IMFINZI

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). ( 1.5 ) 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 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).

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 ) 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, and in patients with resectable NSCLC enrolled in the AEGEAN 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 1500 mg every 3 weeks in the neoadjuvant phase was 12 weeks (range: 0 to 19 weeks). The median duration of exposure to IMFINZI 1500 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 1.0 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 1.0 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 3.0 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 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 trial. 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 trial 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 trial. 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 trial 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 trial. 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

4 CONTRAINDICATIONS None. None. ( 4 )

11 DESCRIPTION Durvalumab is a programmed cell death ligand 1 (PD-L1) blocking antibody. Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that is produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cell suspension culture. IMFINZI (durvalumab) Injection for intravenous use is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow solution, free from visible particles. Each 500 mg vial of IMFINZI contains 500 mg of durvalumab in 10 mL solution. Each mL contains durvalumab, 50 mg, L-histidine (2 mg), L-histidine hydrochloride monohydrate (2.7 mg), α,α-trehalose dihydrate (104 mg), Polysorbate 80 (0.2 mg), and Water for Injection, USP. Each 120 mg vial of IMFINZI contains 120 mg of durvalumab in 2.4 mL solution. Each mL contains durvalumab, 50 mg, L-histidine (2 mg), L-histidine hydrochloride monohydrate (2.7 mg), α,α-trehalose dihydrate (104 mg), Polysorbate 80 (0.2 mg), and Water for Injection, USP.

2 DOSAGE AND ADMINISTRATION • Administer IMFINZI as an intravenous infusion over 60 minutes after dilution. ( 2.4 ) • Neoadjuvant and Adjuvant Treatment of Resectable NSCLC: o 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 ) o 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 ) • 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) ]. An FDA-approved test for the detection of dMMR in tumor specimens from patients with primary advanced or recurrent endometrial cancer for treatment with IMFINZI is not available. 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 an intravenous infusion after dilution as recommended [ 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 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 all 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 Carboplatin and Paclitaxel • Infuse IMFINZI first and then carboplatin and paclitaxel 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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Expression of programmed cell death ligand-1 (PD-L1) can be induced by inflammatory signals (e.g., IFN-gamma) and can be expressed on both tumor cells and tumor-associated immune cells in the tumor microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation, and cytokine production. Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, without inducing antibody dependent cell-mediated cytotoxicity (ADCC). PD-L1 blockade with durvalumab led to increased T-cell activation in vitro and decreased tumor size in co-engrafted human tumor and immune cell xenograft mouse models. 12.2 Pharmacodynamics The steady state AUC, Ctrough, and C max in patients administered with 1,500 mg every 4 weeks are 6% higher, 19% lower, and 55% higher than those administered with 10 mg/kg every 2 weeks, respectively. Based on the modeling of pharmacokinetic data and exposure relationships for safety, there are no anticipated clinically meaningful differences in efficacy and safety for the doses of 1,500 mg every 4 weeks compared to 10 mg/kg every 2 weeks in patients weighing > 30 kg with NSCLC. 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. 12.6 Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparison of the incidence of ADAs in the studies described below with the incidence of ADAs in other studies including those of IMFINZI. During the 10 to 48 week treatment period across PACIFIC, CASPIAN, TOPAZ-1, HIMALAYA, POSEIDON, DUO-E, AEGEAN and other clinical trials, in patients who received IMFINZI at dosages of 1,500 mg every 4 weeks, 10 mg/kg every 2 weeks, 20 mg/kg every 4 weeks as a single agent or 1,120 mg every 3 weeks, or 1,500 mg every 3 weeks in the combination therapies, 3.2% (151/4668) of evaluable patients tested positive for anti-durvalumab antibodies, and 19.2% (29/151) of ADA positive patients had neutralizing antibodies against durvalumab. There were no identified clinically significant effects of ADAs on durvalumab pharmacokinetics or safety; however, the effect of these ADAs on the effectiveness of IMFINZI is unknown.

12.1 Mechanism of Action Expression of programmed cell death ligand-1 (PD-L1) can be induced by inflammatory signals (e.g., IFN-gamma) and can be expressed on both tumor cells and tumor-associated immune cells in the tumor microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation, and cytokine production. Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, without inducing antibody dependent cell-mediated cytotoxicity (ADCC). PD-L1 blockade with durvalumab led to increased T-cell activation in vitro and decreased tumor size in co-engrafted human tumor and immune cell xenograft mouse models.

12.2 Pharmacodynamics The steady state AUC, Ctrough, and C max in patients administered with 1,500 mg every 4 weeks are 6% higher, 19% lower, and 55% higher than those administered with 10 mg/kg every 2 weeks, respectively. Based on the modeling of pharmacokinetic data and exposure relationships for safety, there are no anticipated clinically meaningful differences in efficacy and safety for the doses of 1,500 mg every 4 weeks compared to 10 mg/kg every 2 weeks in patients weighing > 30 kg with NSCLC.

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.

20241204

29

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

IMFINZI Durvalumab DURVALUMAB DURVALUMAB HISTIDINE HISTIDINE MONOHYDROCHLORIDE MONOHYDRATE POLYSORBATE 80 TREHALOSE DIHYDRATE WATER IMFINZI Durvalumab DURVALUMAB DURVALUMAB HISTIDINE HISTIDINE MONOHYDROCHLORIDE MONOHYDRATE POLYSORBATE 80 TREHALOSE DIHYDRATE WATER

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

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic and genotoxic potential of durvalumab have not been evaluated. Animal fertility studies have not been conducted with durvalumab. In repeat-dose toxicology studies with durvalumab in sexually mature cynomolgus monkeys of up to 3 months duration, there were no notable effects on the male and female reproductive organs.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic and genotoxic potential of durvalumab have not been evaluated. Animal fertility studies have not been conducted with durvalumab. In repeat-dose toxicology studies with durvalumab in sexually mature cynomolgus monkeys of up to 3 months duration, there were no notable effects on the male and female reproductive organs. 13.2 Animal Toxicology and/or Pharmacology In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. Mycobacterium tuberculosis -infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 blockade using a primate anti-PD-1 antibody was also shown to exacerbate M. tuberculosis infection in rhesus macaques. PD-L1 and PD-1 knockout mice and mice receiving PD-L1 blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus.

BLA761069

IMFINZI

Durvalumab

0310-4500

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0310-4500-12 Rx only IMFINZI™ (durvalumab) Injection 120 mg/2.4 mL (50 mg/mL) For Intravenous Infusion After Dilution Single-dose vial. Discard unused portion. Store at 2° to 8°C (36° to 46°F). Do not freeze or shake. Keep vial in original carton to protect from light. Attention Pharmacist: Dispense the accompanying Medication Guide to each patient. Do not use if vial seal is broken or missing. Must dilute before use. See prescribing information. AstraZeneca 0310450012

Indications and Usage ( 1.1 , 1.2 , 1.5 ) 12/2024 Dosage and Administration ( 2.1 , 2.2 , 2.3 , 2.4 ) 12/2024 Warnings and Precautions ( 5.1 ) 12/2024

