Durvalumab

1 INDICATIONS AND USAGE IMFINZI is a programmed death-ligand 1 (PD-L1) blocking antibody indicated: • in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by IMFINZI continued as a single agent as adjuvant treatment after surgery, for the treatment of adult patients with resectable (tumors ≥ 4 cm and/or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements. ( 1.1 ) • as a single agent, for the treatment of adult patients with unresectable, Stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. ( 1.1 ) • in combination with tremelimumab-actl and platinum-based chemotherapy, for the treatment of adult patients with metastatic NSCLC with no sensitizing EGFR mutations or ALK genomic tumor aberrations. ( 1.1 ) • as a single agent, for the treatment of adult patients with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. ( 1.2 ) • in combination with etoposide and either carboplatin or cisplatin, as first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). ( 1.2 ) • in combination with gemcitabine and cisplatin, as treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC). ( 1.3 ) • in combination with tremelimumab-actl, for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC). ( 1.4 ) • in combination with carboplatin and paclitaxel followed by IMFINZI as a single agent, for the treatment of adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) as determined by an FDA-approved test. ( 1.5 , 2.1 ) • in combination with gemcitabine and cisplatin as neoadjuvant treatment, followed by single agent IMFINZI as adjuvant treatment following radical cystectomy, for the treatment of adult patients with muscle invasive bladder cancer (MIBC). ( 1.6 ) • in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy as neoadjuvant and adjuvant treatment, followed by single agent IMFINZI, for the treatment of adult patients with resectable gastric or gastroesophageal junction adenocarcinoma (GC/GEJC). ( 1.7 ) 1.1 Non-Small Cell Lung Cancer • IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by IMFINZI continued as a single agent as adjuvant treatment after surgery, is indicated for the treatment of adult patients with resectable (tumors ≥ 4 cm and/or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements. • IMFINZI, as a single agent, is indicated for the treatment of adult patients with unresectable Stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT). • IMFINZI, in combination with tremelimumab-actl and platinum-based chemotherapy, is indicated for the treatment of adult patients with metastatic NSCLC with no sensitizing EGFR mutations or ALK genomic tumor aberrations. 1.2 Small Cell Lung Cancer • IMFINZI, as a single agent, is indicated for the treatment of adult patients with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT). • IMFINZI, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). 1.3 Biliary Tract Cancers IMFINZI, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC). 1.4 Hepatocellular Carcinoma IMFINZI, in combination with tremelimumab-actl, is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC). 1.5 Endometrial Cancer IMFINZI, in combination with carboplatin and paclitaxel followed by IMFINZI as a single agent, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) as determined by an FDA-approved test [see Dosage and Administration (2.1)]. 1.6 Bladder Cancer IMFINZI in combination with gemcitabine and cisplatin as neoadjuvant treatment, followed by single agent IMFINZI as adjuvant treatment following radical cystectomy, is indicated for the treatment of adult patients with muscle invasive bladder cancer (MIBC). 1.7 Gastric or gastroesophageal junction adenocarcinoma IMFINZI in combination with fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) as neoadjuvant and adjuvant treatment, followed by single-agent IMFINZI, is indicated for the treatment of adult patients with resectable gastric or gastroesophageal junction adenocarcinoma (GC/GEJC).

2 DOSAGE AND ADMINISTRATION • Administer IMFINZI as an intravenous infusion over 60 minutes after dilution. ( 2.4 ) • Neoadjuvant and Adjuvant Treatment of Resectable NSCLC: ∘ Weight ≥ 30 kg: Neoadjuvant : IMFINZI 1,500 mg in combination with chemotherapy every 3 weeks for up to 4 cycles prior to surgery. Adjuvant : IMFINZI 1,500 mg as a single agent every 4 weeks for up to 12 cycles after surgery. ( 2.2 ) ∘ Weight < 30 kg Neoadjuvant : IMFINZI 20 mg/kg every 3 weeks in combination with chemotherapy for up to 4 cycles prior to surgery. Adjuvant : 20 mg/kg every 4 weeks as a single agent for up to 12 cycles after surgery. ( 2.2 ) • Unresectable Stage III NSCLC, following concurrent platinum-based chemotherapy and radiation therapy: ∘ Weight ≥ 30 kg: IMFINZI 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks. ( 2.2 ) ∘ Weight < 30 kg: IMFINZI 10 mg/kg every 2 weeks. ( 2.2 ) • Metastatic NSCLC: ∘ Weight ≥ 30 kg: IMFINZI 1,500 mg every 3 weeks in combination with tremelimumab-actl 75 mg and platinum-based chemotherapy for 4 cycles, and then administer IMFINZI 1,500 mg every 4 weeks as a single agent with histology-based pemetrexed maintenance therapy every 4 weeks, and a fifth dose of tremelimumab-actl 75 mg in combination with IMFINZI dose 6 at week 16. ( 2.2 ) ∘ Weight < 30 kg: IMFINZI 20 mg/kg every 3 weeks in combination with tremelimumab-actl 1 mg/kg and platinum-based chemotherapy, and then administer IMFINZI 20 mg/kg every 4 weeks as a single agent with histology-based pemetrexed therapy every 4 weeks, and a fifth dose of tremelimumab-actl 1 mg/kg in combination with IMFINZI dose 6 at week 16. ( 2.2 ) • LS-SCLC, following concurrent platinum-based chemotherapy and radiation therapy: ∘ Weight ≥ 30 kg: 1,500 mg every 4 weeks. ( 2.2 ) ∘ Weight < 30 kg: 20 mg/kg every 4 weeks. ( 2.2 ) • ES-SCLC: ∘ Weight ≥ 30 kg: With etoposide and either carboplatin or cisplatin, administer IMFINZI 1,500 mg every 3 weeks in combination with chemotherapy, and then 1,500 mg every 4 weeks as a single agent. ( 2.2 ) ∘ Weight < 30 kg: With etoposide and either carboplatin or cisplatin, administer IMFINZI 20 mg/kg every 3 weeks in combination with chemotherapy, and then 10 mg/kg every 2 weeks as a single agent. ( 2.2 ) • BTC: ∘ Weight ≥ 30 kg: administer IMFINZI 1,500 mg every 3 weeks in combination with chemotherapy, and then 1,500 mg every 4 weeks as a single agent. ( 2.2 ) ∘ Weight < 30 kg: administer IMFINZI 20 mg/kg every 3 weeks in combination with chemotherapy, and then 20 mg/kg every 4 weeks as a single agent. ( 2.2 ) • uHCC: ∘ Weight ≥ 30 kg: IMFINZI 1,500 mg in combination with tremelimumab-actl 300 mg as a single dose at Cycle 1/Day 1, followed by IMFINZI as a single agent every 4 weeks. ( 2.2 ) ∘ Weight < 30 kg: IMFINZI 20 mg/kg in combination with tremelimumab-actl 4 mg/kg as a single dose at Cycle 1/Day 1, followed by IMFINZI as a single agent every 4 weeks. ( 2.2 ) • dMMR endometrial cancer: ∘ Weight ≥ 30 kg: IMFINZI 1,120 mg in combination with carboplatin and paclitaxel every 3 weeks for 6 cycles, followed by IMFINZI 1,500 mg every 4 weeks as a single agent. ( 2.1 , 2.2 ) ∘ Weight < 30 kg: IMFINZI 15 mg/kg in combination with carboplatin and paclitaxel every 3 weeks for 6 cycles, followed by IMFINZI 20 mg/kg every 4 weeks as a single agent. ( 2.1 , 2.2 ) • MIBC: ∘ Weight ≥ 30 kg: Neoadjuvant: IMFINZI 1,500 mg in combination with gemcitabine and cisplatin every 3 weeks for 4 cycles prior to surgery. Adjuvant: IMFINZI 1,500 mg every 4 weeks as a single agent for up to 8 cycles after surgery. ( 2.2 ) ∘ Weight < 30 kg: Neoadjuvant: IMFINZI 20 mg/kg in combination with gemcitabine and cisplatin every 3 weeks for 4 cycles prior to surgery. Adjuvant: IMFINZI 20 mg/kg every 4 weeks as a single agent for up to 8 cycles after surgery. ( 2.2 ) • See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions. 2.1 Patient Selection Advanced or Recurrent dMMR Endometrial Cancer Select patients for treatment based on the presence of dMMR in tumor specimens [see Clinical Studies (14.5) ]. Information on FDA-approved tests for the detection of dMMR status in endometrial cancer is available at https://www.fda.gov/companiondiagnostics . 2.2 Recommended Dosage The recommended dosages for IMFINZI as a single agent and IMFINZI in combination with other therapeutic agents are presented in Table 1. The recommended dosage schedule and regimens for IMFINZI for the treatment of metastatic NSCLC are provided in Tables 2 and 3 [see Indications and Usage (1.1) ]. Administer IMFINZI as a 60 minute intravenous infusion after dilution [ see Dosage and Administration (2.3) ]. Table 1. Recommended Dosages of IMFINZI Indication Recommended IMFINZI Dosage Duration of Therapy Neoadjuvant and Adjuvant Treatment of Resectable NSCLC Patients with a body weight of ≥ 30 kg: Neoadjuvant: IMFINZI 1,500 mg in combination with chemotherapy Administer IMFINZI prior to chemotherapy on the same day. Refer to the Prescribing Information for the agent administered in combination with IMFINZI for recommended dosage information, as appropriate. every 3 weeks for up to 4 cycles prior to surgery Adjuvant: IMFINZI 1,500 mg as a single agent every 4 weeks for up to 12 cycles after surgery. Patients with a body weight of < 30 kg: Neoadjuvant: IMFINZI 20 mg/kg every 3 weeks in combination with chemotherapy for up to 4 cycles prior to surgery. Adjuvant: IMFINZI 20 mg/kg every 4 weeks for up to 12 cycles as a single agent after surgery. Until disease progression that precludes definitive surgery, recurrence, unacceptable toxicity, or a maximum of 12 cycles after surgery Unresectable Stage III NSCLC Following concurrent platinum-based chemotherapy and radiation therapy: Patients with a body weight of ≥ 30 kg: 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks Patients with a body weight of < 30 kg: 10 mg/kg every 2 weeks Until disease progression, unacceptable toxicity, or a maximum of 12 months Limited Stage SCLC Following concurrent platinum-based chemotherapy and radiation therapy: Patients with a body weight of ≥ 30 kg: 1,500 mg every 4 weeks Patients with a body weight of < 30 kg: 20 mg/kg every 4 weeks Until disease progression, unacceptable toxicity, or a maximum of 24 months Extensive Stage SCLC Patients with a body weight of ≥ 30 kg: 1,500 mg in combination with chemotherapy every 3 weeks (21 days) for 4 cycles, followed by 1,500 mg every 4 weeks as a single agent Patients with a body weight of < 30 kg: 20 mg/kg in combination with chemotherapy every 3 weeks (21 days) for 4 cycles, followed by 10 mg/kg every 2 weeks as a single agent Until disease progression or until unacceptable toxicity BTC Patients with a body weight of ≥ 30 kg: 1,500 mg in combination with chemotherapy every 3 weeks (21 days) up to 8 cycles followed by 1,500 mg every 4 weeks as a single agent Patients with a body weight of < 30 kg: 20 mg/kg in combination with chemotherapy every 3 weeks (21 days) up to 8 cycles, followed by 20 mg/kg every 4 weeks as a single agent Until disease progression or until unacceptable toxicity uHCC Patients with a body weight of ≥ 30 kg: IMFINZI 1,500 mg following a single dose of tremelimumab-actl Administer tremelimumab-actl prior to IMFINZI on the same day. When tremelimumab-actl is administered in combination with IMFINZI, refer to the Prescribing Information for tremelimumab-actl dosing information. 