information.. oInfuse IMJUDO, followed by durvalumab on the same day of dosing.. oInfuse IMJUDO first, followed by durvalumab and then platinum-based chemotherapy on the day of dosing. oInfuse IMJUDO first, followed by durvalumab and then pemetrexed treatment on the day of dosing.. oObserve patient for 60 minutes following completion of IMJUDO infusion [see Warnings and Precautions (5.2)]. Then administer durvalumab as separate intravenous infusion over 60 minutes oInfuse IMJUDO over one hour. One to two hours after completion of IMJUDO infusion, infuse durvalumab over one hour. One to two hours after completion of durvalumab infusion, administer platinum-based chemotherapy.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Injection: 25 mg/1.25mL (20mg/mL) and 300 mg/15 mL (20 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in single-dose vial. oInjection: 25 mg/1.25 mL (20 mg/mL) solution in single-dose vial. (3)oInjection: 300 mg/15 mL (20 mg/mL) solution in single-dose vial. (3). oInjection: 25 mg/1.25 mL (20 mg/mL) solution in single-dose vial. (3). oInjection: 300 mg/15 mL (20 mg/mL) solution in single-dose vial. (3).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential IMJUDO can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].Pregnancy TestingVerify pregnancy status of females of reproductive potential prior to initiating treatment with IMJUDO.ContraceptionAdvise females of reproductive potential to use effective contraception during treatment with IMJUDO and for months after the last dose. Refer to the Prescribing Information for the agents administered in combination with IMJUDO for recommended contraception duration, as appropriate.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING IMJUDO (tremelimumab-actl) Injection is clear to slightly opalescent, colorless to slightly yellow solution supplied in carton containing one single-dose vial in the following concentrations:o25 mg/1.25 mL (20 mg/mL) (NDC 0310-4505-25) o300 mg/15 mL (20 mg/mL) (NDC 0310-4535-30)Store in refrigerator at 2C to 8C (36F to 46F) in original carton to protect from light.Do not freeze. Do not shake.. o25 mg/1.25 mL (20 mg/mL) (NDC 0310-4505-25) o300 mg/15 mL (20 mg/mL) (NDC 0310-4535-30).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE IMJUDO is cytotoxic T-lymphocyte-associated antigen (CTLA-4) blocking antibody indicated:oin combination with durvalumab, for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC). (1.1)oin combination with durvalumab and platinum-based chemotherapy for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. (1.2). oin combination with durvalumab, for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC). (1.1). oin combination with durvalumab and platinum-based chemotherapy for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. (1.2). 1.1 Hepatocellular Carcinoma IMJUDO in combination with durvalumab is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC).. 1.2 Non-Small Cell Lung Cancer (NSCLC) IMJUDO, in combination with durvalumab and platinum-based chemotherapy, is indicated for the treatment of adult patients with metastatic NSCLC with no sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.

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 IMJUDO in combination with durvalumab, including [see Warnings and Precautions (5.1)]:oPneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath.oColitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain.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.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 aseptic meningitis, 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)].Embryo-Fetal Toxicity:oAdvise females of reproductive potential that IMJUDO can cause harm to fetus and to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)].oAdvise females of reproductive potential to use effective contraception during treatment and for at least months after the last dose of IMJUDO [see Use in Specific Populations (8.3)].Lactation:oAdvise female patients not to breastfeed while taking IMJUDO and for at least months after the last dose [see Warnings and Precautions (5.X) and Use in Specific Populations (8.2)].Manufactured for:AstraZeneca Pharmaceuticals LPWilmington, DE 19850Manufactured By: AstraZeneca ABSodertalje, Sweden SE-15185 US License No. 2059IMJUDO(R) is registered trademark of AstraZeneca group of companies.