MEDICATION GUIDE MEDICATION GUIDE IMFINZI ® (im-FIN-zee) (durvalumab) injection What is the most important information I should know about IMFINZI? IMFINZI is a medicine that may treat certain cancers by working with your immune system. IMFINZI 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. ∘ cough ∘ shortness of breath ∘ chest pain • Intestinal problems. ∘ diarrhea (loose stools) or more frequent bowel movements than usual ∘ stools that are black, tarry, sticky, or have blood or mucus ∘ severe stomach-area (abdomen) pain or tenderness • Liver problems. ∘ Yellowing of your skin or the whites of your eyes ∘ Severe nausea or vomiting ∘ Pain on the right side of your stomach-area (abdomen) ∘ Dark urine (tea colored) ∘ Bleeding or bruising more easily than normal • Hormone gland problems . o headaches that will not go away or unusual headaches o eye sensitivity to light o eye problems o rapid heartbeat o increase sweating o extreme tiredness o weight gain or weight loss o feeling more hungry or thirsty than usual o urinating more often than usual o hair loss o feeling cold o constipation o your voice gets deeper o dizziness or fainting o changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness • Kidney problems. ∘ decrease in your amount of urine ∘ blood in your urine ∘ swelling of your ankles ∘ loss of appetite • Skin problems. ∘ rash ∘ itching ∘ skin blistering or peeling ∘ painful sores or ulcers in mouth or nose, throat or genital area ∘ fever or flu-like symptons ∘ swollen lymph nodes • Pancreas problems ∘ Pain in your upper stomach area (abdomen) ∘ Severe nausea or vomiting ∘ Loss 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 IMFINZI. Call or see your healthcare provider right away for any new or worsening signs or symptoms, which may include: ∘ chest pain, irregular heartbeats, shortness of breath or swelling of ankles ∘ confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems ∘ tingling, numbness or weakness of the arms or legs ∘ double vision, blurry vision, sensitivity to light, eye pain, changes in eye-sight ∘ persistent or severe muscle pain or weakness, muscle cramps, joint pain, joint stiffness or swelling ∘ low red blood cells, bruising • Infusion reactions that can sometimes be severe or life-threatening. Signs and symptoms of infusion reactions may include: ∘ chills or shaking ∘ itching or rash ∘ flushing ∘ shortness of breath or wheezing ∘ dizziness ∘ feel like passing out ∘ fever ∘ back or neck pain • Complications, including graft-versus-host disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with IMFINZI. Your healthcare provider will monitor you for these complications. Getting 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 IMFINZI. 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 IMFINZI, if you have severe side effects. What is IMFINZI? IMFINZI is a prescription medicine used to treat adults with: • a type of lung cancer called non-small cell lung cancer (NSCLC) . o IMFINZI may be used in combination with chemotherapy that contains platinum prior to surgery and alone after surgery when your NSCLC: ▪ can be removed by surgery, and ▪ is not known to have an abnormal “EGFR” or “ALK” gene. o IMFINZI may be used alone when your NSCLC: ▪ has not spread outside your chest ▪ cannot be removed by surgery, and ▪ has responded or stabilized with initial treatment with chemotherapy that contains platinum, given at the same time as radiation therapy. o IMFINZI may be used in combination with tremelimumab-actl and chemotherapy that contains platinum when your NSCLC: ▪ has spread to other parts of your body (metastatic), and ▪ does not have an abnormal “EGFR” or “ALK” gene. • a type of lung cancer called small cell lung cancer (SCLC) . ∘ for limited-stage small cell lung cancer (LS-SCLC), IMFINZI may be used alone when your LS-SCLC cannot be removed by surgery, and ∘ has responded or stabilized after initial treatment with chemotherapy that contains platinum, given at the same time as radiation therapy. ∘ for extensive-stage small cell lung cancer (ES-SCLC), IMFINZI may be used with the chemotherapy medicines etoposide and either carboplatin or cisplatin as your first treatment when your ES-SCLC has spread within your lungs or to other parts of the body. • a type of cancer called biliary tract cancer (BTC), including cancer of the bile ducts (cholangiocarcinoma) and gallbladder cancer. IMFINZI may be used in combination with chemotherapy medicines gemcitabine and cisplatin when your BTC: ∘ has spread to nearby tissues (locally advanced), or ∘ has spread to other parts of the body (metastatic). • a type of liver cancer that cannot be removed by surgery (unresectable hepatocellular carcinoma or uHCC). IMFINZI is used in combination with tremelimumab-actl to treat uHCC. • a type of uterine cancer called endometrial cancer . IMFINZI may be used in combination with chemotherapy medicines carboplatin and paclitaxel followed by IMFINZI alone when your endometrial cancer: ∘ has spread (advanced) or has come back (recurrent), and ∘ a laboratory test shows that your tumor is mismatch repair deficient (dMMR). It is not known if IMFINZI is safe and effective in children. Before you receive IMFINZI, tell your healthcare provider about all of your medical conditions, including if you: • have immune system problems such as Crohn's disease, ulcerative colitis, or lupus • have received an organ transplant • have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic) • have received radiation treatment to your chest area • have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome • are pregnant or plan to become pregnant. IMFINZI can harm your unborn baby Females who are able to become pregnant: ∘ Your healthcare provider will give you a pregnancy test before you start treatment with IMFINZI. ∘ You should use an effective method of birth control during your treatment and for 3 months after the last dose of IMFINZI. Talk to your healthcare provider about birth control methods that you can use during this time. ∘ Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with IMFINZI. • are breastfeeding or plan to breastfeed. It is not known if IMFINZI passes into your breast milk. Do not breastfeed during treatment and for 3 months after the last dose of IMFINZI. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How will I receive IMFINZI? • Your healthcare provider will give you IMFINZI into your vein through an intravenous (IV) line over 60 minutes. • IMFINZI is usually given every 2, 3 or 4 weeks. • Your healthcare provider will decide how many treatments you need. • Your healthcare provider will test your blood to check you for certain side effects. • If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment. What are the possible side effects of IMFINZI? IMFINZI can cause serious side effects, including: See “What is the most important information I should know about IMFINZI?” The most common side effects of IMFINZI when used with platinum-containing chemotherapy in adults with NSCLC that can be removed by surgery include: • low red blood cells (anemia) • nausea • constipation • feeling tired • muscle or bone pain • rash The most common side effects of IMFINZI when used alone in adults with NSCLC that cannot be removed by surgery include: • cough • feeling tired • inflammation in the lungs • upper respiratory tract infections • shortness of breath • rash The most common side effects of IMFINZI when used with tremelimumab-actl and platinum-containing chemotherapy in adults with metastatic NSCLC include: • nausea • feeling tired or weak • muscle or bone • decreased appetite • rash • diarrhea The most common side effects of IMFINZI when used alone in adults with LS-SCLC include: • inflammation in the lungs • feeling tired or weak The most common side effects of IMFINZI when used with other anticancer medicines in adults with ES-SCLC include: • nausea • hair loss • feeling tired or weak The most common side effects of IMFINZI when used with other anticancer medicines in adults with BTC include: • feeling tired • nausea • constipation • decreased appetite • stomach (abdominal) pain • rash • fever The most common side effects of IMFINZI when used with tremelimumab-actl in adults with uHCC include: • rash • diarrhea • feeling tired • itchiness • muscle or bone pain • stomach (abdominal) pain The most common side effects of IMFINZI when used with carboplatin and paclitaxel in adults with endometrial cancer include: • inflammation of the nerves causing numbness, weakness, tingling or burning pain of the arms and legs • muscle or bone pain • nausea • hair loss • feeling tired • stomach (abdominal) pain • constipation • rash • decreased level of magnesium in the blood • increased liver function tests • diarrhea • vomiting • cough • decreased level of potassium in the blood • shortness of breath • headache • increased level of alkaline phosphatase in the blood Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of IMFINZI. 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 IMFINZI. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information about IMFINZI, talk with your healthcare provider. You can ask your healthcare provider for information about IMFINZI that is written for health professionals. What are the ingredients in IMFINZI? Active ingredient: durvalumab Inactive ingredients: L-histidine, L-histidine hydrochloride monohydrate, α,α-trehalose dihydrate, polysorbate 80, Water for Injection, USP. Manufactured for: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 By: AstraZeneca UK Limited, 1 Francis Crick Ave. Cambridge, England CB2 0AA US License No. 2043 IMFINZI is a registered trademark of AstraZeneca group of companies. For more information, call 1-800-236-9933 or go to www.IMFINZI.com © AstraZeneca 2024 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 12/2024