300 mg at Day 1 of Cycle 1; Continue IMFINZI 1,500 mg as a single agent every 4 weeks Patients with a body weight of < 30 kg: IMFINZI 20 mg/kg following a single dose of tremelimumab-actl 4 mg/kg at Day 1 of Cycle 1; Continue IMFINZI 20 mg/kg as a single agent every 4 weeks After Cycle 1 of combination therapy, administer IMFINZI as a single agent every 4 weeks until disease progression or unacceptable toxicity dMMR endometrial cancer Patients with a body weight of ≥ 30 kg: IMFINZI 1,120 mg in combination with carboplatin and paclitaxel every 3 weeks (21 days) for 6 cycles, followed by IMFINZI 1,500 mg every 4 weeks as a single agent Patients with a body weight of < 30 kg: IMFINZI 15 mg/kg in combination with carboplatin and paclitaxel every 3 weeks (21 days) for 6 cycles, followed by IMFINZI 20 mg/kg every 4 weeks as a single agent Until disease progression or unacceptable toxicity Neoadjuvant and Adjuvant Treatment of MIBC Patients with a body weight of ≥30 kg: Neoadjuvant: 1,500 mg in combination with gemcitabine and cisplatin every 3 weeks for 4 cycles prior to surgery Adjuvant: IMFINZI 1,500 mg as a single agent every 4 weeks for up to 8 cycles after surgery Patients with a body weight of < 30 kg: Neoadjuvant: 20 mg/kg in combination with gemcitabine and cisplatin every 3 weeks for 4 cycles prior to surgery Adjuvant: IMFINZI 20 mg/kg as a single agent every 4 weeks for up to 8 cycles after surgery Until disease progression that precludes definitive surgery, recurrence, or unacceptable toxicity or a maximum of 8 cycles after surgery Neoadjuvant and Adjuvant Treatment of Resectable GC/GEJC Patients with a body weight of ≥ 30 kg: Neoadjuvant: IMFINZI 1,500 mg every 4 weeks with FLOT FLOT chemotherapy is administered on days 1 and 15 of each 4 week cycle [See Clinical Studies ( 14.7 )] . for up to 2 cycles prior to surgery Adjuvant: IMFINZI 1,500 mg every 4 weeks with FLOT for up to 2 cycles, followed by IMFINZI 1,500 mg as a single agent every 4 weeks for up to 10 cycles Patients with a body weight of < 30 kg: Neoadjuvant: IMFINZI 20 mg/kg every 4 weeks with FLOT*± for up to 2 cycles prior to surgery Adjuvant: IMFINZI 20 mg/kg every 4 weeks with FLOT for up to 2 cycles, followed by IMFINZI 20 mg/kg as a single agent every 4 weeks for up to 10 cycles Neoadjuvant: Until disease progression that precludes definitive surgery or unacceptable toxicity IMFINZI in Combination with Tremelimumab-actl and Platinum-Based Chemotherapy The recommended dosage schedule and regimens for IMFINZI for the treatment of metastatic NSCLC are provided in Tables 2 and 3. Weigh patients prior to each infusion. Calculate the appropriate dose using Table 3 below based on the patient’s weight and tumor histology. Table 2. Recommended Dosage Schedule for Metastatic NSCLC Week continue IMFINZI until disease progression or intolerable toxicity. note the dosing interval change from every 3 weeks to every 4 weeks starting at cycle 5. 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Cycle: 1 2 3 4 5 6 7 8 IMFINZI intravenous infusion over 60 minutes [see Dosage and Administration (2.4) ] . X X X X X X X X Tremelimumab-actl if patients receive fewer than 4 cycles of platinum-based chemotherapy, the remaining cycles of tremelimumab-actl (up to a total of 5) should be given after the platinum-based chemotherapy phase, in combination with IMFINZI, every 4 weeks. X X X X X Chemotherapy X X X X X optional pemetrexed therapy from week 12 until disease progression or intolerable toxicity for patients with non-squamous disease who received treatment with pemetrexed and carboplatin/cisplatin. X X X Table 3. Recommended Regimen and Dosage for Metastatic NSCLC Tumor Histology Patient Weight IMFINZI Dosage Tremelimumab-actl Dosage Refer to the Prescribing Information for dosing information. Platinum-based Chemotherapy Regimen Non-Squamous ≥ 30 kg 1,500 mg 75 mg • carboplatin & nab-paclitaxel OR • carboplatin or cisplatin & pemetrexed < 30 kg 20 mg/kg 1 mg/kg Squamous ≥ 30 kg 1,500 mg 75 mg • carboplatin & nab-paclitaxel OR • carboplatin or cisplatin & gemcitabine < 30 kg 20 mg/kg 1 mg/kg 2.3 Dosage Modifications for Adverse Reactions No dose reduction for IMFINZI is recommended. In general, withhold IMFINZI for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue IMFINZI for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids. Dosage modifications for IMFINZI or IMFINZI in combination with tremelimumab-actl or chemotherapy for adverse reactions that require management different from these general guidelines are summarized in Table 4. Table 4. Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity Based on National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Dosage Modification Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ] Pneumonitis Grade 2 Withhold Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating corticosteroids or an inability to reduce corticosteroid dose to 10 mg of prednisone or less per day (or equivalent) within 12 weeks of initiating corticosteroids. Grade 3 or 4 Permanently discontinue Colitis Grade 2 Withhold Grade 3 Withhold or permanently discontinue Permanently discontinue IMFINZI for Grade 3 colitis when administered as part of a tremelimumab-actl containing regimen. Grade 4 Permanently discontinue Intestinal perforation Any grade Permanently discontinue Hepatitis with no tumor involvement of the liver ALT or AST increases to more than 3 and up to 8 times the ULN or total bilirubin increases to more than 1.5 and up to 3 times ULN Withhold ALT or AST increases to more than 8 times ULN or total bilirubin increases to more than 3 times the ULN Permanently discontinue Hepatitis with tumor involvement of the liver If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue IMFINZI based on recommendations for hepatitis with no liver involvement. AST or ALT is more than 1 and up to 3 times ULN at baseline and increases to more than 5 and up to 10 times ULN or AST or ALT is more than 3 and up to 5 times ULN at baseline and increases to more than 8 and up to 10 times ULN Withhold AST or ALT increases to more than 10 times ULN or total bilirubin increases to more than 3 times ULN Permanently discontinue Endocrinopathies Grade 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity Nephritis with Renal Dysfunction Grade 2 or 3 increased blood creatinine Withhold Grade 4 increased blood creatinine Permanently discontinue Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold Confirmed SJS, TEN, or DRESS Permanently discontinue Myocarditis Grade 2, 3, or 4 Permanently discontinue Neurological Toxicities Grade 2 Withhold Grade 3 or 4 Permanently discontinue Other Adverse Reactions Infusion-related reactions [see Warnings and Precautions (5.2) ] Grade 1 or 2 Interrupt or slow the rate of infusion Grade 3 or 4 Permanently discontinue ALT = 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. 2.4 Preparation and Administration Preparation • Visually inspect drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or visible particles are observed. • Do not shake the vial. • Withdraw the required volume from the vial(s) of IMFINZI and transfer into an intravenous bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. Do not shake the solution. The final concentration of the diluted solution should be between 1 mg/mL and 15 mg/mL. • Discard partially used or empty vials of IMFINZI. Storage of Infusion Solution • IMFINZI does not contain a preservative. • Administer infusion solution immediately once prepared. If the infusion solution is not administered immediately and needs to be stored, the time from preparation until the completion of the infusion should not exceed: ∘ 28 days in a refrigerator at 2°C to 8°C (36°F to 46°F) ∘ 8 hours at room temperature up to 25°C (77°F) • Do not freeze. • Do not shake. Administration • Administer infusion solution intravenously over 60 minutes through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter. • Use separate infusion bags and filters for each drug product. IMFINZI in Combination with Other Products • Administer all intravenous drug products as separate infusions. • Do not co-administer other intravenous drugs through the same infusion line. • For platinum-based chemotherapy, refer to Prescribing Information for administration information. • For pemetrexed therapy, refer to Prescribing Information for administration information. Combination Regimens: Order of Infusions IMFINZI in Combination with Tremelimumab-actl • Infuse tremelimumab-actl first, followed by IMFINZI on the same day of dosing. IMFINZI in Combination with Tremelimumab-actl and Platinum-Based Chemotherapy • Infuse tremelimumab-actl first, followed by IMFINZI and then platinum-based chemotherapy on the day of dosing. IMFINZI in Combination with Tremelimumab-actl and Pemetrexed Therapy • Infuse tremelimumab-actl first, followed by IMFINZI and then pemetrexed therapy on the day of dosing. IMFINZI in Combination with Chemotherapy • Infuse IMFINZI first and then chemotherapy on the same day of dosing. Combination Regimens: Infusion Instructions IMFINZI in Combination with Tremelimumab-actl • Administer tremelimumab-actl over 60 minutes followed by a 60 minute observation period. Then administer IMFINZI as a separate intravenous infusion over 60 minutes. IMFINZI in Combination with Tremelimumab-actl and Platinum-Based Chemotherapy/ Pemetrexed Therapy Cycle 1 • Infuse tremelimumab-actl over 60 minutes. One to two hours after completion of tremelimumab-actl infusion, infuse IMFINZI over 60 minutes. One to two hours after completion of IMFINZI infusion, administer platinum-based chemotherapy. Subsequent Cycles • If there are no infusion reactions during cycle 1, subsequent cycles of IMFINZI can be given immediately after tremelimumab-actl. The time between the end of the IMFINZI infusion and the start of chemotherapy can be reduced to 30 minutes.