(C)AstraZeneca 2022 AstraZeneca 2022. oPneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath.. oColitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain.. 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.. 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 aseptic meningitis, 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 females of reproductive potential that IMJUDO can cause harm to fetus and to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)].. oAdvise females of reproductive potential to use effective contraception during treatment and for at least months after the last dose of IMJUDO [see Use in Specific Populations (8.3)].. oAdvise female patients not to breastfeed while taking IMJUDO and for at least months after the last dose [see Warnings and Precautions (5.X) and Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2 Lactation Risk SummaryThere are no data on the presence of tremelimumab-actl in human milk, its effects on breastfed child, or 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 IMJUDO are unknown. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with IMJUDO and for months after the last dose. Refer to the Prescribing Information for agents administered in combination with IMJUDO for breastfeeding recommendations, as appropriate.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action CTLA-4 is negative regulator of T-cell activity. Tremelimumab--actl is monoclonal antibody that binds to CTLA-4 and blocks the interaction with its ligands CD80 and CD86, releasing CTLA-4-mediated inhibition of T-cell activation. In synergistic mouse tumor models, blocking CTLA-4 activity resulted in decreased tumor growth and increased proliferation of cells in tumors.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic and genotoxic potential of tremelimumab-actl have not been evaluated.Animal fertility studies have not been conducted with tremelimumab-actl,.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0310-4535-30 Rx only IMJUDO(R) 300 mg/15 mL(tremelimumab-actl) (20 mg/mLInjectionFor Intravenous Infusion After DilutionSingle-dose vial. Discard unused portion.Attention Pharmacist:Dispense the accompanying Medication Guide to each patient.AstraZeneca. 300mg.

PEDIATRIC USE SECTION.

8.4 Pediatric Use The safety and effectiveness of tremelimumab-actl have not been established in pediatric patients.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics The pharmacokinetics of tremelimumab-actl was studied in patients with other solid tumors following administration of doses mg/kg, mg/kg, and 10 mg/kg (1- to 10-times the approved recommended dosage) administered once every weeks for doses. The pharmacokinetics of tremelimumab-actl as single dose of 300 mg were evaluated in patients with HCC.The AUC of tremelimumab-actl increased proportionally from mg/kg to 10 mg/kg every weeks (1 to 10-times the approved recommended dosage) and steady state was achieved at approximately 12 weeks.DistributionThe geometric mean (% coefficient of variation [CV%]) of tremelimumab-actl for central (V1) and peripheral (V2) volume of distribution was 3.45 (24%) and 2.66 (34%) L, respectively.EliminationThe geometric mean (CV%) terminal half-life of tremelimumab-actl was 16.9 days (19%) after single dose and 18.2 days (19%) during steady state. The geometric mean (CV%) clearance of tremelimumab-actl was 0.286 L/day (32%) after single dose and 0.263 L/day (32%) during steady state.Specific PopulationsThere were no clinically significant differences in the pharmacokinetics of tremelimumab-actl based on body weight (34 to149 kg), age (18 to 87 years), sex, race (White, Black, Asian, Native Hawaiian, Pacific Islander, or American Indian), serum albumin levels (0.3 to 396 g/L), lactate dehydrogenase levels (12 to 5570 U/L), soluble PD-L1 (67 to 349 pg/mL), tumor type (NSCLC, HCC), organ dysfunction including mild to moderate renal impairment (CLcr 30 to 89 mL/min), and mild to moderate hepatic impairment (bilirubin 3 ULN and any AST).The effect of severe renal impairment (CLcr 15 to 29 mL/min) or severe hepatic impairment (bilirubin 3 ULN and any AST) on the pharmacokinetics of tremelimumab-actl is unknown.

PREGNANCY SECTION.