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Immune-Mediated Adverse Reactions Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of IMFINZI [see Warnings and Precautions (5.1) ] , including: • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath. • Hepatitis: 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. • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain. • Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, type 1 diabetes mellitus, or hypophysitis. • Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis. • Dermatological Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of severe dermatological reactions. • Pancreatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of pancreatitis. • Other Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of pancreatitis, aseptic meningitis, encephalitis, immune thrombocytopenia, myocarditis, hemolytic anemia, myositis, uveitis, keratitis, and myasthenia gravis. Infusion-Related Reactions : • Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2) ] . Complications of Allogeneic HSCT : • Advise patients of potential risk of post-transplant complications [see Warnings and Precautions (5.3) ] . Embryo-Fetal Toxicity: • Advise females of reproductive potential that IMFINZI can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1, 8.3 )] . • Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of IMFINZI [see Use in Specific Populations (8.3) ] . Lactation : • Advise female patients not to breastfeed while taking IMFINZI and for 3 months after the last dose [see Warnings and Precautions (5.4) and Use in Specific Populations (8.2) ] . Manufactured for: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850

14 CLINICAL STUDIES 14.1 Non-Small Cell Lung Cancer (NSCLC) Neoadjuvant and Adjuvant Treatment of Resectable NSCLC – AEGEAN Study The efficacy of IMFINZI in combination with neoadjuvant chemotherapy, followed by surgery and continued adjuvant treatment with IMFINZI as a single agent was investigated in AEGEAN (NCT03800134), a randomized, double-blind, placebo-controlled, multicenter trial conducted in 802 patients with previously untreated and resectable squamous or non-squamous NSCLC (Stage IIA to select Stage IIIB [AJCC, 8th edition]). Patients were enrolled regardless of tumor PD-L1 expression. Eligible patients had no prior exposure to immune-mediated therapy, a WHO/ECOG Performance status of 0 or 1, and at least one RECIST 1.1 target lesion. Patients with active or prior documented autoimmune disease, or use of any immunosuppressive medication within 14 days of the first dose of IMFINZI were ineligible. The population for efficacy analyses was a modified intent-to-treat [mITT] which excluded patients with known EGFR mutations or ALK rearrangements. Crossover between the study arms was not permitted. Randomization was stratified by disease stage (Stage II vs. Stage III) and by PD-L1 expression (TC < 1% vs. TC ≥ 1%) status. Patients were randomized 1:1 to one of the following treatment arms: • Arm 1: Neoadjuvant IMFINZI 1500 mg once every 3 weeks for up to 4 cycles in combination with: Squamous tumor histology: carboplatin AUC 6 and paclitaxel 200 mg/m 2 on Day1 of each 3-week cycle, OR cisplatin 75 mg/m 2 on Day 1 and gemcitabine 1250 mg/m 2 on Day 1 and Day 8 of each 3-week cycle, for 4 cycles Non-squamous tumor histology: pemetrexed 500 mg/m 2 and cisplatin 75 mg/m 2 on Day 1 of each 3-week cycle, for 4 cycles OR pemetrexed 500 mg/m 2 and carboplatin AUC 5 on Day 1 of each 3-week cycle, for 4 cycles. Followed by adjuvant IMFINZI 1500 mg as a single agent for up to 12 cycles post-surgery. • Arm 2: Neoadjuvant placebo in combination with 4 cycles of chemotherapy (see above) prior to surgery. Followed by placebo for up to 12 cycles post-surgery. All study medications were administered via intravenous infusion. In the event of unfavorable tolerability, patients who met the eligibility criteria were switched from cisplatin to carboplatin therapy at any point during the study. In patients with comorbidities or unable to tolerate cisplatin as per Investigators judgment, carboplatin AUC 5 could be administered from cycle 1. Treatment with IMFINZI or placebo continued until completion of the treatment, disease progression that precluded definitive surgery, inability to complete definitive surgery, disease recurrence in the adjuvant phase, or unacceptable toxicity. A RECIST 1.1 tumor assessment was performed at baseline, and upon completion of the neoadjuvant period (prior to surgery). Tumor assessments were conducted at 5 weeks postoperatively, prior to the start of adjuvant therapy and every 12 weeks until week 48, every 24 weeks for approximately 4 years, and then every 48 weeks thereafter until disease progression, consent withdrawal, or death. The trial was not designed to isolate the effect of IMFINZI in each phase (neoadjuvant or adjuvant) of treatment. The major efficacy outcome measures of the study were pathological complete response (pCR) by blinded central pathology review and event-free survival (EFS) by blinded independent central review (BICR) assessment. Additional efficacy outcome measures were major pathological response (MPR) by blinded central pathology review, DFS by BICR, and OS. The demographics and baseline disease characteristics were as follows: male (72%); median age 65 years (range: 30 to 88); age ≥ 65 years (52%); WHO/ECOG PS 0 (68%), WHO/ECOG PS 1 (32); White (54%), Asian (41%), Black or African American (0.9%), American Indian or Alaska Native (1.4%), Other Race (2.6%); Not Hispanic or Latino (84%); current or past smokers (86%); squamous histology (49%) and non-squamous histology (51%); Stage II (28%), Stage III (71%); PD-L1 expression status TC ≥ 1% (67%), PD-L1 expression status TC < 1% (33%). In the mITT population, 78% of patients in Arm 1 completed definitive surgery compared to 77% of patients in Arm 2. The trial demonstrated statistically significant improvements in EFS and pCR rate (see Table 21 and Figure 1) in the IMFINZI in combination with chemotherapy arm compared to the placebo in combination with chemotherapy arm. Table 21. Efficacy Results for the AEGEAN Study (mITT) IMFINZI 1,500 mg every 3 weeks with chemotherapy/ IMFINZI (N = 366) Placebo with Chemotherapy/Placebo (N = 374) EFS Results are based on planned EFS interim analysis and pCR final analysis (DCO: 10 November 2022) which occurred 46.3 months after study initiation. Number of events, n (%) 98 (27) 138 (37) Median EFS (95% CI) (months) NR (31.9, NR) 25.9 (18.9, NR) Hazard ratio (95% CI) 0.68 (0.53, 0.88) 2-sided p-value Compared to a two-sided p-value boundary of 0.00989. Based on a pre-specified pCR interim analysis (DCO: 14 January 2022) in n = 402, the pCR rate was statistically significant (p = 0.000036) compared to significance level of 0.0082%. § 0.0039 pCR , , The 2-sided p-value for pCR was calculated based on a stratified CMH test. The 2-sided p-value for EFS was calculated based on based on a stratified log-rank test. Stratification factors include PD-L1 and disease stage. Number of patients with response 63 16 pCR rate, % (95% CI) 17.2 (13.5, 21.5) 4.3 (2.5, 6.8) p-value < 0.0001 Difference in proportions, % (95% CI) Confidence interval for the difference in proportions was calculated based on stratified Miettinen and Nurminen method. 13.0 (8.7, 17.6) Figure 1. Kaplan-Meier Curve of EFS At the interim analysis, the trial demonstrated a statistically significant difference in MPR rate (34% vs. 14%; p < 0.0001). At the time of the prespecified interim analyses, overall survival (OS) was not formally tested for statistical significance. Unresectable Stage III NSCLC - PACIFIC The efficacy of IMFINZI was evaluated in the PACIFIC study (NCT02125461), a multicenter, randomized, double-blind, placebo-controlled study in patients with unresectable Stage III NSCLC who completed at least 2 cycles of concurrent platinum-based chemotherapy and definitive radiation within 42 days prior to initiation of the study drug and had a WHO performance status of 0 or 1. The study excluded patients who had progressed following concurrent chemoradiation, patients with active or prior documented autoimmune disease within 2 years of initiation of the study or patients with medical conditions that required systemic immunosuppression. Randomization was stratified by sex, age (< 65 years vs. ≥ 65 years), and smoking history (smoker vs. non-smoker). Patients were randomized 2:1 to receive IMFINZI 10 mg/kg or placebo intravenously every 2 weeks for up to 12 months or until unacceptable toxicity or confirmed RECIST v1.1-defined progression. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were progression-free survival (PFS) as assessed by a BICR RECIST v1.1, and overall survival (OS). Additional efficacy outcome measures included ORR and DoR assessed by BICR. A total of 713 patients were randomized: 476 patients to the IMFINZI arm and 237 to the placebo arm. The study population characteristics were: median age of 64 years (range: 23 to 90); 70% male; 69% White and 27% Asian; 16% current smokers, 75% former smokers, and 9% never smokers; 51% WHO performance status of 1; 53% with Stage IIIA and 45% were Stage IIIB; 46% with squamous and 54% with non-squamous histology. All patients received definitive radiotherapy as per protocol, of which 92% received a total radiation dose of 54 Gy to 66 Gy; 99% of patients received concomitant platinum-based chemotherapy (55% cisplatin-based, 42% carboplatin-based chemotherapy, and 2% switched between cisplatin and carboplatin). At a pre-specified interim analysis for OS based on 299 events (61% of total planned events), the study demonstrated a statistically significant improvement in OS in patients randomized to IMFINZI compared to placebo. The pre-specified interim analysis of PFS based on 371 events (81% of total planned events) demonstrated a statistically significant improvement in PFS in patients randomized to IMFINZI compared to placebo. Table 22 and Figure 2 summarizes the efficacy results for PACIFIC. Table 22. Efficacy Results for the PACIFIC Study Endpoint IMFINZI (N = 476) Among the ITT population, 7% in the IMFINZI arm and 10% in the placebo arm had non-measurable disease as assessed by BICR according to RECIST v1.1 Placebo (N = 237) Overall Survival (OS) OS results are based on the interim OS analysis conducted at 299 OS events which occurred 46 months after study initiation. Number of deaths 183 (38%) 116 (49%) Median in months (95% CI) NR (34.7, NR) 28.7 (22.9, NR) Hazard Ratio (95% CI) Two -sided p-value based on a log-rank test stratified by sex, age, and smoking history 0.68 (0.53, 0.87) p-value Compared with allocated α of 0.00274 (Lan‑DeMets spending function approximating O’Brien Fleming boundary) for interim analysis 0.0025 Progression-Free Survival (PFS) As assessed by BICR RECIST v1.1 PFS results are based on the interim PFS analysis conducted at 371 PFS events which occurred 33 months after study initiation. Number (%) of patients with event 214 (45%) 157 (66%) Median in months (95% CI) 16.8 (13.0, 18.1) 5.6 (4.6, 7.8) Hazard Ratio (95% CI) Pike estimator 0.52 (0.42, 0.65) p-value Compared with allocated α of 0.011035 (Lan‑DeMets spending function approximating O’Brien Fleming boundary) for interim analysis < 0.0001 Figure 2. Kaplan-Meier Curves of Overall Survival in the PACIFIC Study Metastatic NSCLC - POSEIDON The efficacy of IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy in previously untreated metastatic NSCLC patients with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations was investigated in POSEIDON, a randomized, multicenter, active-controlled, open-label trial (NCT03164616). Eligible patients had Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 and must have had no prior chemotherapy or any other systemic therapy for metastatic NSCLC. Choice of platinum-based chemotherapy was at the investigator’s discretion, taking into consideration the calculated creatinine clearance. Patients with active and/or untreated brain metastases; a history of active primary immunodeficiency; autoimmune disorders including active or prior documented autoimmune or inflammatory disorders; use of systemic immunosuppressants within 14 days before the first dose of the treatment except physiological dose of systemic corticosteroids were ineligible. Randomization was stratified by tumor cells (TC) PD-L1 expression (TC ≥ 50% vs. TC < 50%), disease stage (Stage IVA vs. Stage IVB), and histology (non-squamous vs. squamous). Patients were randomized 1:1:1 to receive IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy according to the regimens listed below, IMFINZI and platinum-based chemotherapy (an unapproved regimen for metastatic NSCLC), or platinum-based chemotherapy. The evaluation of efficacy for metastatic NSCLC relied on comparison between: • IMFINZI 1,500 mg with tremelimumab-actl 75 mg (or 1 mg/kg for patients < 30 kg) and platinum-based chemotherapy every 3 weeks for 4 cycles, followed by IMFINZI 1,500 mg every 4 weeks as a single agent. A fifth dose of tremelimumab-actl 75 mg (or 1 mg/kg for patients < 30 kg) was given at Week 16 in combination with IMFINZI dose 6. • Platinum-based chemotherapy every 3 weeks as monotherapy for 4 cycles. Patients could receive an additional 2 cycles (a total of 6 cycles post-randomization), as clinically indicated, at investigator’s discretion. Patients received IMFINZI in combination with tremelimumab-actl with one of the following platinum-based chemotherapy regimens: • Non-squamous NSCLC • Pemetrexed 500 mg/m 2 with carboplatin AUC 5-6 or cisplatin 75 mg/m 2 every 3 weeks for 4 cycles. • Squamous NSCLC • Gemcitabine 1,000 or 1,250 mg/m 2 on Days 1 and 8 with cisplatin 75 mg/m 2 or carboplatin AUC 5-6 on Day 1 every 3 weeks for 4 cycles. • Non-squamous and Squamous NSCLC • Nab-paclitaxel 100 mg/m 2 on Days 1, 8, and 15 with carboplatin AUC 5-6 on Day 1 every 3 weeks for 4 cycles. Tremelimumab-actl was given up to a maximum of 5 doses. IMFINZI and histology-based pemetrexed continued every 4 weeks until disease progression or unacceptable toxicity. Administration of IMFINZI monotherapy was permitted beyond disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Patients with disease progression during IMFINZI monotherapy were given the option to be retreated with 4 additional cycles of tremelimumab-actl in combination with IMFINZI. Tumor assessments were performed at Week 6, Week 12, and then every 8 weeks thereafter. The major efficacy outcome measures were progression free survival (PFS) and overall survival (OS) of IMFINZI and tremelimumab-actl in combination with platinum-based chemotherapy compared to platinum-based chemotherapy alone. Additional efficacy outcome measures were overall response rate (ORR) and duration of response (DoR). PFS, ORR, and DoR were assessed using Blinded Independent Central Review (BICR) according to RECIST v1.1. A total of 675 patients were randomized to receive either IMFINZI with tremelimumab-actl and platinum-based-chemotherapy (n = 338) or platinum-based chemotherapy (n = 337). The median age was 63 years (range: 27 to 87), 46% of patients age ≥ 65 years, 77% male, 57% White, 34% Asian, 0.3% Native Hawaiian or Other Pacific Islander, 3% American Indian or Alaska Native, 2% Black or African American, 4% Other Race, 79% former or current smoker, 34% ECOG PS 0, and 66% ECOG PS 1. Thirty-six percent had squamous histology, 63% non-squamous histology, 29% PD-L1 expression TC ≥ 50%, 71% PD-L1 expression TC < 50%. Efficacy results are summarized in Table 21 and Figure 3. Table 23. Efficacy Results for POSEIDON IMFINZI with tremelimumab-actl and platinum-based chemotherapy (n = 338) Platinum-based chemotherapy (n = 337) OS PFS/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-value 2-sided p-values based on log-rank tests stratified by PD-L1, histology and disease stage and compared to a boundary value of 0.00735 for PFS and 0.00797 for OS. 0.00304 PFS 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 0.00031 ORR % (95% CI) Confirmed responses with 95% Clopper-Pearson confidence interval. 39 (34, 44) 24 (20, 29) Median DoR (months) (95% CI) 9.5 (7.2, NR) 5.1 (4.4, 6.0) NR=Not Reached, CI=Confidence Interval Figure 3. Kaplan-Meier curves of OS in POSEIDON figure1 figure2 figure3 14.2 Small Cell Lung Cancer (SCLC) Limited-stage SCLC - ADRIATIC The efficacy of IMFINZI was evaluated in the ADRIATIC Study (NCT03703297), a randomized, double-blind, placebo-controlled, multicenter study in 730 patients with histologically or cytologically confirmed LS-SCLC (Stage I to III according to AJCC, 8th edition) whose disease had not progressed following concurrent chemoradiation therapy (cCRT). Patients who had Stage I or II disease had to be medically inoperable as determined by the investigator. Eligible patients completed cCRT consisting of 4 cycles of platinum-based chemotherapy and either 60-66 Gy once daily over 6 weeks or 45 Gy twice daily over 3 weeks radiation therapy within 42 days prior to the first dose of IMFINZI or placebo. Prophylactic cranial irradiation (PCI) could be delivered at the discretion of the investigator after cCRT and had to be completed within 42 days prior to the first dose of IMFINZI or placebo. Patients with active or prior documented autoimmune disease within 5 years of initiation into the study; a history of active primary immunodeficiency; a history of Grade ≥ 2 pneumonitis or active tuberculosis or hepatitis B or C or HIV infection; active interstitial lung disease were ineligible. Patients with mixed SCLC and NSCLC histology were also ineligible. Randomization was stratified by stage (I/II versus III) and receipt of PCI (yes versus no). Patients were randomized 1:1:1 to receive IMFINZI as a single agent, IMFINZI in combination with another agent, or placebo. All study medications were administered intravenously. The evaluation of efficacy for LS-SCLC relied on comparison between: • Arm 1: IMFINZI 1,500 mg in combination with placebo every 4 weeks for 4 cycles, followed by IMFINZI 1,500 mg every 4 weeks. • Arm 2: Placebo in combination with a second placebo every 4 weeks for 4 cycles, followed by a single placebo every 4 weeks. A total of 530 patients were randomized between Arms 1 and 2, 264 patients to the IMFINZI arm and 266 patients to the placebo arm. Treatment