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. • Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ]. • Infusion-Related Reactions [see Warnings and Precautions (5.2) ]. IMFINZI in Combination with Chemotherapy • Most common adverse reactions (≥ 20%) of patients with resectable, Stage II/III NSCLC [neoadjuvant /adjuvant]) are anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash. ( 6.1 ) IMFINZI as a Single Agent • Most common adverse reactions (≥ 20%) of patients with unresectable, Stage III NSCLC) are cough, fatigue, pneumonitis/radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash. ( 6.1 ) IMFINZI in Combination with Tremelimumab-actl and Platinum-Based Chemothe rapy • Most common adverse reactions (≥ 20%) of patients with metastatic NSCLC) are nausea, fatigue, musculoskeletal pain, decreased appetite, rash, and diarrhea. ( 6.1 ) IMFINZI as a Single Agent • Most common adverse reactions (≥ 20%) of patients with limited-stage SCLC) are pneumonitis or radiation pneumonitis, and fatigue. ( 6.1 ) IMFINZI in Combination with Platinum-Based Chemotherapy • Most common adverse reactions (≥ 20%) of patients with extensive-stage SCLC) are nausea, fatigue/asthenia, and alopecia. ( 6.1 ) IMFINZI in Combination with Gemcitabine and Cisplatin • Most common adverse reactions (≥ 20%) of patients with BTC) are fatigue, nausea, constipation, decreased appetite, abdominal pain, rash, and pyrexia. ( 6.1 ) IMFINZI in Combination with Tremelimumab-actl • Most common adverse reactions (≥ 20%) of patients with uHCC) are rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain. ( 6.1 ) IMFINZI in Combination with Carboplatin and Paclitaxel, followed by IMFINZI as a single agent • Most common adverse reactions (≥ 20%) of patients with endometrial cancer) were peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, decreased magnesium, increased ALT, increased AST, diarrhea, vomiting, cough, decreased potassium, dyspnea, headache, and increased alkaline phosphatase. ( 6.1 ) IMFINZI in Combination with Gemcitabine and Cisplatin, followed by IMFINZI as a single agent • Most common adverse reactions (≥ 20% of patients with MIBC) were decreased hemoglobin, decreased neutrophils, increased blood creatinine, decreased sodium, nausea, increased ALT, decreased calcium, decreased platelets, fatigue, increased potassium, decreased lymphocytes, increased AST, constipation, decreased magnesium, decreased appetite, increased alkaline phosphate, rash, pyrexia, diarrhea, vomiting and abdominal pain. ( 6.1 ) IMFINZI in Combination with FLOT Chemotherapy followed by IMFINZI as a single agent • Most common adverse reactions (≥ 20% of patients with resectable GC/GEJC) were diarrhea, nausea, peripheral neuropathy, fatigue, alopecia, decreased appetite, rash, abdominal pain, vomiting, musculoskeletal pain, pyrexia, and stomatitis ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to IMFINZI as a single agent in a total of 1,889 patients enrolled in the PACIFIC study (a randomized, placebo-controlled study that enrolled 475 patients with unresectable Stage III NSCLC), Study 1108 (an open-label, single-arm, multicohort study that enrolled 970 patients with advanced solid tumors), and an additional open-label, single-arm study (ATLANTIC Study) that enrolled 444 patients with advanced solid tumors, including NSCLC. In these studies, IMFINZI was administered at a dose of 10 mg/kg every 2 weeks. Among the 1889 patients, 38% were exposed for 6 months or more and 18% were exposed for 12 months or more. The data also reflect exposure to IMFINZI 1,500 mg every 4 weeks as a single agent in 262 patients from the ADRIATIC study (a randomized, double-blind study in patients with LS-SCLC) and to IMFINZI in combination with chemotherapy in 265 patients from the CASPIAN study (a randomized, open-label study in patients with ES-SCLC) and in 338 patients from the TOPAZ-1 study (a randomized, double-blind study in patients with BTC). In the CASPIAN and TOPAZ-1 studies, IMFINZI was administered at a dose of 1,500 mg every 3 or 4 weeks. The data also reflect exposure to IMFINZI 1,120 mg in combination with carboplatin and paclitaxel (every 3 weeks for up to 6 cycles) followed by IMFINZI 1,500 mg (every 4 weeks) as a single agent in 235 patients in DUO-E (a randomized, placebo-controlled trial in endometrial cancer). Among the 235 patients, 77% (181 patients) were exposed to IMFINZI for 6 months or more and 41% (96 patients) for 12 months or more. The data also reflect exposure to IMFINZI 1,500 mg in combination with tremelimumab-actl 300 mg in 388 patients in HIMALAYA. In the HIMALAYA study patients received IMFINZI 1,500 mg in combination with tremelimumab-actl as a single intravenous infusion of 300 mg, followed by IMFINZI 1,500 mg every 4 weeks. The pooled safety population (N = 596) described in the WARNINGS AND PRECAUTIONS section reflect exposure to IMFINZI 1,500 mg in combination with tremelimumab-actl 75 mg and histology-based platinum chemotherapy regimens in 330 patients in POSEIDON [see Clinical Studies (14.1) ] , and 266 patients with ES-SCLC in CASPIAN who received up to four cycles of platinum-etoposide plus IMFINZI 1,500 mg with tremelimumab-actl 75 mg every 3 weeks, followed by IMFINZI 1,500 mg every 4 weeks (an unapproved regimen for extensive stage small cell lung cancer). Among the 596 patients, 55% were exposed to IMFINZI for 6 months or more and 24% were exposed for 12 months or more. The data described in this section reflect exposure to IMFINZI in patients with unresectable Stage III NSCLC enrolled in the PACIFIC study, in patients with metastatic NSCLC enrolled in the POSEIDON study, in patients with LS-SCLC enrolled in the ADRIATIC study, in patients with ES-SCLC enrolled in the CASPIAN study, in patients with BTC enrolled in the TOPAZ‑1 study, in patients with uHCC included in the HIMALAYA study, in patients with dMMR endometrial cancer enrolled in the DUO-E study, in patients with resectable NSCLC enrolled in the AEGEAN study, in patients with MIBC enrolled in the NIAGARA study and in patients with resectable GC/GEJC enrolled in the MATTERHORN study. Non-Small Cell Lung Cancer Neoadjuvant and Adjuvant Treatment of Resectable NSCLC – AEGEAN The safety of IMFINZI in combination with neoadjuvant platinum-containing chemotherapy followed by surgery, and continued adjuvant treatment with IMFINZI as a single agent after surgery, was investigated in AEGEAN, a randomized, double-blind, placebo-controlled, multicenter study for patients with resectable NSCLC (Stage IIA to select Stage IIIB [AJCC, 8 th edition]); squamous or non-squamous) [see Clinical Studies (14.1) ] . Safety data are available for the 799 patients who received IMFINZI in combination with chemotherapy (n=401) or placebo in combination with chemotherapy (n=398). The median duration of exposure to IMFINZI 1,500 mg every 3 weeks in the neoadjuvant phase was 12 weeks (range: 0 to 19 weeks). The median duration of exposure to IMFINZI 1,500 mg every 4 weeks in the adjuvant phase was 37 weeks (range: 4 to 67 weeks). The median age of patients who received IMFINZI was 65 years (range: 30 to 88), 52% age 65 or older, 12% age 75 or older; 65% male; 54% White, 41% Asian, 1% Black, 3% Other races; and 17% Hispanic or Latino. The most common adverse reactions (occurring in ≥ 20% of patients) were anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash. Table 5 summarizes the adverse reactions that occurred in (≥ 10%) patients treated with IMFINZI in combination with chemotherapy. Table 5. Adverse Reactions Occurring in ≥ 10% of Patients in the AEGEAN Study Adverse Reaction IMFINZI with Chemotherapy N=401 Placebo with Chemotherapy N=398 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Gastrointestinal disorders Nausea 25 0.2 29 0.3 Constipation 25 0.2 21 0 Diarrhea includes colitis, diarrhea, enteritis, and proctitis. 14 1 13 1.3 Vomiting 11 0.7 11 1.0 General disorders and administration site conditions Fatigue includes fatigue and asthenia. 25 0 25 1.5 Skin and subcutaneous tissue disorders Rash includes dermatitis, dermatitis acneiform, drug eruption, eczema, eczema asteatotic, erythema, palmar‑erythrodysaesthesia syndrome, pemphigoid, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular, skin exfoliation, and urticarial dermatitis. 22 0.5 14 0.3 Pruritus 12 0.2 6 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain includes arthralgia, arthritis, back pain, bone pain, chest pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, musculoskeletal stiffness,myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain. 24 1 29 0.5 Metabolism and nutrition disorders Decreased appetite 18 0.2 18 0.3 Nervous system disorders Peripheral neuropathy includes dysaesthesia, hypoaesthesia, neuralgia, neuropathy peripheral, paraesthesia, peripheral sensory neuropathy, and polyneuropathy. 