8.1 Pregnancy Risk summaryBased on findings from animal studies and its mechanism of action, IMJUDO can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of IMJUDO in pregnant women. In animal studies, CTLA-4 blockade is associated with increased risk of immune-mediated rejection of the developing fetus and fetal death (see Data).Human immunoglobulin G2 (IgG2) is known to cross the placental barrier; therefore, IMJUDO has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women and females of reproductive potential 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 2% to 4% and 15% to 20%, respectively.DataAnimal DataIn reproduction study, administration of tremelimumab-actl to pregnant cynomolgus monkeys during the period of organogenesis was not associated with maternal toxicity or effects on embryo-fetal development at exposure levels approximately to 31-times higher than those observed at recommended dose range of 75 mg to 300 mg based on area under the curve (AUC). CTLA-4 plays role in maintaining maternal immune tolerance to the fetus to preserve pregnancy and in immune regulation of the newborn. In murine model of pregnancy, CTLA-4 blockade resulted in increased resorptions and reduced live fetuses. Mated genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/-) gave birth to CTLA-4+/- offspring and offspring deficient in CTLA-4 (homozygous negative, CTLA-4-/-) that appeared healthy at birth. The CTLA-4-/- homozygous negative offspring developed signs of lymphoproliferative disorder and died by to weeks of age with multiorgan tissue destruction. Based on its mechanism of action, fetal exposure to tremelimumab-actl may increase the risk of developing immune-mediated disorders or altering the normal immune response.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1.2) 11/2022Dosage and Administration (2.1, 2.3) 11/2022 Warnings and Precautions (5.1, 5.2) 11/2022.

SPL MEDGUIDE SECTION.

MEDICATION GUIDEIMJUDO(R) (im-JEW-doh) (tremelimumab-actl)injectionWhat is the most important information should know about IMJUDOIMJUDO is medicine that may treat certain cancers by working with your immune system.IMJUDO in combination with durvalumab can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one of these problems at the same time. These problems may happen anytime during treatment or even after your treatment has ended.Call or see your healthcare provider right away if you develop any new or worsening signs or symptoms, including:Lung problems.ocoughoshortness of breathochest painIntestinal problems.odiarrhea (loose stools) or more frequent bowel movements than usual ostools that are black, tarry, sticky, or have blood or mucusosevere stomach-area (abdomen) pain or tenderness Liver problems.oyellowing of your skin or the whites of your eyesosevere nausea or vomitingopain on the right side of your stomach-area (abdomen)odark urine (tea colored)obleeding or bruising more easily than normalHormone gland problems.oheadaches that will not go away or unusual headaches oeye sensitivity to light oeye problems orapid heartbeat oincrease sweating oextreme tiredness oweight gain or weight loss ofeeling more hungry or thirsty than usualourinating more often than usual ohair loss ofeeling cold oconstipation oyour voice gets deeper odizziness or fainting ochanges in mood or behavior, such as decreased sex drive, irritability, or forgetfulnessKidney problems.odecrease in your amount of urineoblood in your urineoswelling of your anklesoloss of appetiteSkin problems.orashoitchingoskin blistering or peelingopainful sores or ulcers in mouth or nose, throat, or genital areaofever or flu-like symptomsoswollen lymph nodesPancreas problems.oPain in your upper stomach-area (abdomen)osevere nausea or vomiting oloss of appetite Problems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune system problems that can happen with IMJUDO. Call or see your healthcare provider right away for any new or worsening signs or symptoms, which may include:oChest pain, irregular heartbeats, shortness of breath or swelling of anklesoConfusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legsoDouble vision, blurry vision, sensitivity to light, eye pain, changes in eye sightoPersistent or severe muscle pain or weakness, muscle crampsoLow red blood cells, bruising.Infusion reactions that can sometimes be severe or life-threatening. Signs and symptoms of infusion reactions may include:ochills or shakingoitching or rashoflushingoshortness of breath or wheezingodizziness ofeel like passing out ofever oback or neck painGetting medical treatment right away may help keep these problems from becoming more serious.Your healthcare provider will check you for these problems during your treatment with IMJUDO. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with IMJUDO if you have severe side effects.What is IMJUDO IMJUDO is prescription medicine used in combination with durvalumab to treat adults with: oa type of liver cancer called unresectable hepatocellular carcinoma (uHCC). IMJUDO may be used in combination with durvalumab when your uHCC cannot be removed by surgery.oa type of lung cancer called non-small cell lung cancer (NSCLC). IMJUDO may be used in combination with durvalumab and chemotherapy that contains platinum when your NSCLC:ohas spread to other parts of your body (metastatic), and oyour tumor does not have an abnormal EGFR or ALK gene. It is not known if IMJUDO is safe and effective in children.Before you receive IMJUDO, tell your healthcare provider about all of your medical conditions, including if you:ohave immune system problems such as Crohns disease, ulcerative colitis, or lupusohave condition that affects your nervous system, such as myasthenia gravis or Guillain-Barre syndrome oare pregnant or plan to become pregnant. IMJUDO can harm your unborn baby.oare breastfeeding or plan to breastfeed. It is not known if IMJUDO passes into your breast milk. Do not breastfeed during treatment and for months after your last dose of IMJUDO.Females who are able to become pregnantoYour healthcare provider should do pregnancy test before you start treatment with IMJUDO.oYou should use an effective method of birth control during your treatment and for months after your last dose of IMJUDO. Talk to your healthcare provider about birth control methods that you can use during this time.oTell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with IMJUDO.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive IMJUDOoYour healthcare provider will determine your treatment schedule and cycles of treatment.oYour healthcare provider will give you IMJUDO into your vein through an intravenous (IV) line over 60 minutes. oFor the treatment of uHCC:oOn the same day you receive IMJUDO, you will receive durvalumab through an intravenous (IV) line over 60 minutes.oIMJUDO is given to you as single dose.oYou will then receive durvalumab every weeksoFor the treatment of NSCLC:oOn the same day you receive IMJUDO, you will receive durvalumab followed by platinum-containing chemotherapy. You will receive combination chemotherapy every weeks for four cycles (Cycle 1-4).oYou will receive IMJUDO in combination with durvalumab for one cycle only (Cycle 6).oYou will then receive durvalumab every weeks. You healthcare provider will decide if you will also receive chemotherapy every weeks.oYour healthcare provider will test your blood to check you for certain side effects.oIf you miss your appointment, call your healthcare provider as soon as possible to reschedule your appointment.What are the possible side effects of IMJUDOIMJUDO can cause serious side effects, including:See What is the most important information should know about IMJUDOThe most common side effects of IMJUDO when used in combination with durvalumab include:orashodiarrheaofeeling tired oitchiness omuscle or bone painostomach (abdominal)pain The most common side effects of IMJUDO when used in combination with durvalumab and platinum-containing chemotherapy in adults with metastatic NSCLC include:onauseaofeeling tired or weakomuscle or bone pain odecreased apetite orashodiarrhea Tell your doctor if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of IMJUDO. Ask your healthcare provider or pharmacist for more information.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of IMJUDO.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. If you would like more information about IMJUDO, talk with your healthcare provider. You can ask your healthcare provider for information about IMJUDO that is written for health professionals.What are the ingredients in IMJUDOActive ingredient: tremelimumab-actlInactive ingredients: edetate disodium, histidine, L-histidine hydrochloride monohydrate, polysorbate 80, trehalose, and Water for Injection, USP.Manufactured for: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850Manufactured by: AstraZeneca AB, Sodertalje, Sweden SE-15185US License No. 2059IMJUDO(R) is registered trademark of AstraZeneca group of companies.For more information, call 1-800-236-9933 or go to www.IMJUDO.com(C) AstraZeneca 2022The Medication Guide has been approved by the U.S. Food and Drug Administration Revised 11/2022. ocough. oshortness of breath. ochest pain. odiarrhea (loose stools) or more frequent bowel movements than usual ostools that are black, tarry, sticky, or have blood or mucus. osevere stomach-area (abdomen) pain or tenderness. oyellowing of your skin or the whites of your eyes. osevere nausea or vomiting. opain on the right side of your stomach-area (abdomen). odark urine (tea colored). obleeding or