continued until disease progression, until unacceptable toxicity, or for a maximum of 24 months. Tumor assessments were conducted every 8 weeks for the first 72 weeks, then every 12 weeks up to 96 weeks and then every 24 weeks thereafter. The major efficacy outcome measures were OS and PFS assessed by BICR according to RECIST v1.1. The baseline demographics and disease characteristics for patients in the IMFINZI and placebo arms were as follows: male (69%); age ≥ 65 years (39%); White (50%), Black or African-American (0.8%), Asian (48%), other race (1.3%); Hispanic or Latino (4.2%); current smoker (22%), past-smoker (68%), never smoker (9%); WHO/ECOG PS 0 (49%), WHO/ECOG PS 1 (51%); and Stage I (3.6%), Stage II (9%), Stage III (87%). Prior to randomization, all patients received platinum-based chemotherapy (66% cisplatin-etoposide, 34% carboplatin-etoposide) with 88% of patients receiving 4 cycles; 72% of patients received once daily radiation (of which 92% received ≥ 60 - ≤ 66 Gy QD); 28% received twice daily radiation (of which 97% received 45 Gy twice daily) and 54% of patients received PCI. Efficacy results are presented in Table 24 and Figure 4. Table 24. Efficacy Results for the ADRIATIC Study IMFINZI (n=264) Placebo (n=266) OS Number of deaths (%) 115 (44) 146 (55) Median OS (months) (95% CI) Calculated using the Kaplan Meier technique. CI for median derived based on Brookmeyer-Crowley method. 55.9 (37.3, NR) 33.4 (25.5, 39.9) HR (95% CI) Based on Cox proportional hazards model stratified by receipt of PCI. 0.73 (0.57, 0.93) p-value Compared with allocated alpha of 0.0168 for OS and 0.0280 for PFS (Lan‑DeMets spending function approximating O’Brien Fleming boundary) for interim analysis. 0.0104 PFS Assessed by BICR according to RECIST v1.1. Number of events (%) 139 (53) 169 (64) Median PFS (months) (95% CI) 16.6 (10.2, 28.2) 9.2 (7.4, 12.9) HR (95% CI) Based on Cox proportional hazards model stratified by TNM stage and receipt of PCI. 0.76 (0.61, 0.95) p-value 0.0161 Figure 4. Kaplan-Meier Curves of OS in the ADRIATIC Study Extensive-stage SCLC – CASPIAN The efficacy of IMFINZI in combination with etoposide and either carboplatin or cisplatin in previously untreated ES-SCLC was investigated in CASPIAN, a randomized, multicenter, active-controlled, open-label trial (NCT03043872). Eligible patients had WHO Performance Status of 0 or 1 and were suitable to receive a platinum-based chemotherapy regimen as first-line treatment for SCLC. Patients with asymptomatic or treated brain metastases were eligible. Choice of platinum agent was at the investigator’s discretion, taking into consideration the calculated creatinine clearance. Patients with history of chest radiation therapy; a history of active primary immunodeficiency; autoimmune disorders including paraneoplastic syndrome; active or prior documented autoimmune or inflammatory disorders; use of systemic immunosuppressants within 14 days before the first dose of the treatment except physiological dose of systemic corticosteroids were ineligible. Randomization was stratified by the planned platinum-based therapy in cycle 1 (carboplatin or cisplatin). The evaluation of efficacy for ES-SCLC relied on comparison between: IMFINZI 1,500 mg, and investigator’s choice of carboplatin (AUC 5 or 6 mg/mL/min) or cisplatin (75-80 mg/m 2 ) on Day 1 and etoposide (80-100 mg/m 2 ) intravenously on Days 1, 2, and 3 of each 21-day cycle for 4 cycles, followed by IMFINZI 1,500 mg every 4 weeks until disease progression or unacceptable toxicity, or Investigator’s choice of carboplatin (AUC 5 or 6 mg/mL/min) or cisplatin (75-80 mg/m 2 ) on Day 1 and etoposide (80-100 mg/m 2 ) intravenously on Days 1, 2, and 3 of each 21-day cycle, up to 6 cycles. After completion of chemotherapy, PCI as administered per investigator discretion. Administration of IMFINZI as a single agent was permitted beyond disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. The major efficacy outcome measure was overall survival (OS) of IMFINZI plus chemotherapy vs. chemotherapy alone. Additional efficacy outcome measures were investigator-assessed progression-free survival (PFS) and objective response rate (ORR), per RECIST v1.1. The study population characteristics were: median age of 63 years (range: 28 to 82); 40% age 65 or older; 70% male; 84% White, 15% Asian, and 0.9% Black; 65% WHO/ECOG PS of 1; and 93% were former/current smokers. Ninety percent of patients had Stage IV disease and 10% had brain metastasis at baseline. A total of 25% of the patients received cisplatin and 74% of the patients received carboplatin. In the chemotherapy alone arm, 57% of the patients received 6 cycles of chemotherapy, and 8% of the patients received PCI. The OS results are summarized in Table 25 and Figure 5. Table 25. OS Result for the CASPIAN Study Endpoint IMFINZI with Etoposide and either Carboplatin or Cisplatin (n = 268) Etoposide and either Carboplatin or Cisplatin (n = 269) Overall Survival (OS) Number of deaths (%) At a pre-specified interim analysis, 336 OS events (79% of total planned events) were observed, and the boundary for declaring efficacy (0.0178) was determined by a Lan-Demets alpha spending function with O’Brien Fleming type boundary. 155 (58) 181 (67) Median OS (months) (95% CI) 13.0 (11.5, 14.8) 10.3 (9.3, 11.2) Hazard Ratio (95% CI) The analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin) and using the rank tests of association approach. 0.73 (0.59, 0.91) p-value 0.0047 Figure 5. Kaplan-Meier Curves of Overall Survival in the CASPIAN Study Investigator-assessed PFS (96% of total planned events) showed a HR of 0.78 (95% CI: 0.65, 0.94), with median PFS of 5.1 months (95% CI: 4.7, 6.2) in the IMFINZI plus chemotherapy arm and 5.4 months (95% CI: 4.8, 6.2) in the chemotherapy alone arm. The investigator-assessed confirmed ORR was 68% (95% CI: 62%, 73%) in the IMFINZI plus chemotherapy arm and 58% (95% CI: 52%, 63%) in the chemotherapy alone arm. In the exploratory subgroup analyses of OS based on the planned platinum chemotherapy received at cycle 1, the HR was 0.70 (95% CI 0.55, 0.89) in patients who received carboplatin, and the HR was 0.88 (95% CI 0.55, 1.41) in patients who received cisplatin. Figure_4 figure4 14.3 Biliary Tract Cancer (BTC) Locally Advanced or Metastatic BTC - TOPAZ-1 The efficacy of IMFINZI in combination with gemcitabine and cisplatin in patients with locally advanced or metastatic BTC was investigated in TOPAZ-1 (NCT03875235), a randomized, double-blind, placebo-controlled, multicenter trial that enrolled 685 patients with histologically confirmed locally advanced unresectable or metastatic BTC who have not previously received systemic therapy. Patients with recurrent disease > 6 months after surgery and/or completion of adjuvant therapy were eligible. Patients had an ECOG Performance status of 0 and 1 and at least one target lesion by RECIST 1.1. Patients with ampullary carcinoma; active or prior documented autoimmune or inflammatory disorders; HIV infection or active infections, including tuberculosis or hepatitis C; current or prior use of immunosuppressive medication within 14 days before the first dose of IMFINZI were ineligible. Randomization was stratified by disease status (recurrent vs. initially unresectable) and primary tumor location (intrahepatic cholangiocarcinoma [ICCA] vs. extrahepatic cholangiocarcinoma [ECCA] vs. gallbladder cancer [GBC]). Patients were randomized 1:1 to receive: • IMFINZI 1,500 mg on Day 1+ gemcitabine 1,000 mg/m 2 and cisplatin 25 mg/m 2 on Days 1 and 8 of each 21-day cycle up to 8 cycles, followed by IMFINZI 1,500 mg every 4 weeks, or • Placebo on Day 1+ gemcitabine 1,000 mg/m 2 and cisplatin 25 mg/m 2 on Days 1 and 8 of each 21-day cycle up to 8 cycles, followed by placebo every 4 weeks. Treatment with IMFINZI or placebo continued until disease progression, or unacceptable toxicity. Treatment beyond disease progression was permitted if the patient was clinically stable and deriving clinical benefit as determined by the investigator. The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures were investigator-assessed progression-free survival (PFS), objective response rate (ORR) and duration of response (DoR). Tumor assessments were conducted every 6 weeks for the first 24 weeks after the date of randomization, and then every 8 weeks until confirmed objective disease progression. The study population characteristics were: 50% male, median age of 64 years (range 20-85), 47% age 65 or older; 56% Asian, 37% White, 2% Black or African American, 0.1% American Indian or Alaskan Native, and 4% other; 51% had an ECOG PS of 1; primary tumor location was ICCA 56%, ECCA 18% and GBC 25%; 20% of patients had recurrent disease; 86% of patients had metastatic and 14% had locally advanced disease. At a pre-specified interim analysis, the trial demonstrated a statistically significant improvement in OS and PFS in patients randomized to IMFINZI in combination with chemotherapy compared to placebo in combination with chemotherapy. Table 26 summarizes the efficacy results for TOPAZ-1. Table 26. Efficacy Results for the TOPAZ-1 Study Endpoint IMFINZI with Gemcitabine and