16 0.5 22 0.8 Endocrine disorders Hypothyroidism includes blood thyroid stimulating hormone increased and hypothyroidism. 11 0 3.8 0 Respiratory, thoracic and mediastinal disorders Cough / Productive cough 11 0 13 0 Pneumonia includes lower respiratory tract infection, lung abscess, paracancerous pneumonia, pneumonia, pneumonia aspiration, pneumonia bacterial, pneumonia chlamydial, pneumonia cryptococcal, pneumonia fungal, pneumonia pseudomonal, pneumonia streptococcal, pneumonia viral, and post-procedural pneumonia. , Five Grade 5 events in the IMFINZI arm and four Grade 5 events in the Placebo arm. 11 3.5 10 3 COVID-19 Includes COVID-19 and COVID-19 Pneumonia. Five Grade 5 events in the IMFINZI arm and One Grade 5 event in the placebo arm. 11 0.2 9 0.8 Psychiatric Disorders Insomnia 10 0 12 0 Table 6 summarizes the laboratory abnormalities in patients treated with IMFINZI in combination with chemotherapy. Table 6. Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with Disease Who Received IMFINZI with Chemotherapy in AEGEAN Laboratory Abnormality Graded per NCI CTCAE V5. IMFINZI with Chemotherapy The denominator used to calculate the rate varied from 349 to 399 based on the number of patients with a baseline value and at least one post-treatment value. Placebo with Chemotherapy The denominator used to calculate the rate varied from 333 to 398 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Hemoglobin decreased 78 10 75 9 Leukocytes decreased 63 12 64 11 Neutrophils decreased 52 24 56 27 Platelets decreased 46 7 44 8 Lymphocytes decreased 41 11 37 9 Chemistry Calcium corrected, decreased 51 3.3 52 4.5 Alanine aminotransferase increased 49 6 42 2 Aspartate aminotransferase increased 47 3.5 37 1.8 Potassium increased 33 1.5 29 2 Sodium decreased 35 5 33 6 Gamma glutamyl transferase increased 36 4.7 35 2.1 Creatinine increased 32 2.3 27 3.3 Amylase increased 25 4.7 24 3.6 Magnesium decreased 22 2.8 20 3.6 Lipase increased 23 4.9 24 7 Neoadjuvant Phase of AEGEAN A total of 401 patients received at least 1 dose of IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment and 398 patients received at least 1 dose of placebo in combination with platinum-containing chemotherapy as neoadjuvant treatment. Serious adverse reactions occurred in 21% of patients who received IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥1%) serious adverse reactions were pneumonia (2.7%), anemia (1.5%), myelosuppression (1.5%), vomiting (1.2%), neutropenia (1%), and acute kidney injury (1%). Fatal adverse reactions occurred in 2% of patients, including death due to COVID-19 pneumonia (0.5%), sepsis (0.5%), myocarditis (0.2%), decreased appetite (0.2%), hemoptysis (0.2%), and death not otherwise specified (0.2%). Permanent discontinuation of any study drug due to an adverse reaction occurred in 14% of patients who received IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (>0.5%) adverse reactions that led to permanent discontinuation of any study drug were anemia (1.5%), neutropenia (0.7%), myelosuppression (0.7%), and periphery sensory neuropathy (0.7%). Permanent discontinuation of IMFINZI due to an adverse reaction occurred in 6.7% of patients who received IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥0.5%) adverse reactions that led to permanent discontinuation of IMFINZI were peripheral sensory neuropathy (0.7%) and pneumonitis (0.5%). Of the 401 IMFINZI-treated patients and 398 placebo-treated patients who received neoadjuvant treatment, 1.7% (n=7) and 1% (n=4), respectively, did not receive surgery due to adverse reactions. Adverse reactions that led to cancellation of surgery in the IMFINZI arm were COVID-19 pneumonia, HIV infection, pneumonitis, prostate cancer, colon cancer, pruritus, and colitis. Of the 325 IMFINZI-treated patients who received surgery, 4% (n=15) experienced delay of surgery (a surgical delay is defined as on-study surgery occurring more than 40 days after the last dose of study treatment in the neoadjuvant period) due to adverse reactions. Of the 326 placebo-treated patients who received surgery, 4% (n=16) experienced delay of surgery due to adverse reactions. Of the 325 IMFINZI-treated patients who received surgery, 6.5% (n=21) did not receive adjuvant treatment due to adverse reactions. Of the 326 placebo-treated patients who received surgery, 5.8% (n=19) did not receive adjuvant treatment due to adverse reactions. Adjuvant Phase of AEGEAN A total of 265 patients in the IMFINZI arm and 254 patients in the placebo arm received at least 1 dose of adjuvant treatment. Of the patients who received single agent IMFINZI as adjuvant treatment, 13% experienced serious adverse reactions. The most frequent serious adverse reactions reported in >1% of patients were pneumonia (1.9%), pneumonitis (1.1%), and COVID-19 (1.1%). Four fatal adverse reactions occurred during the adjuvant phase of the study, including COVID-19 pneumonia, pneumonia aspiration, interstitial lung disease and aortic aneurysm. Permanent discontinuation of adjuvant IMFINZI due to an adverse reaction occurred in 8% of patients. The most frequent (≥0.5%) adverse reaction that led to permanent discontinuation of adjuvant IMFINZI was pneumonitis (1.1%) and rash (0.8%). Unresectable Stage III NSCLC - PACIFIC The safety of IMFINZI in patients with Stage III NSCLC who completed concurrent platinum-based chemoradiotherapy within 42 days prior to initiation of study drug was evaluated in the PACIFIC study, a multicenter, randomized, double-blind, placebo-controlled study. A total of 475 patients received IMFINZI 10 mg/kg intravenously every 2 weeks. The study excluded patients who had disease progression following chemoradiation, with active or prior autoimmune disease within 2 years of initiation of the study or with medical conditions that required systemic immunosuppression [see Clinical Studies (14.1) ]. The study population characteristics were: median age of 64 years (range: 23 to 90), 45% age 65 years or older, 70% male, 69% White, 27% Asian, 75% former smoker, 16% current smoker, and 51% had WHO performance status (PS) of 1. All patients received definitive radiotherapy as per protocol, of which 92% received a total radiation dose of 54 Gy to 66 Gy. The median duration of exposure to IMFINZI was 10 months (range: 0.2 to 12.6). IMFINZI was discontinued due to adverse reactions in 15% of patients. The most common adverse reactions leading to IMFINZI discontinuation were pneumonitis or radiation pneumonitis in 6% of patients. Serious adverse reactions occurred in 29% of patients receiving IMFINZI. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonitis or radiation pneumonitis (7%) and pneumonia (6%). Fatal pneumonitis or radiation pneumonitis and fatal pneumonia occurred in < 2% of patients and were similar across arms. The most common adverse reactions (occurring in ≥ 20% of patients) were cough, fatigue, pneumonitis or radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash. Table 7 summarizes the adverse reactions that occurred in at least 10% of patients treated with IMFINZI. Table 7. Adverse Reactions Occurring in ≥ 10% of Patients in the PACIFIC Study IMFINZI N = 475 Placebo N = 234 Adverse Reaction All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Respiratory, Thoracic, and Mediastinal Disorders Cough/Productive Cough 40 0.6 30 0.4 Pneumonitis Includes acute interstitial pneumonitis, interstitial lung disease, pneumonitis, pulmonary fibrosis. /Radiation Pneumonitis 34 3.4 25 3 Dyspnea Includes dyspnea, and exertional dyspnea. 25 1.5 25 2.6 General Disorders Fatigue Includes asthenia and fatigue. 34 0.8 32 1.3 Pyrexia 15 0.2 9 0 Infections Upper respiratory tract infections Includes laryngitis, nasopharyngitis, peritonsillar abscess, pharyngitis, rhinitis, sinusitis, tonsillitis, tracheobronchitis, and upper respiratory tract infection. 26 0.4 19 0 Pneumonia Includes lung infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia adenoviral, pneumonia bacterial, pneumonia cytomegaloviral, pneumonia haemophilus, pneumonia klebsiella, pneumonia necrotizing, pneumonia pneumococcal, and pneumonia streptococcal. 17 7 12 6 Skin and Subcutaneous Tissue Disorders Rash Includes rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, erythema, eczema, rash, and dermatitis. 23 0.6 12 0 Pruritus Includes pruritus generalized and pruritus. 12 0 6 0 Gastrointestinal Disorders Diarrhea 18 0.6 19 1.3 Abdominal pain Includes abdominal pain, abdominal pain lower, abdominal pain upper, and flank pain. 10 0.4 6 0.4 Endocrine Disorders Hypothyroidism Includes autoimmune hypothyroidism and hypothyroidism. 12 0.2 1.7 0 Other adverse reactions occurring in less than 10% of patients treated with IMFINZI were dysphonia, dysuria, night sweats, peripheral edema, and increased susceptibility to infections. Table 8 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI. Table 8. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients in the PACIFIC Study IMFINZI Placebo Laboratory Abnormality All Grades Graded according to NCI CTCAE version 4.0. (%) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI (range: 464 to 470) and placebo (range: 224 to 228). Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Chemistry Hyperglycemia 52 8 51 8 Hypocalcemia 46 0.2 41 0 Increased ALT 39 2.3 22 0.4 Increased AST 36 2.8 21 0.4 Hyponatremia 33 3.6 30 3.1 Hyperkalemia 32 1.1 29 1.8 Increased GGT 24 3.4 22 1.7 Hematology Lymphopenia 43 17 39 18 Metastatic NSCLC - POSEIDON The safety of IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy in patients with metastatic NSCLC was evaluated in POSEIDON (NCT03164616), a randomized, open-label, multicenter, active-controlled study. A total of 330 patients received IMFINZI 1,500 mg in combination with tremelimumab-actl (≥ 30 kg body weight received 75 mg and < 30 kg body weight received 1 mg/kg) and histology-based platinum chemotherapy regimens [see Clinical Studies (14.1) ] . Of these patients, 66% received the maximum 5 doses of tremelimumab-actl and 79% received at least 4 doses. Treatment was continued with IMFINZI as a single agent (or with IMFINZI and histologically-based pemetrexed for non-squamous patients based on the investigator’s decision) until disease progression or unacceptable toxicity. The study excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids or immunosuppressants [see Clinical Studies (14.1) ]. The median age of patients who received IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy was 63 years (range: 27 to 87); 80% male; 61% White, 29% Asian, 58% former smoker, 25% current smoker, and 68% ECOG performance of 1. Serious adverse reactions occurred in 44% of patients receiving IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (11%), anemia (5%), diarrhea (2.4%), thrombocytopenia (2.4%), pyrexia (2.4%), and febrile neutropenia (2.1%). Fatal adverse reactions occurred in a total of 4.2% of patients receiving IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy. These include hepatitis, nephritis, myocarditis, pancreatitis (all in the same patient), death (2 patients), sepsis (2 patients), pneumonitis (2 patients), acute kidney injury (2 patients), febrile neutropenia (1 patient), chronic obstructive pulmonary disease (COPD) (1 patient), dyspnea (1 patient), sudden death (1 patient), and ischemic stroke (1 patient). Permanent discontinuation of IMFINZI or tremelimumab-actl due to an adverse reaction occurred in 17% of the patients. Adverse reactions which resulted in permanent discontinuation of IMFINZI or tremelimumab-actl in > 2% of patients included pneumonia. Dosage interruption or delay of IMFINZI and tremelimumab-actl due to an adverse reaction occurred in 41% of patients. Adverse reactions which required dosage interruption or delay of IMFINZI and tremelimumab-actl in > 1% of patients included anemia, leukopenia/white blood cell count decreased, pneumonia, pneumonitis, colitis, diarrhea, hepatitis, rash, asthenia, amylase increased, alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased, neutropenia/ neutrophil count decreased, and thrombocytopenia/platelet count decreased. The most common adverse reactions (occurring in ≥ 20% of patients) were nausea, fatigue, musculoskeletal pain, decreased appetite, rash, and diarrhea. Grade 3 or 4 laboratory abnormalities (≥ 10%) were neutropenia, anemia, leukopenia, lymphocytopenia, lipase increased, hyponatremia and thrombocytopenia. Table 9 summarizes the adverse reactions in POSEIDON. Table 9. Adverse Reactions (≥ 10%) in Patients with NSCLC Who Received IMFINZI in the POSEIDON Study IMFINZI with tremelimumab-actl and platinum-based chemotherapy N = 330 Platinum-based chemotherapy N = 333 Adverse Reaction All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Gastrointestinal disorders Nausea 42 1.8 37 2.1 Diarrhea 22 1.5 15 1.5 Constipation 19 0 24 0.6 Vomiting 18 1.2 14 1.5 Stomatitis Includes mucosal inflammation and stomatitis. 10 0 6 0.3 General disorders and administration site conditions Fatigue/Asthenia Includes asthenia and fatigue. 36 5 32 4.5 Pyrexia Includes body temperature increased, hyperpyrexia, hyperthermia, and pyrexia. 19 0 8 0 Edema Includes face edema, localized edema, and edema peripheral. 10 0 10 0.6 Musculoskeletal and connective tissue disorders Musculoskeletal Pain Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, and spinal pain. 29 0.6 22 1.5 Metabolism and nutrition disorders Decreased appetite 28 1.5 25 1.2 Skin and subcutaneous tissue disorders Rash Includes eczema, erythema, dermatitis, drug eruption, erythema multiforme, pemphigoid, rash, rash maculo-papular, rash papular, rash pruritic, and rash pustular. 27 2.4 10 0.6 Pruritus 11 0 4.5 0 Alopecia 10 0 6 0 Infections and Infestations Pneumonia Includes lower respiratory tract infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia aspiration, and pneumonia bacterial. 17 8 12 4.2 Upper respiratory tract infections Includes laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, tonsillitis, tracheobronchitis and upper respiratory tract infection. 15 0.6 9 0.9 Endocrine disorders Hypothyroidism Includes blood thyroid stimulating hormone increased and hypothyroidism. 13 0 2.1 0 Respiratory, thoracic and mediastinal disorders Cough/Productive Cough Includes cough and productive cough. 12 0 8 0.3 Nervous system disorders Headache Includes headache and migraine. 11 0 8 0.6 Table 10 summarizes the laboratory abnormalities in POSEIDON. Table 10. Select Laboratory Abnormalities (≥ 10%) That Worsened from Baseline in Patients with NSCLC Who Received IMFINZI in the POSEIDON Study Laboratory Abnormality Graded according to NCI CTCAE version 4.03. IMFINZI with tremelimumab-actl and platinum-based chemotherapy The denominator used to calculate the rate varied from 45 to 326 based on the number of patients with a baseline value and at least one post-treatment value. Platinum-based chemotherapy The denominator used to calculate the rate varied from 43 to 323 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Chemistry Blood creatinine increased 89 4 83 1.9 Increased ALT 64 6 56 4.7 Increased AST 63 5 55 2.2 Hypocalcemia 58 0.9 49 0.9 Hyponatremia 55 13 50 11 Hyperkalemia 49 2.2 35 2.8 Hyperglycemia 42 6 37 3.1 Amylase increased 41 9 25 6 Gamma Glutamyl Transferase increased 38 2.2 35 4.7 Lipase increased 35 14 25 5 Increased Alkaline Phosphatase 33 3.4 26 1.2 Albumin decreased 27 1.9 18 0.9 Hypokalemia 21 7 17 2.8 Bilirubinemia 16 0.9 8 0.3 Hypernatremia 15 0 14 0 Hypomagnesemia 12 4 23 0 Hematology Anemia 84 24 84 25 Leukopenia 77 21 81 18 Neutropenia 71 37 69 32 Lymphocytopenia 67 20 60 19 Thrombocytopenia 53 11 54 12 Small Cell Lung Cancer Limited Stage Small Cell Lung Cancer – ADRIATIC The safety of IMFINZI as a single agent in patients with LS-SCLC without disease progression following completion of concurrent platinum-based chemoradiotherapy (60-66 Gy once daily over 6 weeks or 45 Gy twice daily over 3 weeks) within 42 days prior to initiation of study drug, was evaluated in the ADRIATIC study, a multicenter, randomized, double-blind, placebo-controlled study [see Clinical Studies (14.2) ]. A total of 262 patients received IMFINZI 1,500 mg every 4 weeks until disease progression or unacceptable toxicity or a maximum of 24 months. The study excluded patients with Stage I or II LS-SCLC who were considered medically operable and patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids or immunosuppressants. The study population characteristics were: median age of 62 years (range: 28 to 84); 39% age 65 years or older, 6% age 75 years or older; 69% male; 50% white, 48% Asian, 1.3% other races; 4.2% Hispanic or Latino; 68% former smoker, 22% current smoker; and 51% had WHO performance status of 1. Sixty-seven percent of patients received a total radiation dose of 60 Gy to 66 Gy once daily and 27% of patients received a total radiation dose of 45 Gy twice daily. The median duration of exposure to IMFINZI was 9.2 months (range: 0.92 to 25) in the IMFINZI arm. Serious adverse reactions occurred in 30% of patients receiving IMFINZI. The most frequent serious adverse reactions reported in ≥ 1% of patients receiving IMFINZI were pneumonitis or radiation pneumonitis (12%), and pneumonia (5%). Fatal adverse reactions occurred in 2.7% of patients who received IMFINZI including pneumonia (1.5%), cardiac failure, encephalopathy and pneumonitis (0.4% each). Permanent discontinuation of IMFINZI due to adverse reactions occurred in 16% of the patients. Adverse reactions which resulted in permanent discontinuation of IMFINZI in ≥ 1% of patients included pneumonitis or radiation pneumonitis (9%) and pneumonia (1.5%). Dosage interruptions of IMFINZI due to an adverse reaction occurred in 35% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients included pneumonitis or radiation pneumonitis (17%). The most common adverse reactions occurring in ≥ 20% of patients receiving IMFINZI were pneumonitis or radiation pneumonitis (38%), and fatigue (21%). Table 11 summarizes the adverse reactions that occurred in patients treated with IMFINZI in the ADRIATIC study. Table 11. Adverse Reactions (≥ 10%) in Patients with LS-SCLC Who Received IMFINZI in the ADRIATIC Study IMFINZI (N=262) Placebo (N=265) Adverse Reaction All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Respiratory, thoracic and mediastinal disorders Pneumonitis or Radiation pneumonitis Includes pneumonitis, immune-mediated lung disease, interstitial lung disease, radiation pneumonitis, and lung radiation fibrosis 38 3.1 30 2.6 Cough/Productive cough 17 0 14 0 Dyspnea Includes dyspnea and exertional dyspnea. 11 0.4 7 0 General disorders Fatigue Includes fatigue and asthenia. 21 0.4 20 2.3 Skin and subcutaneous tissue disorders Rash Includes dermatitis, acneiform dermatitis, eczema, rash, maculo-papular rash, papular rash, pruritic rash, and skin exfoliation. 18 0.4 11 0 Pruritus 13 0 7 0 Endocrine disorders Hypothyroidism Includes hypothyroidism, increased blood thyroid stimulating hormone, and decreased thyroxine free. 17 0 4.9 0 Hyperthyroidism Includes hyperthyroidism, decreased blood thyroid stimulating hormone, increased thyroxine free, increased thyroxine, increased tri-iodothyronine free, and increased tri-iodothyronine. 12 0 1.9 0 Metabolism and nutrition disorders Decreased appetite 17 0 13 0 Nervous system disorders Dizziness Includes dizziness, postural dizziness, vertigo, and positional vertigo. 14 0 9 0 Infections and infestations Pneumonia Includes pneumonia, atypical pneumonia, lower respiratory tract infection, bacterial pneumonia, pneumocystis jirovecii pneumonia, legionella pneumonia, and viral pneumonia. 13 3.1 9 4.2 Gastrointestinal disorders Nausea 13 0 11 0 Diarrhea 11 1.9 8 0 Constipation 10 0 10 0 Table 12 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI. Table 12. Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with LS-SCLC Who Received IMFINZI in the ADRIATIC Study Laboratory Abnormality Graded according to NCI CTCAE version 4.03, except creatinine increased which is graded according to NCI CTCAE version 5.0. IMFINZI The denominator used to calculate the rate varied from 63 to 259 based on the number of patients with a baseline value and at least one post-treatment value. Placebo The denominator used to calculate the rate varied from 65 to 262 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Chemistry Hypocalcemia 43 0 43 0.8 Hyperglycemia 38 3.2 45 1.5 ALT increased 36 2.3 29 2.3 AST increased 33 2.3 28 1.5 Gamma Glutamyl Transferase increased 32 7 27 2.9 Hyponatremia 32 5 29 6.2 Hyperkalemia 23 1.2 17 0.8 Creatinine increased 21 0 17 0.8 Hematology Lymphocytes decreased 34 10 33 10 Leukocytes decreased 26 0.4 33 1.1 Extensive Stage Small Cell Lung Cancer – CASPIAN The safety of IMFINZI in combination with etoposide and either carboplatin or cisplatin in previously untreated ES-SCLC was evaluated in CASPIAN, a randomized, open-label, multicenter, active-controlled study. A total of 265 patients received IMFINZI 1,500 mg in combination with chemotherapy every 3 weeks for 4 cycles followed by IMFINZI 1,500 mg every 4 weeks until disease progression or unacceptable toxicity. The study excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids or immunosuppressants [see Clinical Studies (14.2) ] . Among 265 patients receiving IMFINZI, 49% were exposed for 6 months or longer and 19% were exposed for 12 months or longer. Among 266 patients receiving chemotherapy alone, 57% of the patients received 6 cycles of chemotherapy and 8% of the patients received prophylactic cranial irradiation (PCI) after chemotherapy. IMFINZI was discontinued due to adverse reactions in 7% of the patients receiving IMFINZI plus chemotherapy. These include pneumonitis, hepatotoxicity, neurotoxicity, sepsis, diabetic ketoacidosis and pancytopenia (1 patient each). Serious adverse reactions occurred in 31% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 1% of patients were febrile neutropenia (4.5%), pneumonia (2.3%), anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%) and COPD (1.1%). Fatal adverse reactions occurred in 4.9% of patients receiving IMFINZI plus chemotherapy. These include pancytopenia, sepsis, septic shock, pulmonary artery thrombosis, pulmonary embolism, and hepatitis (1 patient each) and sudden death (2 patients). The most common adverse reactions (occurring in ≥ 20% of patients) were nausea, fatigue/asthenia and alopecia. Table 13 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy. Table 13. Adverse Reactions Occurring in ≥ 10% of Patients in the CASPIAN Study IMFINZI with etoposide and either carboplatin or cisplatin N = 265 Etoposide and either carboplatin or cisplatin N = 266 Adverse Reaction All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Gastrointestinal disorders Nausea 34 0.4 34 1.9 Constipation 17 0.8 19 0 Vomiting 15 0 17 1.1 Diarrhea 10 1.1 11 1.1 General disorders and administration site conditions Fatigue/Asthenia 32 3.4 32 2.3 Skin and subcutaneous tissue disorders Alopecia 31 1.1 34 0.8 Rash Includes rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, erythema, eczema, rash and dermatitis. 11 0 6 0 Metabolism and nutrition disorders Decreased appetite 18 0.8 17 0.8 Respiratory, thoracic and mediastinal disorders Cough/Productive Cough 15 0.8 9 0 Endocrine disorders Hyperthyroidism Includes hyperthyroidism and Basedow's disease. 10 0 0.4 0 Table 14 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI plus chemotherapy. Table 14. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% The frequency cut off is based on any grade change from baseline. of Patients in the CASPIAN Study IMFINZI with Etoposide and either Carboplatin or Cisplatin Etoposide and either Carboplatin or Cisplatin Laboratory Abnormality Grade Graded according to NCI CTCAE version 4.03. 3 or 4 (%) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI (range: 258 to 263) and chemotherapy (range: 253 to 262) except magnesium IMFINZI with chemotherapy (18) and chemotherapy (16). Grade 3 or 4 (%) Chemistry Hyponatremia 11 13 Hypomagnesemia 11 6 Hyperglycemia 5 5 Increased Alkaline Phosphatase 4.9 3.5 Increased ALT 4.9 2.7 Increased AST 4.6 1.2 Hypocalcemia 3.5 2.4 Blood creatinine increased 3.4 1.1 Hyperkalemia 1.5 3.1 TSH decreased < LLN LLN = lower limit of normal. and ≥ LLN at baseline NA NA Hematology Neutropenia 41 48 Lymphopenia 14 13 Anemia 13 22 Thrombocytopenia 12 15 Biliary Tract Cancer Locally Advanced or Metastatic BTC - TOPAZ-1 The safety of IMFINZI in combination with gemcitabine and cisplatin in locally advanced or metastatic BTC was evaluated in TOPAZ-1, a randomized, double-blind, placebo-controlled, multicenter study. A total of 338 patients received IMFINZI 1,500 mg in combination with gemcitabine and cisplatin every 3 weeks up to 8 cycles followed by IMFINZI 1,500 mg every 4 weeks until disease progression or unacceptable toxicity. Patients with active or prior documented autoimmune or inflammatory disorders, HIV infection or other active infections, including tuberculosis or hepatitis C were ineligible [see Clinical Studies (14.3) ]. IMFINZI was discontinued due to adverse reactions in 6% of the patients receiving IMFINZI plus chemotherapy. The most frequently reported events resulting in discontinuation were sepsis (3 patients) and ischemic stroke (2 patients). The remaining events were dispersed across system organ classes and reported in 1 patient each. Serious adverse reactions occurred in 47% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%) and acute kidney injury (2.4%). Fatal adverse reactions occurred in 3.6% of patients receiving IMFINZI plus chemotherapy. These include ischemic or hemorrhagic stroke (4 patients), sepsis (2 patients) and upper gastrointestinal hemorrhage (2 patients). The most common adverse reactions (occurring in ≥ 20% of patients) were fatigue, nausea, constipation, decreased appetite, abdominal pain, rash and pyrexia. Table 15 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy. Table 15. Adverse Reactions Occurring in ≥ 10% of Patients in the TOPAZ-1 Study IMFINZI with Gemcitabine and Cisplatin N = 338 Placebo with Gemcitabine and Cisplatin N = 342 Adverse Reaction All Grades Graded according to NCI CTCAE version 5.0. (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) General disorders and administration site conditions Fatigue Includes fatigue, malaise, cancer fatigue and asthenia. 42 6 43 6 Pyrexia 20 1.5 16 0.6 Gastrointestinal disorders Nausea 40 1.5 34 1.8 Constipation 32 0.6 29 0.3 Abdominal pain Includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain. 24 0.6 23 2.9 Vomiting 18 1.5 18 2.0 Diarrhea 17 1.2 15 1.8 Metabolism and nutrition disorders Decreased appetite 26 2.1 23 0.9 Skin and subcutaneous tissue disorders Rash Includes rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, rash pustular, rash erythematous, dermatitis acneiform, dermatitis bullous, drug eruption, eczema, erythema, dermatitis and rash. 23 0.9 14 0 Pruritus 11 0 8 0 Psychiatric disorders Insomnia 10 0 11 0 Table 16 summarizes the laboratory abnormalities in patients treated with IMFINZI plus chemotherapy. Table 16. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% The frequency cut off is based on any grade change from baseline. of Patients in the TOPAZ-1 Study IMFINZI with Gemcitabine and Cisplatin Placebo with Gemcitabine and Cisplatin Laboratory Abnormality Grade Graded according to NCI CTCAE version 5.0. Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI with gemcitabine/cisplatin (range: 312 to 335) and Placebo with gemcitabine/cisplatin (range: 319 to 341). 3 or 4 (%) Grade 3 or 4 (%) Chemistry Hyponatremia 18 13 Gamma-glutamyltransferase increased 12 13 Increased bilirubin 10 14 Hypokalemia 8 4.4 Increased AST 8 8 Increased ALT 7 6 Blood creatinine increased 5 2.1 Hypomagnesemia 4.5 2.2 Hypoalbuminemia 3.6 2.9 Hyperkalemia 2.1 2.1 Increased Alkaline Phosphatase 1.8 3.8 Hypocalcemia 1.8 2.4 Hematology Neutropenia 48 49 Anemia 31 28 Leukopenia 28 28 Lymphopenia 23 15 Thrombocytopenia 18 18 Hepatocellular Carcinoma Unresectable HCC - HIMALAYA The safety of IMFINZI in combination with tremelimumab-actl was evaluated in a total of 388 patients with uHCC in HIMALAYA, a randomized, open-label, multicenter study [see Clinical Studies (14.1) ]. Patients received IMFINZI 1,500 mg administered as a single intravenous infusion in combination with tremelimumab-actl 300 mg on the same day, followed by IMFINZI every 4 weeks or sorafenib 400 mg given orally twice daily. Serious adverse reactions occurred in 41% of patients who received IMFINZI in combination with tremelimumab-actl. Serious adverse reactions in > 1% of patients included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%). Fatal adverse reactions occurred in 8% of patients who received IMFINZI in combination with tremelimumab-actl, including death (1%), hemorrhage intracranial (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and immune-mediated hepatitis (0.5%). The most common adverse reactions (occurring in ≥ 20% of patients) were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain. Permanent discontinuation of treatment regimen due to an adverse reaction occurred in 14% of patients; the most common adverse reactions leading to treatment discontinuation (≥ 1%) were hemorrhage (1.8%), diarrhea (1.5%), AST increased (1%), and hepatitis (1%). Dosage interruptions or delay of the treatment regimen due to an adverse reaction occurred in 35% of patients. Adverse reactions which required dosage interruption or delay in ≥ 1% of patients included ALT increased (3.6%), diarrhea (3.6%), rash (3.6%), amylase increased (3.4%), AST increased (3.1%), lipase increased (2.8%), pneumonia (1.5%), hepatitis (1.5%), pyrexia (1.5%), anemia (1.3%), thrombocytopenia (1%), hyperthyroidism (1%), pneumonitis (1%), and blood creatinine increased (1%). Table 17 summarizes the adverse reactions that occurred in patients treated with IMFINZI in combination with tremelimumab-actl in the HIMALAYA study. Table 17. Adverse Reactions Occurring in ≥ 10% of Patients in the HIMALAYA Study IMFINZI and Tremelimumab-actl (N = 388) Sorafenib (N = 374) Adverse Reaction All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Skin and subcutaneous tissue disorders Rash Represents a composite of multiple related terms. 32 2.8 57 12 Pruritus 23 0 6 0.3 Gastrointestinal disorders Diarrhea 27 6 45 4.3 Abdominal pain 20 1.8 24 4 Nausea 12 0 14 0 General disorders and administration site conditions Fatigue 26 3.9 30 6 Pyrexia 13 0.3 9 0.3 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 22 2.6 17 0.8 Metabolism and nutrition disorders Decreased appetite 17 1.3 18 0.8 Endocrine disorders Hypothyroidism 14 0 6 0 Psychiatric disorders Insomnia 10 0.3 4.3 0 Table 18 summarizes the laboratory abnormalities that occurred in patients treated with IMFINZI in combination with tremelimumab-actl in the HIMALAYA study. Table 18. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients in the HIMALAYA Study IMFINZI and Tremelimumab-actl Sorafenib Laboratory Abnormality Any grade Graded according to NCI CTCAE version 4.03. (%) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI with tremelimumab-actl (range: 367-378) and sorafenib (range:344-352). Grade 3 or 4 (%) Any grade (%) Grade 3 or 4 (%) Chemistry Aspartate Aminotransferase increased 63 27 55 21 Alanine Aminotransferase increased 56 18 53 12 Sodium decreased 46 15 40 11 Bilirubin increased 41 8 47 11 Alkaline Phosphatase increased 41 8 44 5 Glucose increased 39 14 29 4 Calcium decreased 34 0 43 0.3 Albumin decreased 31 0.5 37 1.7 Potassium increased 28 3.8 21 2.6 Creatinine increased 21 1.3 15 0.9 Hematology Hemoglobin decreased 52 4.8 40 6 Lymphocytes decreased 41 11 39 10 Platelets decreased 29 1.6 35 3.1 Leukocytes decreased 20 0.8 30 1.1 Endometrial Cancer Advanced or Recurrent dMMR Endometrial Cancer – DUO-E The safety of IMFINZI in combination with carboplatin and paclitaxel followed by IMFINZI as a single agent was evaluated in 44 patients with dMMR advanced or recurrent endometrial cancer in DUO-E, a randomized, double-blind, placebo-controlled trial [See Clinical Studies (14.5) ]. Patients received IMFINZI 1,120 mg with carboplatin and paclitaxel every 3 weeks for up to six 21-day cycles followed by IMFINZI 1,500 mg every 4 weeks or carboplatin and paclitaxel every 3 weeks for up to six 21-day cycles alone. Treatment was continued until disease progression or unacceptable toxicity. The median duration of exposure to IMFINZI with carboplatin and paclitaxel was 14.8 months (range: 0.7 to 31.7). Serious adverse reactions occurred in 30% of patients who received IMFINZI with carboplatin and paclitaxel. The most common serious adverse reactions (≥4%) were constipation (4.5%) and rash (4.5%). Permanent discontinuation of IMFINZI due to adverse reactions occurred in 11% of patients. The adverse reaction which resulted in permanent discontinuation of IMFINZI (≥4%) was rash (4.5%). Dosage interruptions of IMFINZI due to adverse reactions occurred in 52% of patients. Adverse reactions which required dosage interruptions of IMFINZI (≥ 4%) were anemia (11%), thrombocytopenia (9%), neutropenia (9%), COVID-19 (9%), increased ALT (4.5%), and pneumonitis (4.5%). The most common adverse reactions (> 20%), including laboratory abnormalities, were peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, decreased magnesium, increased ALT, increased AST, diarrhea, vomiting, cough, decreased potassium, dyspnea, headache, increased alkaline phosphatase, and decreased appetite. Tables 19 and 20 summarize adverse reactions and laboratory abnormalities in DUO-E, respectively. Table 19. Adverse Reactions Occurring in ≥ 10% of Patients with dMMR tumors in DUO-E Adverse Reactions IMFINZI with Carboplatin and Paclitaxel (N=44) Carboplatin and Paclitaxel (N=46) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Nervous system disorders Peripheral neuropathy Includes neuropathy peripheral, peripheral sensory neuropathy, hypoasthesia, peripheral motor neuropathy, and parasthesia. 61 2.3 61 4.3 Headache 23 0 17 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes arthralgia, pain in extremity, back pain, non-cardiac chest pain, myalgia, musculoskeletal pain, musculoskeletal chest pain, arthritis, bone pain, musculoskeletal stiffness, neck pain, musculoskeletal discomfort, and spinal pain. 59 2.3 52 2.2 Gastrointestinal disorders Nausea 59 0 48 2.2 Abdominal pain Includes abdominal pain, abdominal pain lower, flank pain, abdominal discomfort, and abdominal pain upper. 39 0 24 2.2 Constipation Includes constipation and fecaloma. 39 4.5 35 2.2 Diarrhea 27 2.3 24 2.2 Vomiting 27 0 22 4.3 Skin and subcutaneous tissue disorders Alopecia 52 0 41 0 Rash Includes eczema, rash, rash erythematous, rash maculo-papular, dermatitis, rash pustular, skin exfoliation, and symmetrical drug-related intertriginous, and flexural exanthema. 39 2.3 17 2.2 Pruritus 16 0 11 0 General disorders and administration site conditions Fatigue Includes asthenia and fatigue. 41 4.5 57 11 Peripheral edema Includes peripheral edema, peripheral swelling, and edema. 16 0 13 2.2 Respiratory, thoracic and mediastinal disorders Cough / productive cough 27 0 20 0 Dyspnea Includes dyspnea and exertional dyspnea. 25 2.3 9 0 Metabolism and nutrition disorders Decreased appetite 18 0 18 0 Infections and infestations Upper respiratory tract infection Includes nasopharyngitis, pharyngitis, rhinitis, sinusitis, tracheobronchitis, and upper respiratory tract infection. 14 0 4.3 0 Endocrine disorders Hypothyroidism Includes blood thyroid stimulating hormone increased, and hypothyroidism. 11 0 4.3 0 Clinically relevant adverse reactions in < 10% of patients who received IMFINZI with carboplatin and paclitaxel included autoimmune hemolytic anemia, colitis, immune-mediated thyroiditis, infusion related reaction, interstitial lung disease, myositis, pneumonitis, pulmonary embolism, and sepsis. Table 20 summarizes the laboratory abnormalities that occurred in patients treated with IMFINZI with carboplatin and paclitaxel followed by IMFINZI as a single agent. Table 20. Select Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with dMMR tumors in DUO-E Laboratory Abnormality IMFINZI with Carboplatin and Paclitaxel Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI with carboplatin and paclitaxel (range: 40 to 44), and carboplatin and paclitaxel (range: 37 to 46) Carboplatin and Paclitaxel All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Chemistry Magnesium decreased 36 0 30 2.5 ALT increased 32 2.3 22 2.2 AST increased 30 2.3 22 0 Potassium decreased 25 0 24 2.2 Alkaline phosphatase increased 20 0 16 0 Muscle Invasive Bladder Cancer (MIBC) Neoadjuvant and adjuvant treatment of MIBC – NIAGARA The safety of IMFINZI in combination with neoadjuvant gemcitabine and cisplatin followed by surgery and continued IMFINZI treatment as adjuvant, single-agent therapy was evaluated in NIAGARA, a randomized, open-label, multicenter trial. Patients received IMFINZI in combination with chemotherapy (n=530) or received chemotherapy alone (n=526) [see Clinical Studies (14.6) ] . The median duration of exposure to IMFINZI 1,500 mg every 3 weeks in the neoadjuvant phase was 12 weeks (range: 1.1 to 84 weeks). The median duration of exposure to IMFINZI 1,500 mg every 4 weeks in the adjuvant phase was 32 weeks (range: 2.4 to 50 weeks). The most common adverse reactions, including laboratory abnormalities, in the overall study (occurring in ≥ 20% of patients) were decreased hemoglobin, decreased neutrophils, increased blood creatinine, decreased sodium, nausea, increased ALT, decreased calcium, decreased platelets, fatigue, increased potassium, decreased lymphocytes, increased AST, constipation, decreased magnesium, decreased appetite, increased alkaline phosphate, rash, pyrexia, diarrhea, vomiting, and abdominal pain. Table 21 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy. Table 21. Adverse Reactions Occurring in ≥ 10% of Patients in the NIAGARA Study IMFINZI with gemcitabine and cisplatin N = 530 Gemcitabine and cisplatin N = 526 Adverse Reaction All Grades Graded according to NCI CTCAE version 5.0. (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Gastrointestinal disorders Nausea 54 1.5 48 1 Constipation 39 0.8 39 0.8 Diarrhea 21 1.5 14 0.4 Vomiting Includes multiple similar terms. 20 0.9 19 0.2 Abdominal pain 20 0.9 13 1 General disorders and administration site conditions Fatigue 52 2.3 49 3 Pyrexia 22 0.4 17 0 Edema 13 0.4 13 0 Metabolism and nutrition disorders Decreased appetite 27 0.6 25 0.6 Skin and subcutaneous tissue disorders Rash 23 1.3 12 0.6 Pruritus 15 0 7 0 Nervous system disorders Peripheral neuropathy 16 0.2 14 0 Headache 11 0 11 0 Dizziness 11 0 10 0.2 Endocrine disorders Hypothyroidism 13 0.4 2.3 0 Vascular disorders Hypertension 12 4.5 9 2.9 Hemorrhage 11 0.9 10 2.1 Table 22 summarizes the laboratory abnormalities in patients treated with IMFINZI plus chemotherapy. Table 22. Select Laboratory Abnormalities That Worsened from Baseline in ≥ 20% of Patients Who Received IMFINZI with Chemotherapy in the NIAGARA study Laboratory Abnormality IMFINZI with gemcitabine and cisplatin Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI plus chemotherapy (range: 482 to 528), and chemotherapy (range: 467 to 521). Gemcitabine and cisplatin All Grades Graded per NCI CTCAE V5. (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Chemistry Increased blood creatinine 63 9 58 7 Decreased sodium 54 9 55 10 Increased ALT 53 2.3 54 4.0 Decreased calcium 52 1.3 43 1.2 Increased potassium 51 4.2 49 4.4 Increased AST 42 1.5 39 2.1 Decreased magnesium 38 1.9 37 2.3 Increased alkaline phosphate 26 0.8 25 0.4 Hematology Decreased hemoglobin 88 13 87 13 Decreased neutrophils 76 31 74 34 Decreased platelets 52 6 50 7 Decreased lymphocytes 44 10 40 8 Neoadjuvant Phase of NIAGARA A total of 530 patients received at least 1 dose of IMFINZI in combination with chemotherapy as neoadjuvant treatment in the IMFINZI treatment arm, and 526 patients received at least 1 dose of chemotherapy as neoadjuvant treatment in the chemotherapy treatment arm. In the neoadjuvant phase, serious adverse reactions occurred in 24% of patients who received IMFINZI in combination with chemotherapy; the most frequent (≥1%) serious adverse reactions were pulmonary embolism (1.9%), febrile neutropenia (1.5%), acute kidney injury (1.3%), thrombocytopenia (1.3%), urinary tract infection (1.3%) and pneumonia (1.3%). Fatal adverse reactions occurred in 1.1% of patients including sepsis (0.2%), myocardial infarction (0.2%), and pulmonary embolism (0.2%). One fatal adverse reaction of pneumonia was reported in 1 (0.2%) patient in the post-surgery phase before adjuvant treatment started. Permanent discontinuation of IMFINZI due to an adverse reaction in the neoadjuvant phase occurred in 9% of patients while receiving IMFINZI in combination with chemotherapy. The most frequent (≥ 0.5%) adverse reactions that led to permanent discontinuation of IMFINZI were blood creatinine increased (0.9%), neutropenia (0.6%), acute kidney injury (0.6%), asthenia (0.6%) and fatigue (0.6%). Of the 530 patients in the IMFINZI treatment arm and 526 patients in the chemotherapy treatment arm who received neoadjuvant treatment, 1 (0.2%) patient in each treatment arm did not receive surgery due to adverse reactions. The adverse reaction that led to cancellation of surgery in the IMFINZI treatment arm was interstitial lung disease. Of the 469 patients in the IMFINZI treatment arm who underwent radical cystectomy, 4 (0.8%) patients experienced delay of surgery (defined as occurring more than 56 days after the last dose of neoadjuvant treatment) due to adverse reactions. Adjuvant Phase of NIAGARA A total of 383 patients (72%) in the IMFINZI treatment arm received at least 1 dose of adjuvant treatment. Serious adverse reactions occurred in 26% of patients receiving IMFINZI as adjuvant treatment. The most frequent serious adverse reactions (occurring in ≥1% of patients) were urinary tract infection (7%), acute kidney injury (3.7%), hydronephrosis (2.1%), pyelonephritis (2.1%), urosepsis (1.8%), and sepsis (1.6%). Fatal adverse reactions occurred in 1.8% of patients, including COVID-19 (0.3%), severe acute respiratory syndrome (0.3%), cardiopulmonary failure (0.3%), gastrointestinal haemorrhage (0.3%), and chronic hepatic failure (0.3%). Permanent discontinuation of adjuvant IMFINZI due to an adverse reaction occurred in 5% of patients. The most frequent (≥0.5%) adverse reactions that led to permanent discontinuation of adjuvant IMFINZI were nephritis (0.8%), fatigue (0.5%), diarrhea (0.5%), decreased appetite (0.5%) and pneumonitis (0.5%). Gastric or Gastroesophageal Junction Adenocarcinoma (GC/GEJC) Neoadjuvant and Adjuvant Treatment of Resectable GC/GEJC – MATTERHORN The safety of IMFINZI with FLOT as neoadjuvant and adjuvant treatment, followed by single-agent IMFINZI, was evaluated in MATTERHORN, a randomized, double-blind, placebo-controlled, multicenter study of patients with resectable GC/GEJC (Stage II to Stage IVA [AJCC, 8th edition]) [see Clinical Studies ( 14.7 )] . Safety data are available for the 944 patients who received IMFINZI with FLOT (n=475) or placebo with FLOT (n=469). The median duration of exposure to IMFINZI 1,500 mg every 4 weeks in the neoadjuvant phase was 8 weeks (range: 1.4 to 8.7 weeks). The median duration of exposure to IMFINZI 1,500 mg every 4 weeks in the adjuvant phase was 48 weeks (range: 1.9 to 50.1 weeks). The most common adverse reactions (occurring in ≥ 20% of patients) were diarrhea, nausea, peripheral neuropathy, fatigue, alopecia, decreased appetite, rash, abdominal pain, vomiting, musculoskeletal pain, pyrexia, and stomatitis. Table 23 summarizes the adverse reactions that occurred in ≥ 10% of patients treated with IMFINZI in combination with FLOT chemotherapy. Table 23: Adverse Reactions Occurring in ≥ 10% of Patients in the MATTERHORN study Adverse Reaction IMFINZI with FLOT Chemotherapy N=475 Placebo with FLOT Chemotherapy N=469 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Gastrointestinal disorders Diarrhea Includes multiple similar terms. 64 8 59 7 Nausea 51 2.5 51 1.5 Vomiting 26 2.1 26 3 Abdominal pain 27 2.3 29 1.3 Stomatitis 20 1.1 15 0.6 Constipation 16 0 17 0.9 Dysphagia 10 1.5 8 1.5 Nervous system disorders Peripheral neuropathy 51 3.6 47 2.3 Dysgeusia 19 0 15 0 General disorders and administration site conditions Fatigue 47 5 45 5 Pyrexia 20 0.8 16 1.3 Skin and subcutaneous tissue disorders Alopecia 31 0 32 0 Rash 30 1.5 20 0.4 Pruritus 11 0 5 0 Metabolism and nutrition disorders Decreased appetite 31 3.2 30 2.1 Musculoskeletal and connective tissue disorders Musculoskeletal pain 21 1.5 19 0.6 Infections and infestations COVID-19 19 1.7 16 0.6 Pneumonia 11 3.8 10 4.3 Investigations Weight decreased 15 2.1 19 3.4 Vascular disorders Hemorrhage 14 2.5 15 2.8 Respiratory, thoracic and mediastinal disorders Cough 10 0 10 0 Table 24 summarizes the laboratory abnormalities in patients treated with IMFINZI in combination with FLOT chemotherapy. Table 24: Laboratory Abnormalities (> 20%) That Worsened from Baseline in Patients with Disease Who Received IMFINZI with FLOT Chemotherapy in MATTERHORN Laboratory Abnormality Graded per NCI CTCAE v5.0 IMFINZI with FLOT Chemotherapy The denominator used to calculate the rate varied from 444 to 472 based on the number of patients with a baseline value and at least one post-treatment value. Placebo with FLOT Chemotherapy The denominator used to calculate the rate varied from 443 to 468 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Decreased leukocytes 75 14 79 17 Decreased neutrophils 70 41 74 44 Decreased hemoglobin 68 7 73 8 Decreased lymphocytes 49 13 45 13 Decreased platelets 47 1.1 46 1.9 Chemistry Increased AST 72 6 69 6 Increased ALT 70 7 65 6 Increased GGT 57 10 51 6 Increased lipase 55 16 55 15 Increased alkaline phosphatase 53 3.2 51 1.5 Decreased calcium 45 0.8 47 2.6 Increased amylase 42 6 39 4.5 Decreased potassium 39 8 40 8 Decreased sodium 33 4.4 32 4.7 Decreased albumin 31 1.5 31 0.2 Increased potassium 22 0.6 26 1.3 Adverse Reactions by Phase of Treatment Table 25 summarizes safety profile by Phase of treatment. Table 25: Safety Profile by Phase of Treatment IMFINZI with FLOT Chemotherapy Placebo with FLOT Chemotherapy Neoadjuvant Phase Number of Patients 475 469 Serious Adverse Reactions 21% 18% Deaths during Treatment-emergent period 1.9% 1.7% Permanent discontinuation of IMFINZI or Placebo 2.5% 2.1% No surgery due to Adverse Reaction 0.6% 0.4% Delay in surgery due to Adverse Reaction 2.3% 2.6% Adjuvant Phase Number of Patients 365 351 Serious Adverse Reactions 29% 26% Deaths during Treatment-emergent period 2.2% 2.6% Permanent discontinuation of IMFINZI or Placebo 7% 4.6% Adjuvant Phase (IMFINZI as a single-agent) Number of Patients 345 331 Serious Adverse Reactions 14% 15% Deaths during Treatment-emergent period 1.7% 2.4% Permanent discontinuation of IMFINZI or Placebo 6% 2.7% Serious adverse reactions (≥2%) in the IMFINZI arm were diarrhea (2.5%) during the neoadjuvant phase, and pneumonia (2.5%) in the adjuvant phase. Deaths (≥2 patients) in the IMFINZI arm were septic shock (0.6%) and acute coronary syndrome (0.4%) during the neoadjuvant phase; gastrointestinal perforation (0.5%) and COVID-19 (0.5%) during adjuvant phase; and gastrointestinal perforation (0.6%) and COVID-19 (0.6%) in the single-agent adjuvant phase. Permanent discontinuation of IMFINZI (≥2 patients) due an adverse reaction in the IMFINZI arm were nephritis (0.4%) during the neoadjuvant phase; hepatitis (1.1%), pneumonitis (1.1%), rash (0.8%), musculoskeletal pain (0.5%), and renal failure (0.5%) during adjuvant phase; and hepatitis (0.9%), pneumonitis (0.9%), musculoskeletal pain (0.6%), and renal failure (0.6%) during the single-agent adjuvant phase.

12.3 Pharmacokinetics The pharmacokinetics of durvalumab as a single agent was studied in patients with doses ranging from 0.1 mg/kg (0.01 times the approved recommended dosage) to 20 mg/kg (2 times the approved recommended dosage) administered once every two, three, or four weeks. PK exposure increased more than dose-proportionally at doses < 3 mg/kg (0.3 times the approved recommended dosage) and dose proportionally at doses ≥ 3 mg/kg every 2 weeks. Steady state was achieved at approximately 16 weeks. The pharmacokinetics of durvalumab is similar when assessed as a single agent, when in combination with chemotherapy, when in combination with tremelimumab-actl and when in combination with tremelimumab-actl and platinum-based chemotherapy. Distribution The geometric mean (% coefficient of variation [CV%]) steady state volume of distribution (Vss) was 5.4 (13.1%) L. Elimination Durvalumab clearance decreases over time, with a mean maximal reduction (CV%) from baseline values of approximately 23% (57%) resulting in a geometric mean (CV%) steady state clearance (CLss) of 8 mL/h (39%) at day 365; the decrease in CLss is not considered clinically relevant. The geometric mean (CV%) terminal half-life, based on baseline CL was approximately 21 (26%) days. Specific Populations There were no clinically significant differences in the pharmacokinetics of durvalumab based on body weight (31 to 175 kg), age (18 to 96 years), sex, race (White, Black, Asian, Native Hawaiian, Pacific Islander, or Native American), albumin levels (4 to 57 g/L), lactate dehydrogenase levels (18 to 15,800 U/L), soluble PD-L1 (67 to 3,470 pg/mL), tumor type (NSCLC, SCLC, BTC and HCC), mild or moderate renal impairment (CLcr 30 to 89 mL/min), and mild or moderate hepatic impairment (bilirubin ≤ 3x ULN and any AST). The effect of severe renal impairment (CLcr 15 to 29 mL/min) or severe hepatic impairment (bilirubin > 3x ULN and any AST) on the pharmacokinetics of durvalumab is unknown.