bruising more easily than normal. oheadaches that will not go away or unusual headaches oeye sensitivity to light oeye problems orapid heartbeat oincrease sweating oextreme tiredness oweight gain or weight loss ofeeling more hungry or thirsty than usual. ourinating more often than usual ohair loss ofeeling cold oconstipation oyour voice gets deeper odizziness or fainting ochanges in mood or behavior, such as decreased sex drive, irritability, or forgetfulness. odecrease in your amount of urine. oblood in your urine. oswelling of your ankles. oloss of appetite. orash. oitching. oskin blistering or peeling. opainful sores or ulcers in mouth or nose, throat, or genital area. ofever or flu-like symptoms. oswollen lymph nodes. oPain in your upper stomach-area (abdomen). osevere nausea or vomiting. oloss of appetite. oChest pain, irregular heartbeats, shortness of breath or swelling of ankles. oConfusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs. oDouble vision, blurry vision, sensitivity to light, eye pain, changes in eye sight. oPersistent or severe muscle pain or weakness, muscle cramps. oLow red blood cells, bruising.. ochills or shaking. oitching or rash. oflushing. oshortness of breath or wheezing. odizziness ofeel like passing out ofever oback or neck pain. IMJUDO is prescription medicine used in combination with durvalumab to treat adults with: oa type of liver cancer called unresectable hepatocellular carcinoma (uHCC). IMJUDO may be used in combination with durvalumab when your uHCC cannot be removed by surgery.. oa type of lung cancer called non-small cell lung cancer (NSCLC). IMJUDO may be used in combination with durvalumab and chemotherapy that contains platinum when your NSCLC:ohas spread to other parts of your body (metastatic), and oyour tumor does not have an abnormal EGFR or ALK gene. ohas spread to other parts of your body (metastatic), and oyour tumor does not have an abnormal EGFR or ALK gene.. ohave immune system problems such as Crohns disease, ulcerative colitis, or lupus. ohave condition that affects your nervous system, such as myasthenia gravis or Guillain-Barre syndrome oare pregnant or plan to become pregnant. IMJUDO can harm your unborn baby.. oare breastfeeding or plan to breastfeed. It is not known if IMJUDO passes into your breast milk. Do not breastfeed during treatment and for months after your last dose of IMJUDO.. oYour healthcare provider should do pregnancy test before you start treatment with IMJUDO.. oYou should use an effective method of birth control during your treatment and for months after your last dose of IMJUDO. Talk to your healthcare provider about birth control methods that you can use during this time.. oTell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with IMJUDO.. oYour healthcare provider will determine your treatment schedule and cycles of treatment.. oYour healthcare provider will give you IMJUDO into your vein through an intravenous (IV) line over 60 minutes. oFor the treatment of uHCC:oOn the same day you receive IMJUDO, you will receive durvalumab through an intravenous (IV) line over 60 minutes.oIMJUDO is given to you as single dose.oYou will then receive durvalumab every weeks. oOn the same day you receive IMJUDO, you will receive durvalumab through an intravenous (IV) line over 60 minutes.. oIMJUDO is given to you as single dose.. oYou will then receive durvalumab every weeks. oFor the treatment of NSCLC:oOn the same day you receive IMJUDO, you will receive durvalumab followed by platinum-containing chemotherapy. You will receive combination chemotherapy every weeks for four cycles (Cycle 1-4).oYou will receive IMJUDO in combination with durvalumab for one cycle only (Cycle 6).oYou will then receive durvalumab every weeks. You healthcare provider will decide if you will also receive chemotherapy every weeks.. oOn the same day you receive IMJUDO, you will receive durvalumab followed by platinum-containing chemotherapy. You will receive combination chemotherapy every weeks for four cycles (Cycle 1-4).. oYou will receive IMJUDO in combination with durvalumab for one cycle only (Cycle 6).. oYou will then receive durvalumab every weeks. You healthcare provider will decide if you will also receive chemotherapy every weeks.. oYour healthcare provider will test your blood to check you for certain side effects.. oIf you miss your appointment, call your healthcare provider as soon as possible to reschedule your appointment.. orash. odiarrhea. ofeeling tired. oitchiness omuscle or bone pain. ostomach (abdominal)pain. onausea. ofeeling tired or weak. omuscle or bone pain. odecreased apetite orash. odiarrhea.

SPL UNCLASSIFIED SECTION.

1.1 Hepatocellular Carcinoma IMJUDO in combination with durvalumab is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC).