Cisplatin (n = 341) Placebo with Gemcitabine and Cisplatin (n = 344) Overall Survival (OS) Number of deaths (%) 198 (58) 226 (66) Median OS (months) (95% CI) Kaplan-Meier estimated median with 95% CI derived using Brookmeyer-Crowley method 12.8 (11.1, 14) 11.5 (10.1, 12.5) Hazard Ratio (95% CI) Based on Cox proportional hazards model stratified by disease status and primary tumor location 0.80 (0.66, 0.97) p-value 2-sided p-value based on a stratified log-rank test compared with alpha boundary of 0.030 0.021 Progression-Free Survival (PFS) Number of events (%) 276 (81) 297 (86) Median in months (95% CI) 7.2 (6.7, 7.4) 5.7 (5.6, 6.7) Hazard Ratio (95% CI) 0.75 (0.63, 0.89) p-value 2-sided p-value based on a stratified log-rank test compared with alpha boundary of 0.048 0.001 The investigator-assessed ORR was 27% (95% CI: 22% - 32%) in the IMFINZI plus chemotherapy arm and 19% (95% CI: 15%-23%) in the chemotherapy alone arm. Figure 6: Kaplan-Meier Curves of OS in TOPAZ-1 Study figure5 14.4 Hepatocellular Carcinoma (HCC) Unresectable HCC - HIMALAYA The efficacy of IMFINZI in combination with tremelimumab-actl was evaluated in the HIMALAYA study (NCT03298451), a randomized (1:1:1), open-label, multicenter study in patients with confirmed uHCC who had not received prior systemic treatment for HCC. Patients were randomized to one of two investigational arms (IMFINZI plus trememlimumab-actl or IMFINZI) or sorafenib. Study treatment consisted of IMFINZI 1,500 mg in combination with tremelimumab-actl as a one-time single intravenous infusion of 300 mg on the same day, followed by IMFINZI every 4 weeks; IMFINZI 1,500 mg every 4 weeks; or sorafenib 400 mg given orally twice daily, until disease progression or unacceptable toxicity. The efficacy assessment of IMFINZI is based on patients randomized to the IMFINZI plus tremelimumab-actl arm versus the sorafenib arm. Randomization was stratified by macrovascular invasion (MVI) (yes or no), etiology of liver disease (hepatitis B virus vs. hepatitis C virus vs. others) and ECOG performance status (0 vs. 1). The study enrolled patients with BCLC Stage C or B (not eligible for locoregional therapy). The study excluded patients with co-infection of viral hepatitis B and hepatitis C; active or prior documented gastrointestinal (GI) bleeding within 12 months; ascites requiring non-pharmacologic intervention within 6 months; hepatic encephalopathy within 12 months before the start of treatment; active or prior documented autoimmune or inflammatory disorders. Esophagogastroduodenoscopy was not mandated prior to enrollment but adequate endoscopic therapy, according to institutional standards, was required for patients with history of esophageal variceal bleeding or those assessed as high risk for esophageal variceal bleeding by the treating physician. Study treatment was permitted beyond disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. The major efficacy outcome measure was overall survival (OS) between the IMFINZI plus tremelimumab-actl arm versus the sorafenib arm. Additional efficacy outcomes were investigator-assessed progression-free survival (PFS), objective response rate (ORR) and duration of response (DoR) according to RECIST v1.1. Tumor assessments were conducted every 8 weeks for the first 12 months and then every 12 weeks thereafter. The baseline demographics of the IMFINZI plus tremelimumab-actl and sorafenib arms were as follows: male (85%), age < 65 years (50%), median age of 65 years (range: 18 to 88 years), White (46%), Asian (49%), Black or African American (2%), Native Hawaiian or other Pacific Islander (0.1%), race Unknown (2%), Hispanic or Latino (5%), Not Hispanic or Latino (94%), ethnicity Unknown (1%), ECOG PS 0 (62%); Child-Pugh Class score A (99%), macrovascular invasion (26%), extrahepatic spread (53%), viral etiology; hepatitis B (31%), hepatitis C (27%), and uninfected (42%). Efficacy results are presented in Table 27 and Figure 7. Table 27. Efficacy Results for the HIMALAYA Study Endpoint IMFINZI and Tremelimumab-actl (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 (IMFINZI and tremelimumab-actl vs. sorafenib) based on the stratified Cox proportional hazard model. 0.78 (0.66, 0.92) p-value Based on a stratified log-rank test. Based on a Lan-DeMets alpha spending function with O'Brien Fleming type boundary and the actual number of events observed, the boundary for declaring statistical significance for IMFINZI and tremelimumab-actl vs. sorafenib was 0.0398 (Lan and DeMets 1983). 0.0035 PFS Number of events (%) 335 (85.2) 327 (84.1) Median in (months) (95% CI) 3.8 (3.7, 5.3) 4.1 (3.7, 5.5) HR (95% CI) 0.90 (0.77, 1.05) 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 n (%) 12 (3.1) 0 Partial Response n (%) 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 ≥ 6 months 82.3 78.9 % with duration ≥ 12 months 65.8 63.2 CI=Confidence Interval, HR=Hazard Ratio, NR=Not Reached Figure 7. Kaplan-Meier Curves of OS figure6 14.5 Endometrial cancer Advanced or Recurrent dMMR Endometrial Cancer - DUO-E IMFINZI was evaluated in combination with carboplatin and paclitaxel in DUO-E (NCT04269200), a randomized, multicenter, double-blind, placebo-controlled trial in patients with advanced or recurrent endometrial cancer. The trial enrolled patients with newly diagnosed Stage III disease (with measurable disease per RECIST v1.1), or newly diagnosed Stage IV disease. The trial also enrolled patients with recurrent disease with a low potential for cure by radiation therapy or surgery. For patients with recurrent disease, prior chemotherapy was allowed only if it was administered in the adjuvant setting and at least 12 months had elapsed from the date of last dose of chemotherapy to the date of relapse. The trial included patients with epithelial endometrial carcinomas of all histologies, including carcinosarcomas. Patients with endometrial sarcoma were excluded, and patients who had active autoimmune disease or a medical condition that required immunosuppression were ineligible. Randomization was stratified by tumor mismatch repair (MMR) status (proficient or deficient), disease status (recurrent or newly diagnosed), and geographic region (Asia or rest of the world). MMR status was assessed using an immunohistochemistry tumor tissue test. Patients were randomized (1:1:1) to one of the following treatment arms: • IMFINZI 1,120 mg in combination with carboplatin and paclitaxel every 3 weeks for a maximum of 6 cycles. Following completion of chemotherapy treatment, patients received IMFINZI 1,500 mg every 4 weeks as maintenance treatment until disease progression. • Placebo in combination with carboplatin and paclitaxel every 3 weeks for a maximum of 6 cycles. Following completion of chemotherapy treatment, patients received placebo every 4 weeks as maintenance treatment until disease progression. • An additional investigational combination regimen. Treatment was continued until Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression of disease or unacceptable toxicity. Assessment of tumor status was performed every 9 weeks for the first 18 weeks and every 12 weeks thereafter. The major efficacy outcome measure was progression-free survival (PFS), determined by investigator assessment using RECIST 1.1. Additional efficacy outcome measures included overall response rate (ORR), duration of response (DOR) and overall survival (OS). Among 95 patients with dMMR tumor, the baseline characteristics were median age of 63 years (range: 34 to 85); 47% age 65 or older; 62% White, 31% Asian, 2% Black or African American; 7% Hispanic or Latino, 1% American Indian or Alaska Native, and 4% other or not reported; ECOG PS of 0 (55%) or 1 (45%); 48% newly diagnosed (11% Stage III and 38% Stage IV) and 52% recurrent disease. The histologic subtypes were endometrioid (78%), mixed epithelial (6%), carcinosarcoma (5%), serous (4%), undifferentiated (1%), and other (5%). While a statistically significant improvement in PFS was observed in the overall population for IMFINZI with carboplatin and paclitaxel compared to carboplatin and paclitaxel alone, based on an exploratory analysis by MMR status, the PFS improvement in the overall population was primarily attributed to patients with dMMR tumors. Efficacy results for DUO-E are summarized in Table 28 and Figure 8 for patients with dMMR tumors. OS data in this subpopulation at the time of PFS analysis were immature with 26% of patients who died. Table 28. Efficacy Results for Patients with dMMR Tumors in DUO-E Endpoint IMFINZI with Carboplatin and Paclitaxel N=46 Carboplatin and Paclitaxel N=49 PFS Investigator assessed. Number of events (%) 15 (32.6) 25 (51.0) Median in months (95% CI) Calculated using the Kaplan-Meier technique. NR (NR, NR) 7.0 (6.7, 14.8) HR (95% CI) 0.42 (0.22, 0.80) ORR N=42 N=42 ORR % (95% CI) 71.4 (55.4, 84.3) 40.5 (25.6, 56.7) Complete response % 12 (28.6) 4 (9.5) Partial response % 18 (42.9) 13 (31.0) DOR Median in months (range) NR (2.4+, 26.9+) 10.5 (2.1+, 25.2+) CI=Confidence Interval, HR=Hazard Ratio, NR=Not Reached, + = response ongoing at last assessment. Figure 8. Kaplan-Meier curve of PFS for Patients with dMMR Tumors in DUO-E figure7