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, IMJUDO can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of IMJUDO in pregnant women. In animal studies, CTLA-4 blockade is associated with increased risk of immune-mediated rejection of the developing fetus and fetal death (see Data).Human immunoglobulin G2 (IgG2) is known to cross the placental barrier; therefore, IMJUDO has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women and females of reproductive potential 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 2% to 4% and 15% to 20%, respectively.DataAnimal DataIn reproduction study, administration of tremelimumab-actl to pregnant cynomolgus monkeys during the period of organogenesis was not associated with maternal toxicity or effects on embryo-fetal development at exposure levels approximately to 31-times higher than those observed at recommended dose range of 75 mg to 300 mg based on area under the curve (AUC). CTLA-4 plays role in maintaining maternal immune tolerance to the fetus to preserve pregnancy and in immune regulation of the newborn. In murine model of pregnancy, CTLA-4 blockade resulted in increased resorptions and reduced live fetuses. Mated genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/-) gave birth to CTLA-4+/- offspring and offspring deficient in CTLA-4 (homozygous negative, CTLA-4-/-) that appeared healthy at birth. The CTLA-4-/- homozygous negative offspring developed signs of lymphoproliferative disorder and died by to weeks of age with multiorgan tissue destruction. Based on its mechanism of action, fetal exposure to tremelimumab-actl may increase the risk of developing immune-mediated disorders or altering the normal immune response.. 8.2 Lactation Risk SummaryThere are no data on the presence of tremelimumab-actl in human milk, its effects on breastfed child, or 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 IMJUDO are unknown. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with IMJUDO and for months after the last dose. Refer to the Prescribing Information for agents administered in combination with IMJUDO for breastfeeding recommendations, as appropriate.. 8.3 Females and Males of Reproductive Potential IMJUDO can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].Pregnancy TestingVerify pregnancy status of females of reproductive potential prior to initiating treatment with IMJUDO.ContraceptionAdvise females of reproductive potential to use effective contraception during treatment with IMJUDO and for months after the last dose. Refer to the Prescribing Information for the agents administered in combination with IMJUDO for recommended contraception duration, as appropriate.. 8.4 Pediatric Use The safety and effectiveness of tremelimumab-actl have not been established in pediatric patients.. 8.5 Geriatric Use Of the 393 patients with uHCC treated with IMJUDO in combination with durvalumab, 50% of patients were 65 years or older and 13% of patients were 75 years or older. No overall differences in safety or efficacy of IMJUDO have been observed between patients 65 years or older and younger adult patients.Of the 330 patients with metastatic NSCLC treated with IMJUDO in combination with durvalumab and platinum-based chemotherapy, 143 (43%) patients were 65 years or older and 35 (11%) patients were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oImmune-Mediated Adverse Reactions (5.1)oImmune-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 with renal dysfunction and immune-mediated pancreatitis.oMonitor for early identification and management. Evaluate liver enzymes, creatinine, adrenocorticotropic hormone level and thyroid function at baseline and before each dose.oWithhold or permanently discontinue based on severity and type of reaction.oInfusion-Related Reactions: Interrupt, slow the rate of infusion, or permanently discontinue treatment based on the severity of the reaction. (5.2)oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and use of effective contraception. (5.3, 8.1, 8.3). oImmune-Mediated Adverse Reactions (5.1)oImmune-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 with renal dysfunction and immune-mediated pancreatitis.oMonitor for early identification and management. Evaluate liver enzymes, creatinine, adrenocorticotropic hormone level and thyroid function at baseline and before each dose.oWithhold or permanently discontinue based on severity and type of reaction.. oImmune-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 with renal dysfunction and immune-mediated pancreatitis.oMonitor for early identification and management. Evaluate liver enzymes, creatinine, adrenocorticotropic hormone level and thyroid function at baseline and before each dose.oWithhold or permanently discontinue based on severity and type of reaction.. oMonitor for early identification and management. Evaluate liver enzymes, creatinine, adrenocorticotropic hormone level and thyroid function at baseline and before each dose.. oWithhold or permanently discontinue based on severity and type of reaction.. oInfusion-Related Reactions: Interrupt, slow the rate of infusion, or permanently discontinue treatment based on the severity of the reaction. (5.2). oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and use of effective contraception. (5.3, 8.1, 8.3). 5.1 Severe and Fatal Immune-Mediated Adverse Reactions IMJUDO is monoclonal antibody that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, thereby removing inhibition of the immune response. In combination with durvalumab, PD-L1 inhibitor, these drugs have the potential for induction of immune-mediated adverse reactions. Immune-mediated adverse reactions listed herein may not be inclusive of all possible severe and fatal immune-mediated reactions.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 IMJUDO in combination with durvalumab. While immune-mediated adverse reactions usually manifest during treatment, immune-mediated adverse reactions can also manifest after discontinuation of IMJUDO and/or durvalumab.Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of IMJUDO in combination with durvalumab. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and before each dose. Institute medical management promptly, including specialty consultation as appropriate.Withhold or permanently discontinue IMJUDO and durvalumab depending on severity [see Dosage and Administration (2.2)]. In general, if combination of IMJUDO and durvalumab requires interruption or discontinuation, administer systemic corticosteroid therapy (1 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 PneumonitisIMJUDO in combination with durvalumab can cause immune-mediated pneumonitis, which may be fatal.IMJUDO with DurvalumabImmune-mediated pneumonitis occurred in 1.3% (5/388) of patients receiving IMJUDO in combination with durvalumab, 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.IMJUDO with Durvalumab and Platinum-Based ChemotherapyImmune-mediated pneumonitis occurred in 3.5% (21/596) of patients receiving IMJUDO in combination with durvalumab 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 ColitisIMJUDO in combination with durvalumab 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.IMJUDO with DurvalumabImmune-mediated colitis or diarrhea occurred in 6% (23/388) of patients receiving IMJUDO in combination with durvalumab, 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 IMJUDO in combination with durvalumab.Immune-Mediated HepatitisIMJUDO in combination with durvalumab can cause immune-mediated hepatitis, which may be fatal.IMJUDO with DurvalumabImmune-mediated hepatitis occurred in 7.5% (29/388) of patients receiving IMJUDO in combination with durvalumab, 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.IMJUDO with Durvalumab and Platinum-Based ChemotherapyImmune-mediated hepatitis occurred in 3.9% (23/596) of patients receiving IMJUDO in combination with durvalumab and platinum-based chemotherapy, including fatal (0.3%), Grade (0.5%), and Grade (2%) adverse reactions. Events resolved in 12 of the 23 patients and resulted in permanent discontinuation in 27 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: IMJUDO in combination with durvalumab 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 IMJUDO in combination with durvalumab based on the severity [see Dosage and Administration (2.2)]. IMJUDO with DurvalumabImmune-mediated adrenal insufficiency occurred in 1.5% (6/388) of patients receiving IMJUDO in combination with durvalumab, 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).IMJUDO with Durvalumab and Platinum-Based ChemotherapyImmune-mediated adrenal insufficiency occurred in 2.2% (13/596) of patients receiving IMJUDO in combination with durvalumab and platinum-based chemotherapy, 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.Hypophysitis: IMJUDO in combination with durvalumab 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 IMJUDO in combination with durvalumab depending on severity [see Dosage and Administration (2.2)]. IMJUDO with DurvalumabImmune-mediated hypophysitis/hypopituitarism occurred in 1% (4/388) of patients receiving IMJUDO in combination with durvalumab. 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.IMJUDO with Durvalumab and Platinum-Based ChemotherapyImmune-mediated hypophysitis occurred in 1.3% (8/596) of patients receiving IMJUDO in combination with durvalumab and platinum-based chemotherapy, 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 Disorders: IMJUDO in combination with durvalumab 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 IMJUDO in combination with durvalumab based on the severity [see Dosage and Administration (2.2)]. Thyroiditis:IMJUDO with DurvalumabImmune-mediated thyroiditis thyroiditis occurred in 1.5% (6/388) of patients receiving IMJUDO in combination with durvalumab. 