8.5 Geriatric Use Of the 401 patients with resectable NSCLC treated with IMFINZI in combination with chemotherapy in the AEGEAN study, 209 (52%) patients were 65 years or older and 49 (12%) patients were 75 years or older. There were no overall clinically meaningful differences in safety or efficacy between patients ≥ 65 years of age and younger patients. Of the 476 patients with unresectable, Stage III NSCLC treated with IMFINZI in the PACIFIC study, 45% were 65 years or older, while 7.6% were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients. The PACIFIC study did not include sufficient numbers of patients aged 75 years and over to determine whether they respond differently from younger patients. Of the 330 patients with metastatic NSCLC treated with IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy, 143 (43%) patients were 65 years or older and 35 (11%) patients were 75 years or older. There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients. Of the 262 patients with LS-SCLC treated with IMFINZI, 103 (39%) patients were 65 years or older and 15 (6%) patients were 75 years or older. There were no clinically meaningful differences in safety and efficacy between patients 65 years or older and younger patients. Of the 265 patients with ES-SCLC treated with IMFINZI in combination with chemotherapy 101 (38%) patients were 65 years or older and 19 (7.2%) patients were 75 years or older. There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients. Of the 338 patients with BTC treated with IMFINZI in combination with chemotherapy in the TOPAZ-1 study, 158 (47%) patients were 65 years or older and 38 (11%) patients were 75 years or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients. Of the 393 patients with uHCC treated with IMFINZI in combination with tremelimumab-actl, 50% of patients were 65 years of age or older and 13% of patients were 75 years of age or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients. Of the 235 patients with endometrial cancer treated with IMFINZI with carboplatin and paclitaxel, 49% of patients were 65 years of age or older and 12% of patients were 75 years of age or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients.