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.IMJUDO with Durvalumab and Platinum-Based ChemotherapyImmune-mediated thyroiditis occurred in 1.2% (7/596) of patients receiving IMJUDO in combination with durvalumab and platinum-based chemotherapy. 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.Hyperthyroidism:IMJUDO with DurvalumabImmune-mediated hyperthyroidism occurred in 4.6% (18/388) of patients receiving IMJUDO in combination with durvalumab, 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).IMJUDO with Durvalumab and Platinum-Based ChemotherapyImmune-mediated hyperthyroidism occurred in 5% (30/596) of patients receiving IMJUDO in combination with durvalumab and platinum-based chemotherapy, 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. Hypothyroidism:IMJUDO with DurvalumabImmune-mediated hypothyroidism occurred in 11% (42/388) of patients receiving IMJUDO in combination with durvalumab. 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).IMJUDO with Durvalumab and Platinum-Based ChemotherapyImmune-mediated hypothyroidism occurred in 8.6% (51/596) of patients receiving IMJUDO in combination with durvalumab and platinum-based chemotherapy, including Grade (0.5%) adverse reactions. Systemic corticosteroids were required in patients (2/51) and all patients required endocrine therapy.Type Diabetes Mellitus, Which Can Present with Diabetic Ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue IMJUDO in combination with durvalumab based on the severity [see Dosage and Administration (2.2)].IMJUDO with DurvalumabTwo patients (0.5%, 2/388) had events of hyperglycemia requiring insulin therapy that had not resolved at last follow-up.IMJUDO with Durvalumab and Platinum-Based ChemotherapyImmune-mediated Type Diabetes Mellitus occurred in 0.5% (3/596) of patients receiving IMJUDO in combination with durvalumab and platinum-based chemotherapy, including Grade (0.3%) adverse reactions. All patients required endocrine therapy.Immune-Mediated Nephritis with Renal DysfunctionIMJUDO in combination with durvalumab can cause immune-mediated nephritis. IMJUDO with DurvalumabImmune-mediated nephritis occurred in 1% (4/388) of patients receiving IMJUDO in combination with durvalumab, 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). IMJUDO with Durvalumab and Platinum-Based ChemotherapyImmune-mediated nephritis occurred in 0.7% (4/596) of patients receiving IMJUDO in combination with durvalumab and platinum-based chemotherapy, 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 IMJUDO in combination with durvalumab 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 CTLA-4 and 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 IMJUDO in combination with durvalumab depending on severity [see Dosage and Administration (2.2)]. IMJUDO with DurvalumabImmune-mediated rash or dermatitis occurred in 4.9% (19/388) of patients receiving IMJUDO in combination with durvalumab, 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.IMJUDO with Durvalumab and Platinum-Based ChemotherapyImmune-mediated rash or dermatitis occurred in 7.2% (43/596) of patients receiving IMJUDO in combination with durvalumab and platinum-based chemotherapy, 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 PancreatitisIMJUDO in combination with durvalumab can cause immune-mediated pancreatitis. IMJUDO with DurvalumabImmune-mediated pancreatitis occurred in 2.3% (9/388) of patients receiving IMJUDO in combination with durvalumab, 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 IMJUDO in combination with durvalumab or were reported with the use of other immune-checkpoint inhibitors. 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: Gastritis, duodenitis.Musculoskeletal and connective tissue disorders: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatica.Endocrine: Hypoparathyroidism.Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, and immune thrombocytopenia.. 5.2 Infusion-Related Reactions IMJUDO in combination with durvalumab 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 IMJUDO and durvalumab based on the severity [see Dosage and Administration (2.2)]. For Grade or infusion-related reactions, consider using pre-medications with subsequent doses.IMJUDO with DurvalumabInfusion-related reactions occurred in 10 (2.6%) patients receiving IMJUDO in combination with durvalumab.IMJUDO with Durvalumab and Platinum-Based ChemotherapyInfusion-related reactions occurred in 2.9% (17/596) of patients receiving IMJUDO in combination with durvalumab and platinum-based chemotherapy, including Grade (0.3%) adverse reactions.. 5.3 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, IMJUDO can cause fetal harm when administered to pregnant woman. In animal studies, CTLA-4 blockade is associated with higher incidence of pregnancy loss. Advise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with IMJUDO and for months after the last dose of IMJUDO [see Use in Specific Populations (8.1, 8.3)].