8.4 Pediatric Use The safety and effectiveness of IMFINZI have not been established in pediatric patients. Safety and efficacy were assessed but not established in a multi-center, open-label study (NCT03837899) in 45 pediatric patients aged 1 to < 17 years with advanced solid tumors. All 45 patients received at least a single dose of IMFINZI, and 41 patients received IMFINZI in combination with tremelimumab-actl. No new safety signals were observed in pediatric patients in this study. Durvalumab systemic exposure in pediatric patients weighing ≥ 35 kg was within the range of values previously observed in adults given the same weight-based dose, whereas the systemic exposure in pediatric patients weighing < 35 kg was lower than that observed in adults.

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, IMFINZI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on the use of IMFINZI in pregnant women. In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the clinical dose of 10 mg/kg based on area under the curve (AUC), resulted in an increase in premature delivery, fetal loss, and premature neonatal death ( see Data ). Human immunoglobulin G1 (IgG1) is known to cross the placental barrier; therefore, durvalumab has the potential to be transmitted from the mother to the developing fetus. Apprise pregnant women of the potential risk to a 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. Data Animal Data As reported in the literature, the PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. In mouse allogeneic pregnancy models, disruption of PD-L1 signaling was shown to result in an increase in fetal loss. The effects of durvalumab on prenatal and postnatal development were evaluated in reproduction studies in cynomolgus monkeys. Durvalumab was administered from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at a clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature delivery, fetal loss (abortion and stillbirth), and increase in neonatal deaths. Durvalumab was detected in infant serum on postpartum Day 1, indicating the presence of placental transfer of durvalumab. Based on its mechanism of action, fetal exposure to durvalumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, IMFINZI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on the use of IMFINZI in pregnant women. In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the clinical dose of 10 mg/kg based on area under the curve (AUC), resulted in an increase in premature delivery, fetal loss, and premature neonatal death ( see Data ). Human immunoglobulin G1 (IgG1) is known to cross the placental barrier; therefore, durvalumab has the potential to be transmitted from the mother to the developing fetus. Apprise pregnant women of the potential risk to a 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. Data Animal Data As reported in the literature, the PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. In mouse allogeneic pregnancy models, disruption of PD-L1 signaling was shown to result in an increase in fetal loss. The effects of durvalumab on prenatal and postnatal development were evaluated in reproduction studies in cynomolgus monkeys. Durvalumab was administered from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at a clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature delivery, fetal loss (abortion and stillbirth), and increase in neonatal deaths. Durvalumab was detected in infant serum on postpartum Day 1, indicating the presence of placental transfer of durvalumab. Based on its mechanism of action, fetal exposure to durvalumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. 8.2 Lactation Risk Summary There are no data on the presence of durvalumab in human milk, its effects on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to IMFINZI are unknown. Durvalumab was present in the milk of lactating cynomolgus monkeys and was associated with premature neonatal death (see Data). Because of the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with IMFINZI and for 3 months after the last dose. Refer to the Prescribing Information for the agents administered in combination with IMFINZI for recommended duration to not breastfeed, as appropriate. Data In lactating cynomolgus monkeys, durvalumab was present in breast milk at about 0.15% of maternal serum concentrations after administration of durvalumab from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the recommended clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature neonatal death . 8.3 Females and Males of Reproductive Potential Pregnancy testing Verify pregnancy status of females of reproductive potential prior to initiating treatment with IMFINZI. Contraception Females IMFINZI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with IMFINZI and for 3 months following the last dose of IMFINZI. Refer to the Prescribing Information for the agents administered in combination with IMFINZI for recommended contraception duration, as appropriate. 8.4 Pediatric Use The safety and effectiveness of IMFINZI have not been established in pediatric patients. Safety and efficacy were assessed but not established in a multi-center, open-label study (NCT03837899) in 45 pediatric patients aged 1 to < 17 years with advanced solid tumors. All 45 patients received at least a single dose of IMFINZI, and 41 patients received IMFINZI in combination with tremelimumab-actl. No new safety signals were observed in pediatric patients in this study. Durvalumab systemic exposure in pediatric patients weighing ≥ 35 kg was within the range of values previously observed in adults given the same weight-based dose, whereas the systemic exposure in pediatric patients weighing < 35 kg was lower than that observed in adults. 8.5 Geriatric Use Of the 401 patients with resectable NSCLC treated with IMFINZI in combination with chemotherapy in the AEGEAN study, 209 (52%) patients were 65 years or older and 49 (12%) patients were 75 years or older. There were no overall clinically meaningful differences in safety or efficacy between patients ≥ 65 years of age and younger patients. Of the 476 patients with unresectable, Stage III NSCLC treated with IMFINZI in the PACIFIC study, 45% were 65 years or older, while 7.6% were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients. The PACIFIC study did not include sufficient numbers of patients aged 75 years and over to determine whether they respond differently from younger patients. Of the 330 patients with metastatic NSCLC treated with IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy, 143 (43%) patients were 65 years or older and 35 (11%) patients were 75 years or older. There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients. Of the 262 patients with LS-SCLC treated with IMFINZI, 103 (39%) patients were 65 years or older and 15 (6%) patients were 75 years or older. There were no clinically meaningful differences in safety and efficacy between patients 65 years or older and younger patients. Of the 265 patients with ES-SCLC treated with IMFINZI in combination with chemotherapy 101 (38%) patients were 65 years or older and 19 (7.2%) patients were 75 years or older. There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients. Of the 338 patients with BTC treated with IMFINZI in combination with chemotherapy in the TOPAZ-1 study, 158 (47%) patients were 65 years or older and 38 (11%) patients were 75 years or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients. Of the 393 patients with uHCC treated with IMFINZI in combination with tremelimumab-actl, 50% of patients were 65 years of age or older and 13% of patients were 75 years of age or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients. Of the 235 patients with endometrial cancer treated with IMFINZI with carboplatin and paclitaxel, 49% of patients were 65 years of age or older and 12% of patients were 75 years of age or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients.

16 HOW SUPPLIED/STORAGE AND HANDLING IMFINZI (durvalumab) Injection is a clear to opalescent, colorless to slightly yellow solution supplied in a carton containing one single-dose vial either as: • 500 mg/10 mL (50 mg/mL) (NDC 0310-4611-50) • 120 mg/2.4 mL (50 mg/mL) (NDC 0310-4500-12) Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake.