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) ].

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.

data described in this section reflect exposure to IMFINZI in patients with unresectable Stage III NSCLC enrolled in the PACIFIC study, in patients with metastatic NSCLC enrolled in the POSEIDON study, in patients with LS-SCLC enrolled in the ADRIATIC study, in patients with ES-SCLC enrolled in the CASPIAN study, in patients with BTC enrolled in the TOPAZ 1 study, in patients with uHCC included in the HIMALAYA study, in patients with dMMR endometrial cancer enrolled in the DUO-E study, in patients with resectable NSCLC enrolled in the AEGEAN study, in patients with BCG-naïve, high-risk NMIBC enrolled in the POTOMAC study, and in patients with MIBC enrolled in the NIAGARA 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, 8th edition]); squamous or non-squamous) [see Clinical Studies (14.1) ] .

Safety data are available for the 799 patients who received IMFINZI in combination with chemotherapy (n=401) or placebo in combination with chemotherapy (n=398).

The median duration of exposure to IMFINZI 1,500 mg every 3 weeks in the neoadjuvant phase was 12 weeks (range: 0 to 19 weeks). The median duration of exposure to IMFINZI 1,500 mg every 4 weeks in the adjuvant phase was 37 weeks (range: 4 to 67 weeks). The median age of patients who received IMFINZI was 65 years (range: 30 to 88), 52% age 65 or older, 12% age 75 or older; 65% male; 54% White, 41% Asian, 1% Black, 3% Other races; and 17% Hispanic or Latino.

The most common adverse reactions (occurring in ≥ 20% of patients) were anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash.

Table 5 summarizes the adverse reactions that occurred in (≥ 10%) patients treated with IMFINZI in combination with chemotherapy.

Table 5. Adverse Reactions Occurring in ≥ 10% of Patients in the AEGEAN Study
Adverse Reaction	IMFINZI with Chemotherapy N=401		Placebo with Chemotherapy N=398
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Gastrointestinal disorders
Nausea	25	0.2	29	0.3
Constipation	25	0.2	21	0
Diarrhea includes colitis, diarrhea, enteritis, and proctitis.	14	1	13	1.3
Vomiting	11	0.7	11	1.0
General disorders and administration site conditions
Fatigue includes fatigue and asthenia.	25	0	25	1.5
Skin and subcutaneous tissue disorders
Rash includes dermatitis, dermatitis acneiform, drug eruption, eczema, eczema asteatotic, erythema, palmar‑erythrodysaesthesia syndrome, pemphigoid, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular, skin exfoliation, and urticarial dermatitis.	22	0.5	14	0.3
Pruritus	12	0.2	6	0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain includes arthralgia, arthritis, back pain, bone pain, chest pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, musculoskeletal stiffness,myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain.	24	1	29	0.5
Metabolism and nutrition disorders
Decreased appetite	18	0.2	18	0.3
Nervous system disorders
Peripheral neuropathy includes dysaesthesia, hypoaesthesia, neuralgia, neuropathy peripheral, paraesthesia, peripheral sensory neuropathy, and polyneuropathy.	16	0.5	22	0.8
Endocrine disorders
Hypothyroidism includes blood thyroid stimulating hormone increased and hypothyroidism.	11	0	3.8	0
Respiratory, thoracic and mediastinal disorders
Cough / Productive cough	11	0	13	0
Pneumonia includes lower respiratory tract infection, lung abscess, paracancerous pneumonia, pneumonia, pneumonia aspiration, pneumonia bacterial, pneumonia chlamydial, pneumonia cryptococcal, pneumonia fungal, pneumonia pseudomonal, pneumonia streptococcal, pneumonia viral, and post-procedural pneumonia. ^, Five Grade 5 events in the IMFINZI arm and four Grade 5 events in the Placebo arm.	11	3.5	10	3
COVID-19 Includes COVID-19 and COVID-19 Pneumonia. Five Grade 5 events in the IMFINZI arm and One Grade 5 event in the placebo arm.	11	0.2	9	0.8
Psychiatric Disorders
Insomnia	10	0	12	0

Table 6 summarizes the laboratory abnormalities in patients treated with IMFINZI in combination with chemotherapy.

Table 6. Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with Disease Who Received IMFINZI with Chemotherapy in AEGEAN
Laboratory Abnormality Graded per NCI CTCAE V5.	IMFINZI with Chemotherapy The denominator used to calculate the rate varied from 349 to 399 based on the number of patients with a baseline value and at least one post-treatment value.		Placebo with Chemotherapy The denominator used to calculate the rate varied from 333 to 398 based on the number of patients with a baseline value and at least one post-treatment value.
Laboratory Abnormality Graded per NCI CTCAE V5.	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Hematology
Hemoglobin decreased	78	10	75	9
Leukocytes decreased	63	12	64	11
Neutrophils decreased	52	24	56	27
Platelets decreased	46	7	44	8
Lymphocytes decreased	41	11	37	9
Chemistry
Calcium corrected, decreased	51	3.3	52	4.5
Alanine aminotransferase increased	49	6	42	2
Aspartate aminotransferase increased	47	3.5	37	1.8
Potassium increased	33	1.5	29	2
Sodium decreased	35	5	33	6
Gamma glutamyl transferase increased	36	4.7	35	2.1
Creatinine increased	32	2.3	27	3.3
Amylase increased	25	4.7	24	3.6
Magnesium decreased	22	2.8	20	3.6
Lipase increased	23	4.9	24	7

Neoadjuvant Phase of AEGEAN

A total of 401 patients received at least 1 dose of IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment and 398 patients received at least 1 dose of placebo in combination with platinum-containing chemotherapy as neoadjuvant treatment.

Serious adverse reactions occurred in 21% of patients who received IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥1%) serious adverse reactions were pneumonia (2.7%), anemia (1.5%), myelosuppression (1.5%), vomiting (1.2%), neutropenia (1%), and acute kidney injury (1%). Fatal adverse reactions occurred in 2% of patients, including death due to COVID-19 pneumonia (0.5%), sepsis (0.5%), myocarditis (0.2%), decreased appetite (0.2%), hemoptysis (0.2%), and death not otherwise specified (0.2%).

Permanent discontinuation of any study drug due to an adverse reaction occurred in 14% of patients who received IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (>0.5%) adverse reactions that led to permanent discontinuation of any study drug were anemia (1.5%), neutropenia (0.7%), myelosuppression (0.7%), and periphery sensory neuropathy (0.7%). Permanent discontinuation of IMFINZI due to an adverse reaction occurred in 6.7% of patients who received IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥0.5%) adverse reactions that led to permanent discontinuation of IMFINZI were peripheral sensory neuropathy (0.7%) and pneumonitis (0.5%).

Of the 401 IMFINZI-treated patients and 398 placebo-treated patients who received neoadjuvant treatment, 1.7% (n=7) and 1% (n=4), respectively, did not receive surgery due to adverse reactions. Adverse reactions that led to cancellation of surgery in the IMFINZI arm were COVID-19 pneumonia, HIV infection, pneumonitis, prostate cancer, colon cancer, pruritus, and colitis.

Of the 325 IMFINZI-treated patients who received surgery, 4% (n=15) experienced delay of surgery (a surgical delay is defined as on-study surgery occurring more than 40 days after the last dose of study treatment in the neoadjuvant period) due to adverse reactions. Of the 326 placebo-treated patients who received surgery, 4% (n=16) experienced delay of surgery due to adverse reactions.

Of the 325 IMFINZI-treated patients who received surgery, 6.5% (n=21) did not receive adjuvant treatment due to adverse reactions. Of the 326 placebo-treated patients who received surgery, 5.8% (n=19) did not receive adjuvant treatment due to adverse reactions.

Adjuvant Phase of AEGEAN

A total of 265 patients in the IMFINZI arm and 254 patients in the placebo arm received at least 1 dose of adjuvant treatment.

Of the patients who received single agent IMFINZI as adjuvant treatment, 13% experienced serious adverse reactions. The most frequent serious adverse reactions reported in >1% of patients were pneumonia (1.9%), pneumonitis (1.1%), and COVID-19 (1.1%). Four fatal adverse reactions occurred during the adjuvant phase of the study, including COVID-19 pneumonia, pneumonia aspiration, interstitial lung disease and aortic aneurysm. Permanent discontinuation of adjuvant IMFINZI due to an adverse reaction occurred in 8% of patients. The most frequent (≥0.5%) adverse reaction that led to permanent discontinuation of adjuvant IMFINZI was pneumonitis (1.1%) and rash (0.8%).

Unresectable Stage III NSCLC - PACIFIC

The safety of IMFINZI in patients with Stage III NSCLC who completed concurrent platinum-based chemoradiotherapy within 42 days prior to initiation of study drug was evaluated in the PACIFIC study, a multicenter, randomized, double-blind, placebo-controlled study. A total of 475 patients received IMFINZI 10 mg/kg intravenously every 2 weeks. The study excluded patients who had disease progression following chemoradiation, with active or prior autoimmune disease within 2 years of initiation of the study or with medical conditions that required systemic immunosuppression [see Clinical Studies (14.1) ].

The study population characteristics were: median age of 64 years (range: 23 to 90), 45% age 65 years or older, 70% male, 69% White, 27% Asian, 75% former smoker, 16% current smoker, and 51% had WHO performance status (PS) of 1. All patients received definitive radiotherapy as per protocol, of which 92% received a total radiation dose of 54 Gy to 66 Gy. The median duration of exposure to IMFINZI was 10 months (range: 0.2 to 12.6).

IMFINZI was discontinued due to adverse reactions in 15% of patients. The most common adverse reactions leading to IMFINZI discontinuation were pneumonitis or radiation pneumonitis in 6% of patients. Serious adverse reactions occurred in 29% of patients receiving IMFINZI. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonitis or radiation pneumonitis (7%) and pneumonia (6%). Fatal pneumonitis or radiation pneumonitis and fatal pneumonia occurred in < 2% of patients and were similar across arms. The most common adverse reactions (occurring in ≥ 20% of patients) were cough, fatigue, pneumonitis or radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash.

Table 7 summarizes the adverse reactions that occurred in at least 10% of patients treated with IMFINZI.

Table 7. Adverse Reactions Occurring in ≥ 10% of Patients in the PACIFIC Study
IMFINZI N = 475		Placebo N = 234
Adverse Reaction	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Respiratory, Thoracic, and Mediastinal Disorders
Cough/Productive Cough	40	0.6	30	0.4
Pneumonitis Includes acute interstitial pneumonitis, interstitial lung disease, pneumonitis, pulmonary fibrosis. /Radiation Pneumonitis	34	3.4	25	3
Dyspnea Includes dyspnea, and exertional dyspnea.	25	1.5	25	2.6
General Disorders
Fatigue Includes asthenia and fatigue.	34	0.8	32	1.3
Pyrexia	15	0.2	9	0
Infections
Upper respiratory tract infections Includes laryngitis, nasopharyngitis, peritonsillar abscess, pharyngitis, rhinitis, sinusitis, tonsillitis, tracheobronchitis, and upper respiratory tract infection.	26	0.4	19	0
Pneumonia Includes lung infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia adenoviral, pneumonia bacterial, pneumonia cytomegaloviral, pneumonia haemophilus, pneumonia klebsiella, pneumonia necrotizing, pneumonia pneumococcal, and pneumonia streptococcal.	17	7	12	6
Skin and Subcutaneous Tissue Disorders
Rash Includes rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, erythema, eczema, rash, and dermatitis.	23	0.6	12	0
Pruritus Includes pruritus generalized and pruritus.	12	0	6	0
Gastrointestinal Disorders
Diarrhea	18	0.6	19	1.3
Abdominal pain Includes abdominal pain, abdominal pain lower, abdominal pain upper, and flank pain.	10	0.4	6	0.4
Endocrine Disorders
Hypothyroidism Includes autoimmune hypothyroidism and hypothyroidism.	12	0.2	1.7	0

Other adverse reactions occurring in less than 10% of patients treated with IMFINZI were dysphonia, dysuria, night sweats, peripheral edema, and increased susceptibility to infections.

Table 8 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI.

Table 8. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients in the PACIFIC Study
IMFINZI		Placebo
Laboratory Abnormality	All Grades Graded according to NCI CTCAE version 4.0. (%) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI (range: 464 to 470) and placebo (range: 224 to 228).	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Chemistry
Hyperglycemia	52	8	51	8
Hypocalcemia	46	0.2	41	0
Increased ALT	39	2.3	22	0.4
Increased AST	36	2.8	21	0.4
Hyponatremia	33	3.6	30	3.1
Hyperkalemia	32	1.1	29	1.8
Increased GGT	24	3.4	22	1.7
Hematology
Lymphopenia	43	17	39	18

Metastatic NSCLC - POSEIDON

The safety of IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy in patients with metastatic NSCLC was evaluated in POSEIDON (NCT03164616), a randomized, open-label, multicenter, active-controlled study. A total of 330 patients received IMFINZI 1,500 mg in combination with tremelimumab-actl (≥ 30 kg body weight received 75 mg and < 30 kg body weight received 1 mg/kg) and histology-based platinum chemotherapy regimens [see Clinical Studies (14.1) ] . Of these patients, 66% received the maximum 5 doses of tremelimumab-actl and 79% received at least 4 doses. Treatment was continued with IMFINZI as a single agent (or with IMFINZI and histologically-based pemetrexed for non-squamous patients based on the investigator’s decision) until disease progression or unacceptable toxicity. The study excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids or immunosuppressants [see Clinical Studies (14.1) ].

The median age of patients who received IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy was 63 years (range: 27 to 87); 80% male; 61% White, 29% Asian, 58% former smoker, 25% current smoker, and 68% ECOG performance of 1.

Serious adverse reactions occurred in 44% of patients receiving IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (11%), anemia (5%), diarrhea (2.4%), thrombocytopenia (2.4%), pyrexia (2.4%), and febrile neutropenia (2.1%). Fatal adverse reactions occurred in a total of 4.2% of patients receiving IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy. These include hepatitis, nephritis, myocarditis, pancreatitis (all in the same patient), death (2 patients), sepsis (2 patients), pneumonitis (2 patients), acute kidney injury (2 patients), febrile neutropenia (1 patient), chronic obstructive pulmonary disease (COPD) (1 patient), dyspnea (1 patient), sudden death (1 patient), and ischemic stroke (1 patient).

Permanent discontinuation of IMFINZI or tremelimumab-actl due to an adverse reaction occurred in 17% of the patients. Adverse reactions which resulted in permanent discontinuation of IMFINZI or tremelimumab-actl in > 2% of patients included pneumonia.

Dosage interruption or delay of IMFINZI and tremelimumab-actl due to an adverse reaction occurred in 41% of patients. Adverse reactions which required dosage interruption or delay of IMFINZI and tremelimumab-actl in > 1% of patients included anemia, leukopenia/white blood cell count decreased, pneumonia, pneumonitis, colitis, diarrhea, hepatitis, rash, asthenia, amylase increased, alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased, neutropenia/ neutrophil count decreased, and thrombocytopenia/platelet count decreased.

The most common adverse reactions (occurring in ≥ 20% of patients) were nausea, fatigue, musculoskeletal pain, decreased appetite, rash, and diarrhea. Grade 3 or 4 laboratory abnormalities (≥ 10%) were neutropenia, anemia, leukopenia, lymphocytopenia, lipase increased, hyponatremia and thrombocytopenia.

Table 9 summarizes the adverse reactions in POSEIDON.

Table 9. Adverse Reactions (≥ 10%) in Patients with NSCLC Who Received IMFINZI in the POSEIDON Study
IMFINZI with tremelimumab-actl and platinum-based chemotherapy N = 330		Platinum-based chemotherapy N = 333
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Gastrointestinal disorders
Nausea	42	1.8	37	2.1
Diarrhea	22	1.5	15	1.5
Constipation	19	0	24	0.6
Vomiting	18	1.2	14	1.5
Stomatitis Includes mucosal inflammation and stomatitis.	10	0	6	0.3
General disorders and administration site conditions
Fatigue/Asthenia Includes asthenia and fatigue.	36	5	32	4.5
Pyrexia Includes body temperature increased, hyperpyrexia, hyperthermia, and pyrexia.	19	0	8	0
Edema Includes face edema, localized edema, and edema peripheral.	10	0	10	0.6
Musculoskeletal and connective tissue disorders
Musculoskeletal Pain Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, and spinal pain.	29	0.6	22	1.5
Metabolism and nutrition disorders
Decreased appetite	28	1.5	25	1.2
Skin and subcutaneous tissue disorders
Rash Includes eczema, erythema, dermatitis, drug eruption, erythema multiforme, pemphigoid, rash, rash maculo-papular, rash papular, rash pruritic, and rash pustular.	27	2.4	10	0.6
Pruritus	11	0	4.5	0
Alopecia	10	0	6	0
Infections and Infestations
Pneumonia Includes lower respiratory tract infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia aspiration, and pneumonia bacterial.	17	8	12	4.2
Upper respiratory tract infections Includes laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, tonsillitis, tracheobronchitis and upper respiratory tract infection.	15	0.6	9	0.9
Endocrine disorders
Hypothyroidism Includes blood thyroid stimulating hormone increased and hypothyroidism.	13	0	2.1	0
Respiratory, thoracic and mediastinal disorders
Cough/Productive Cough Includes cough and productive cough.	12	0	8	0.3
Nervous system disorders
Headache Includes headache and migraine.	11	0	8	0.6

Table 10 summarizes the laboratory abnormalities in POSEIDON.

Table 10. Select Laboratory Abnormalities (≥ 10%) That Worsened from Baseline in Patients with NSCLC Who Received IMFINZI in the POSEIDON Study
Laboratory Abnormality Graded according to NCI CTCAE version 4.03.	IMFINZI with tremelimumab-actl and platinum-based chemotherapy The denominator used to calculate the rate varied from 45 to 326 based on the number of patients with a baseline value and at least one post-treatment value.		Platinum-based chemotherapy The denominator used to calculate the rate varied from 43 to 323 based on the number of patients with a baseline value and at least one post-treatment value.
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Chemistry
Blood creatinine increased	89	4	83	1.9
Increased ALT	64	6	56	4.7
Increased AST	63	5	55	2.2
Hypocalcemia	58	0.9	49	0.9
Hyponatremia	55	13	50	11
Hyperkalemia	49	2.2	35	2.8
Hyperglycemia	42	6	37	3.1
Amylase increased	41	9	25	6
Gamma Glutamyl Transferase increased	38	2.2	35	4.7
Lipase increased	35	14	25	5
Increased Alkaline Phosphatase	33	3.4	26	1.2
Albumin decreased	27	1.9	18	0.9
Hypokalemia	21	7	17	2.8
Bilirubinemia	16	0.9	8	0.3
Hypernatremia	15	0	14	0
Hypomagnesemia	12	4	23	0
Hematology
Anemia	84	24	84	25
Leukopenia	77	21	81	18
Neutropenia	71	37	69	32
Lymphocytopenia	67	20	60	19
Thrombocytopenia	53	11	54	12

Small Cell Lung Cancer

Limited Stage Small Cell Lung Cancer – ADRIATIC

The safety of IMFINZI as a single agent in patients with LS-SCLC without disease progression following completion of concurrent platinum-based chemoradiotherapy (60-66 Gy once daily over 6 weeks or 45 Gy twice daily over 3 weeks) within 42 days prior to initiation of study drug, was evaluated in the ADRIATIC study, a multicenter, randomized, double-blind, placebo-controlled study [see Clinical Studies (14.2) ]. A total of 262 patients received IMFINZI 1,500 mg every 4 weeks until disease progression or unacceptable toxicity or a maximum of 24 months. The study excluded patients with Stage I or II LS-SCLC who were considered medically operable and patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids or immunosuppressants.

The study population characteristics were: median age of 62 years (range: 28 to 84); 39% age 65 years or older, 6% age 75 years or older; 69% male; 50% white, 48% Asian, 1.3% other races; 4.2% Hispanic or Latino; 68% former smoker, 22% current smoker; and 51% had WHO performance status of 1. Sixty-seven percent of patients received a total radiation dose of 60 Gy to 66 Gy once daily and 27% of patients received a total radiation dose of 45 Gy twice daily. The median duration of exposure to IMFINZI was 9.2 months (range: 0.92 to 25) in the IMFINZI arm.

Serious adverse reactions occurred in 30% of patients receiving IMFINZI. The most frequent serious adverse reactions reported in ≥ 1% of patients receiving IMFINZI were pneumonitis or radiation pneumonitis (12%), and pneumonia (5%). Fatal adverse reactions occurred in 2.7% of patients who received IMFINZI including pneumonia (1.5%), cardiac failure, encephalopathy and pneumonitis (0.4% each). Permanent discontinuation of IMFINZI due to adverse reactions occurred in 16% of the patients. Adverse reactions which resulted in permanent discontinuation of IMFINZI in ≥ 1% of patients included pneumonitis or radiation pneumonitis (9%) and pneumonia (1.5%). Dosage interruptions of IMFINZI due to an adverse reaction occurred in 35% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients included pneumonitis or radiation pneumonitis (17%). The most common adverse reactions occurring in ≥ 20% of patients receiving IMFINZI were pneumonitis or radiation pneumonitis (38%), and fatigue (21%).

Table 11 summarizes the adverse reactions that occurred in patients treated with IMFINZI in the ADRIATIC study.

Table 11. Adverse Reactions (≥ 10%) in Patients with LS-SCLC Who Received IMFINZI in the ADRIATIC Study
IMFINZI (N=262)		Placebo (N=265)
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis or Radiation pneumonitis Includes pneumonitis, immune-mediated lung disease, interstitial lung disease, radiation pneumonitis, and lung radiation fibrosis	38	3.1	30	2.6
Cough/Productive cough	17	0	14	0
Dyspnea Includes dyspnea and exertional dyspnea.	11	0.4	7	0
General disorders
Fatigue Includes fatigue and asthenia.	21	0.4	20	2.3
Skin and subcutaneous tissue disorders
Rash Includes dermatitis, acneiform dermatitis, eczema, rash, maculo-papular rash, papular rash, pruritic rash, and skin exfoliation.	18	0.4	11	0
Pruritus	13	0	7	0
Endocrine disorders
Hypothyroidism Includes hypothyroidism, increased blood thyroid stimulating hormone, and decreased thyroxine free.	17	0	4.9	0
Hyperthyroidism Includes hyperthyroidism, decreased blood thyroid stimulating hormone, increased thyroxine free, increased thyroxine, increased tri-iodothyronine free, and increased tri-iodothyronine.	12	0	1.9	0
Metabolism and nutrition disorders
Decreased appetite	17	0	13	0
Nervous system disorders
Dizziness Includes dizziness, postural dizziness, vertigo, and positional vertigo.	14	0	9	0
Infections and infestations
Pneumonia Includes pneumonia, atypical pneumonia, lower respiratory tract infection, bacterial pneumonia, pneumocystis jirovecii pneumonia, legionella pneumonia, and viral pneumonia.	13	3.1	9	4.2
Gastrointestinal disorders
Nausea	13	0	11	0
Diarrhea	11	1.9	8	0
Constipation	10	0	10	0

Table 12 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI.

Table 12. Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with LS-SCLC Who Received IMFINZI in the ADRIATIC Study
Laboratory Abnormality Graded according to NCI CTCAE version 4.03, except creatinine increased which is graded according to NCI CTCAE version 5.0.	IMFINZI The denominator used to calculate the rate varied from 63 to 259 based on the number of patients with a baseline value and at least one post-treatment value.		Placebo The denominator used to calculate the rate varied from 65 to 262 based on the number of patients with a baseline value and at least one post-treatment value.
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Chemistry
Hypocalcemia	43	0	43	0.8
Hyperglycemia	38	3.2	45	1.5
ALT increased	36	2.3	29	2.3
AST increased	33	2.3	28	1.5
Gamma Glutamyl Transferase increased	32	7	27	2.9
Hyponatremia	32	5	29	6.2
Hyperkalemia	23	1.2	17	0.8
Creatinine increased	21	0	17	0.8
Hematology
Lymphocytes decreased	34	10	33	10
Leukocytes decreased	26	0.4	33	1.1

Extensive Stage Small Cell Lung Cancer – CASPIAN

The safety of IMFINZI in combination with etoposide and either carboplatin or cisplatin in previously untreated ES-SCLC was evaluated in CASPIAN, a randomized, open-label, multicenter, active-controlled study. A total of 265 patients received IMFINZI 1,500 mg in combination with chemotherapy every 3 weeks for 4 cycles followed by IMFINZI 1,500 mg every 4 weeks until disease progression or unacceptable toxicity. The study excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids or immunosuppressants [see Clinical Studies (14.2) ] . Among 265 patients receiving IMFINZI, 49% were exposed for 6 months or longer and 19% were exposed for 12 months or longer.

Among 266 patients receiving chemotherapy alone, 57% of the patients received 6 cycles of chemotherapy and 8% of the patients received prophylactic cranial irradiation (PCI) after chemotherapy.

IMFINZI was discontinued due to adverse reactions in 7% of the patients receiving IMFINZI plus chemotherapy. These include pneumonitis, hepatotoxicity, neurotoxicity, sepsis, diabetic ketoacidosis and pancytopenia (1 patient each). Serious adverse reactions occurred in 31% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 1% of patients were febrile neutropenia (4.5%), pneumonia (2.3%), anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%) and COPD (1.1%). Fatal adverse reactions occurred in 4.9% of patients receiving IMFINZI plus chemotherapy. These include pancytopenia, sepsis, septic shock, pulmonary artery thrombosis, pulmonary embolism, and hepatitis (1 patient each) and sudden death (2 patients). The most common adverse reactions (occurring in ≥ 20% of patients) were nausea, fatigue/asthenia and alopecia.

Table 13 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy.

Table 13. Adverse Reactions Occurring in ≥ 10% of Patients in the CASPIAN Study
IMFINZI with etoposide and either carboplatin or cisplatin N = 265		Etoposide and either carboplatin or cisplatin N = 266
Adverse Reaction	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
Gastrointestinal disorders
Nausea	34	0.4	34	1.9
Constipation	17	0.8	19	0
Vomiting	15	0	17	1.1
Diarrhea	10	1.1	11	1.1
General disorders and administration site conditions
Fatigue/Asthenia	32	3.4	32	2.3
Skin and subcutaneous tissue disorders
Alopecia	31	1.1	34	0.8
Rash Includes rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, erythema, eczema, rash and dermatitis.	11	0	6	0
Metabolism and nutrition disorders
Decreased appetite	18	0.8	17	0.8
Respiratory, thoracic and mediastinal disorders
Cough/Productive Cough	15	0.8	9	0
Endocrine disorders
Hyperthyroidism Includes hyperthyroidism and Basedow's disease.	10	0	0.4	0

Table 14 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI plus chemotherapy.

Table 14. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% The frequency cut off is based on any grade change from baseline. of Patients in the CASPIAN Study
IMFINZI with Etoposide and either Carboplatin or Cisplatin	Etoposide and either Carboplatin or Cisplatin
Laboratory Abnormality	Grade Graded according to NCI CTCAE version 4.03. 3 or 4 (%) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI (range: 258 to 263) and chemotherapy (range: 253 to 262) except magnesium IMFINZI with chemotherapy (18) and chemotherapy (16).	Grade 3 or 4 (%)
Chemistry
Hyponatremia	11	13
Hypomagnesemia	11	6
Hyperglycemia	5	5
Increased Alkaline Phosphatase	4.9	3.5
Increased ALT	4.9	2.7
Increased AST	4.6	1.2
Hypocalcemia	3.5	2.4
Blood creatinine increased	3.4	1.1
Hyperkalemia	1.5	3.1
TSH decreased < LLN LLN = lower limit of normal. and ≥ LLN at baseline	NA	NA
Hematology
Neutropenia	41	48
Lymphopenia	14	13
Anemia	13	22
Thrombocytopenia	12	15

Biliary Tract Cancer

Locally Advanced or Metastatic BTC - TOPAZ-1

The safety of IMFINZI in combination with gemcitabine and cisplatin in locally advanced or metastatic BTC was evaluated in TOPAZ-1, a randomized, double-blind, placebo-controlled, multicenter study. A total of 338 patients received IMFINZI 1,500 mg in combination with gemcitabine and cisplatin every 3 weeks up to 8 cycles followed by IMFINZI 1,500 mg every 4 weeks until disease progression or unacceptable toxicity.Patients with active or prior documented autoimmune or inflammatory disorders, HIV infection or other active infections, including tuberculosis or hepatitis C were ineligible [see Clinical Studies (14.3) ].

IMFINZI was discontinued due to adverse reactions in 6% of the patients receiving IMFINZI plus chemotherapy. The most frequently reported events resulting in discontinuation were sepsis (3 patients) and ischemic stroke (2 patients). The remaining events were dispersed across system organ classes and reported in 1 patient each. Serious adverse reactions occurred in 47% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%) and acute kidney injury (2.4%). Fatal adverse reactions occurred in 3.6% of patients receiving IMFINZI plus chemotherapy. These include ischemic or hemorrhagic stroke (4 patients), sepsis (2 patients) and upper gastrointestinal hemorrhage (2 patients). The most common adverse reactions (occurring in ≥ 20% of patients) were fatigue, nausea, constipation, decreased appetite, abdominal pain, rash and pyrexia. Table 15 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy.

Table 15. Adverse Reactions Occurring in ≥ 10% of Patients in the TOPAZ-1 Study
IMFINZI with Gemcitabine and Cisplatin N = 338		Placebo with Gemcitabine and Cisplatin N = 342
Adverse Reaction	All Grades Graded according to NCI CTCAE version 5.0. (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
General disorders and administration site conditions
Fatigue Includes fatigue, malaise, cancer fatigue and asthenia.	42	6	43	6
Pyrexia	20	1.5	16	0.6
Gastrointestinal disorders
Nausea	40	1.5	34	1.8
Constipation	32	0.6	29	0.3
Abdominal pain Includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain.	24	0.6	23	2.9
Vomiting	18	1.5	18	2.0
Diarrhea	17	1.2	15	1.8
Metabolism and nutrition disorders
Decreased appetite	26	2.1	23	0.9
Skin and subcutaneous tissue disorders
Rash Includes rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, rash pustular, rash erythematous, dermatitis acneiform, dermatitis bullous, drug eruption, eczema, erythema, dermatitis and rash.	23	0.9	14	0
Pruritus	11	0	8	0
Psychiatric disorders
Insomnia	10	0	11	0

Table 16 summarizes the laboratory abnormalities in patients treated with IMFINZI plus chemotherapy.

Table 16. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% The frequency cut off is based on any grade change from baseline. of Patients in the TOPAZ-1 Study
IMFINZI with Gemcitabine and Cisplatin	Placebo with Gemcitabine and Cisplatin
Laboratory Abnormality	Grade Graded according to NCI CTCAE version 5.0. Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI with gemcitabine/cisplatin (range: 312 to 335) and Placebo with gemcitabine/cisplatin (range: 319 to 341). 3 or 4 (%)	Grade 3 or 4 (%)
Chemistry
Hyponatremia	18	13
Gamma-glutamyltransferase increased	12	13
Increased bilirubin	10	14
Hypokalemia	8	4.4
Increased AST	8	8
Increased ALT	7	6
Blood creatinine increased	5	2.1
Hypomagnesemia	4.5	2.2
Hypoalbuminemia	3.6	2.9
Hyperkalemia	2.1	2.1
Increased Alkaline Phosphatase	1.8	3.8
Hypocalcemia	1.8	2.4
Hematology
Neutropenia	48	49
Anemia	31	28
Leukopenia	28	28
Lymphopenia	23	15
Thrombocytopenia	18	18

Hepatocellular Carcinoma

Unresectable HCC - HIMALAYA

The safety of IMFINZI in combination with tremelimumab-actl was evaluated in a total of 388 patients with uHCC in HIMALAYA, a randomized, open-label, multicenter study [see Clinical Studies (14.1) ]. Patients received IMFINZI 1,500 mg administered as a single intravenous infusion in combination with tremelimumab-actl 300 mg on the same day, followed by IMFINZI every 4 weeks or sorafenib 400 mg given orally twice daily.

Serious adverse reactions occurred in 41% of patients who received IMFINZI in combination with tremelimumab-actl. Serious adverse reactions in > 1% of patients included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%). Fatal adverse reactions occurred in 8% of patients who received IMFINZI in combination with tremelimumab-actl, including death (1%), hemorrhage intracranial (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and immune-mediated hepatitis (0.5%). The most common adverse reactions (occurring in ≥ 20% of patients) were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain.

Permanent discontinuation of treatment regimen due to an adverse reaction occurred in 14% of patients; the most common adverse reactions leading to treatment discontinuation (≥ 1%) were hemorrhage (1.8%), diarrhea (1.5%), AST increased (1%), and hepatitis (1%).

Dosage interruptions or delay of the treatment regimen due to an adverse reaction occurred in 35% of patients. Adverse reactions which required dosage interruption or delay in ≥ 1% of patients included ALT increased (3.6%), diarrhea (3.6%), rash (3.6%), amylase increased (3.4%), AST increased (3.1%), lipase increased (2.8%), pneumonia (1.5%), hepatitis (1.5%), pyrexia (1.5%), anemia (1.3%), thrombocytopenia (1%), hyperthyroidism (1%), pneumonitis (1%), and blood creatinine increased (1%).

Table 17 summarizes the adverse reactions that occurred in patients treated with IMFINZI in combination with tremelimumab-actl in the HIMALAYA study.

Table 17. Adverse Reactions Occurring in ≥ 10% of Patients in the HIMALAYA Study
IMFINZI and Tremelimumab-actl (N = 388)		Sorafenib (N = 374)
Adverse Reaction	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
Skin and subcutaneous tissue disorders
Rash Represents a composite of multiple related terms.	32	2.8	57	12
Pruritus	23	0	6	0.3
Gastrointestinal disorders
Diarrhea	27	6	45	4.3
Abdominal pain	20	1.8	24	4
Nausea	12	0	14	0
General disorders and administration site conditions
Fatigue	26	3.9	30	6
Pyrexia	13	0.3	9	0.3
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain	22	2.6	17	0.8
Metabolism and nutrition disorders
Decreased appetite	17	1.3	18	0.8
Endocrine disorders
Hypothyroidism	14	0	6	0
Psychiatric disorders
Insomnia	10	0.3	4.3	0

Table 18 summarizes the laboratory abnormalities that occurred in patients treated with IMFINZI in combination with tremelimumab-actl in the HIMALAYA study.

Table 18. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients in the HIMALAYA Study
IMFINZI and Tremelimumab-actl		Sorafenib
Laboratory Abnormality	Any grade Graded according to NCI CTCAE version 4.03. (%) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI with tremelimumab-actl (range: 367-378) and sorafenib (range:344-352).	Grade 3 or 4 (%)	Any grade (%)	Grade 3 or 4 (%)
Chemistry
Aspartate Aminotransferase increased	63	27	55	21
Alanine Aminotransferase increased	56	18	53	12
Sodium decreased	46	15	40	11
Bilirubin increased	41	8	47	11
Alkaline Phosphatase increased	41	8	44	5
Glucose increased	39	14	29	4
Calcium decreased	34	0	43	0.3
Albumin decreased	31	0.5	37	1.7
Potassium increased	28	3.8	21	2.6
Creatinine increased	21	1.3	15	0.9
Hematology
Hemoglobin decreased	52	4.8	40	6
Lymphocytes decreased	41	11	39	10
Platelets decreased	29	1.6	35	3.1
Leukocytes decreased	20	0.8	30	1.1

Endometrial Cancer

Advanced or Recurrent dMMR Endometrial Cancer – DUO-E

The safety of IMFINZI in combination with carboplatin and paclitaxel followed by IMFINZI as a single agent was evaluated in 44 patients with dMMR advanced or recurrent endometrial cancer in DUO-E, a randomized, double-blind, placebo-controlled trial [See Clinical Studies (14.5) ]. Patients received IMFINZI 1,120 mg with carboplatin and paclitaxel every 3 weeks for up to six 21-day cycles followed by IMFINZI 1,500 mg every 4 weeks or carboplatin and paclitaxel every 3 weeks for up to six 21-day cycles alone. Treatment was continued until disease progression or unacceptable toxicity. The median duration of exposure to IMFINZI with carboplatin and paclitaxel was 14.8 months (range: 0.7 to 31.7).

Serious adverse reactions occurred in 30% of patients who received IMFINZI with carboplatin and paclitaxel. The most common serious adverse reactions (≥4%) were constipation (4.5%) and rash (4.5%).

Permanent discontinuation of IMFINZI due to adverse reactions occurred in 11% of patients. The adverse reaction which resulted in permanent discontinuation of IMFINZI (≥4%) was rash (4.5%).

Dosage interruptions of IMFINZI due to adverse reactions occurred in 52% of patients. Adverse reactions which required dosage interruptions of IMFINZI (≥ 4%) were anemia (11%), thrombocytopenia (9%), neutropenia (9%), COVID-19 (9%), increased ALT (4.5%), and pneumonitis (4.5%).

The most common adverse reactions (> 20%), including laboratory abnormalities, were peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, decreased magnesium, increased ALT, increased AST, diarrhea, vomiting, cough, decreased potassium, dyspnea, headache, increased alkaline phosphatase, and decreased appetite.

Tables 19 and 20 summarize adverse reactions and laboratory abnormalities in DUO-E, respectively.

Table 19. Adverse Reactions Occurring in ≥ 10% of Patients with dMMR tumors in DUO-E
Adverse Reactions	IMFINZI with Carboplatin and Paclitaxel (N=44)		Carboplatin and Paclitaxel (N=46)
Adverse Reactions	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

Non-Muscle-Invasive Bladder Cancer (NMIBC)

BCG-Naïve, High-Risk NMIBC – POTOMAC

The safety of IMFINZI in combination with intravesical BCG induction and maintenance treatment was evaluated in POTOMAC, a randomized, open-label, multicenter study. Patients received IMFINZI in combination with BCG induction and maintenance treatment (n=336) or BCG induction and maintenance treatment alone (n=339) [see Clinical Studies (14.6) ]. Patients received IMFINZI 1,500 mg every 4 weeks for up to 13 cycles, plus BCG induction every week for 6 weeks, followed by BCG maintenance on a weekly basis for 3 weeks at 3, 6, 12, 18, and 24 months. The median duration of exposure to IMFINZI was 52 weeks (range: 4 to 89 weeks).

Serious adverse reactions occurred in 32% of patients who received IMFINZI with BCG. The most common (≥ 1%) serious adverse reactions were urinary tract infection (4.5%), COVID (1.8%), hepatitis (1.5%), dysuria (1.2%), and prostate cancer (1.2%). Fatal adverse reactions occurred in 2.4% of patients who received IMFINZI with BCG, including congestive cardiac failure (0.6%), COVID (0.3%), cardiovascular disorder (0.3%), dementia with Lewy bodies (0.3%), and pancreatic cancer (0.3%).

Permanent discontinuation of IMFINZI due to adverse reactions occurred in 18% of patients. The adverse reactions which resulted in permanent discontinuation of IMFINZI (≥ 1%) were hepatitis (1.8%), acute kidney injury (1.2%), and diarrhea (1.2%).

Dosage interruptions of IMFINZI due to adverse reactions occurred in 22% of patients. Adverse reactions which required dosage interruptions of IMFINZI (≥ 1%) were increased lipase (3%), rash (1.8%), COVID (1.8%), hypothyroidism (1.5%), increased amylase (1.5%), diarrhea (1.2%), increased ALT (1.2%), and increased pancreatic enzymes (1.2%).

The most common (≥ 20%) adverse reactions, including laboratory abnormalities were increased glucose, increased AST, increased lipase, increased ALT, increased GGT, urinary tract infection, increased potassium, dysuria, decreased hemoglobin, hematuria, increased serum creatinine, musculoskeletal pain, decreased lymphocytes, urinary frequency, decreased sodium, fatigue, rash, and pyrexia.

Table 21 summarizes the adverse reactions that occurred in patients treated with IMFINZI in combination with BCG induction and maintenance treatment.

Table 21. Adverse Reactions Occurring in ≥ 10% of Patients with BCG-Naïve, High-Risk NMIBC Who Received IMFINZI in the POTOMAC study
IMFINZI + BCG BCG was administered as induction and maintenance treatment. (N = 336)		BCG (N = 339)
Adverse Reaction	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
Infections and infestations
Urinary tract infection Includes other related terms	40	4.5	34	1.5
Renal and urinary disorders
Dysuria	37	2.7	36	1.2
Hematuria	33	0.9	31	2.4
Urinary Frequency	26	0	25	0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	28	0.6	15	0.3
General disorders and administration site conditions
Fatigue	21	0.6	10	0.3
Pyrexia	20	0.3	25	0
Skin and subcutaneous tissue disorders
Rash	20	0.6	6	0
Endocrine disorders
Hypothyroidism	13	0.3	0.9	0
Gastrointestinal disorders
Diarrhea	13	1.5	7	0.3
Constipation	11	0	4.7	0
Abdominal pain	10	0	6	0

Clinically relevant adverse reactions in < 10% of patients who received IMFINZI with BCG included hyperthyroidism, hepatitis, thyroiditis, adrenal insufficiency, pancreatitis, polymyalgia rheumatica, pneumonitis, nephritis, myositis, and type 1 diabetes mellitus.

Table 22 summarizes the laboratory abnormalities that occurred in patients treated with IMFINZI in combination with BCG induction and maintenance in the POTOMAC study.

Table 22. Select Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% The frequency cut off is based on any grade change from baseline. of Patients Who Received IMFINZI in the POTOMAC study
IMFINZI + BCG BCG was administered as induction and maintenance treatment.		BCG
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 BCG (range: 289 to 335) and BCG (range: 284 to 333).	Grade 3 or 4 (%)	Any grade (%)	Grade 3 or 4 (%)
Chemistry
Increased glucose	43	7	34	4.5
Increased AST	43	6	28	0
Increased lipase	42	18	29	8
Increased ALT	42	6	26	0.3
Increased GGT	40	7	32	2.2
Increased potassium	39	2.1	33	2.4
Increased creatinine	30	1.2	23	0.9
Decreased sodium	23	3.0	11	0
Hematology
Decreased hemoglobin	35	0.6	24	0.6
Decreased lymphocytes	27	3.0	13	1.2

Muscle Invasive Bladder Cancer (MIBC)

Neoadjuvant and adjuvant treatment of MIBC – NIAGARA

The safety of IMFINZI in combination with neoadjuvant gemcitabine and cisplatin followed by surgery and continued IMFINZI treatment as adjuvant, single-agent therapy was evaluated in NIAGARA, a randomized, open-label, multicenter trial. Patients received IMFINZI in combination with chemotherapy (n=530) or received chemotherapy alone (n=526) [see Clinical Studies (14.6) ] .

The median duration of exposure to IMFINZI 1,500 mg every 3 weeks in the neoadjuvant phase was 12 weeks (range: 1.1 to 84 weeks). The median duration of exposure to IMFINZI 1,500 mg every 4 weeks in the adjuvant phase was 32 weeks (range: 2.4 to 50 weeks).

The most common adverse reactions, including laboratory abnormalities, in the overall study (occurring in ≥ 20% of patients) were decreased hemoglobin, decreased neutrophils, increased blood creatinine, decreased sodium, nausea, increased ALT, decreased calcium, decreased platelets, fatigue, increased potassium, decreased lymphocytes, increased AST, constipation, decreased magnesium, decreased appetite, increased alkaline phosphate, rash, pyrexia, diarrhea, vomiting, and abdominal pain.

Table 23 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy.

Table 23. Adverse Reactions Occurring in ≥ 10% of Patients in the NIAGARA Study
IMFINZI with gemcitabine and cisplatin N = 530		Gemcitabine and cisplatin N = 526
Adverse Reaction	All Grades Graded according to NCI CTCAE version 5.0. (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
Gastrointestinal disorders
Nausea	54	1.5	48	1
Constipation	39	0.8	39	0.8
Diarrhea	21	1.5	14	0.4
Vomiting Includes multiple similar terms.	20	0.9	19	0.2
Abdominal pain	20	0.9	13	1
General disorders and administration site conditions
Fatigue	52	2.3	49	3
Pyrexia	22	0.4	17	0
Edema	13	0.4	13	0
Metabolism and nutrition disorders
Decreased appetite	27	0.6	25	0.6
Skin and subcutaneous tissue disorders
Rash	23	1.3	12	0.6
Pruritus	15	0	7	0
Nervous system disorders
Peripheral neuropathy	16	0.2	14	0
Headache	11	0	11	0
Dizziness	11	0	10	0.2
Endocrine disorders
Hypothyroidism	13	0.4	2.3	0
Vascular disorders
Hypertension	12	4.5	9	2.9
Hemorrhage	11	0.9	10	2.1

Table 24 summarizes the laboratory abnormalities in patients treated with IMFINZI plus chemotherapy.

Table 24. Select Laboratory Abnormalities That Worsened from Baseline in ≥ 20% of Patients Who Received IMFINZI with Chemotherapy in the NIAGARA study
Laboratory Abnormality	IMFINZI with gemcitabine and cisplatin Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI plus chemotherapy (range: 482 to 528), and chemotherapy (range: 467 to 521).		Gemcitabine and cisplatin
Laboratory Abnormality	All Grades Graded per NCI CTCAE V5. (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Chemistry
Increased blood creatinine	63	9	58	7
Decreased sodium	54	9	55	10
Increased ALT	53	2.3	54	4.0
Decreased calcium	52	1.3	43	1.2
Increased potassium	51	4.2	49	4.4
Increased AST	42	1.5	39	2.1
Decreased magnesium	38	1.9	37	2.3
Increased alkaline phosphate	26	0.8	25	0.4
Hematology
Decreased hemoglobin	88	13	87	13
Decreased neutrophils	76	31	74	34
Decreased platelets	52	6	50	7
Decreased lymphocytes	44	10	40	8

Neoadjuvant Phase of NIAGARA

A total of 530 patients received at least 1 dose of IMFINZI in combination with chemotherapy as neoadjuvant treatment in the IMFINZI treatment arm, and 526 patients received at least 1 dose of chemotherapy as neoadjuvant treatment in the chemotherapy treatment arm. In the neoadjuvant phase, serious adverse reactions occurred in 24% of patients who received IMFINZI in combination with chemotherapy; the most frequent (≥1%) serious adverse reactions were pulmonary embolism (1.9%), febrile neutropenia (1.5%), acute kidney injury (1.3%), thrombocytopenia (1.3%), urinary tract infection (1.3%) and pneumonia (1.3%). Fatal adverse reactions occurred in 1.1% of patients including sepsis (0.2%), myocardial infarction (0.2%), and pulmonary embolism (0.2%). One fatal adverse reaction of pneumonia was reported in 1 (0.2%) patient in the post-surgery phase before adjuvant treatment started.

Permanent discontinuation of IMFINZI due to an adverse reaction in the neoadjuvant phase occurred in 9% of patients while receiving IMFINZI in combination with chemotherapy. The most frequent (≥ 0.5%) adverse reactions that led to permanent discontinuation of IMFINZI were blood creatinine increased (0.9%), neutropenia (0.6%), acute kidney injury (0.6%), asthenia (0.6%) and fatigue (0.6%).

Of the 530 patients in the IMFINZI treatment arm and 526 patients in the chemotherapy treatment arm who received neoadjuvant treatment, 1 (0.2%) patient in each treatment arm did not receive surgery due to adverse reactions. The adverse reaction that led to cancellation of surgery in the IMFINZI treatment arm was interstitial lung disease.

Of the 469 patients in the IMFINZI treatment arm who underwent radical cystectomy, 4 (0.8%) patients experienced delay of surgery (defined as occurring more than 56 days after the last dose of neoadjuvant treatment) due to adverse reactions.

Adjuvant Phase of NIAGARA

A total of 383 patients (72%) in the IMFINZI treatment arm received at least 1 dose of adjuvant treatment.

Serious adverse reactions occurred in 26% of patients receiving IMFINZI as adjuvant treatment. The most frequent serious adverse reactions (occurring in ≥1% of patients) were urinary tract infection (7%), acute kidney injury (3.7%), hydronephrosis (2.1%), pyelonephritis (2.1%), urosepsis (1.8%), and sepsis (1.6%). Fatal adverse reactions occurred in 1.8% of patients, including COVID-19 (0.3%), severe acute respiratory syndrome (0.3%), cardiopulmonary failure (0.3%), gastrointestinal haemorrhage (0.3%), and chronic hepatic failure (0.3%).

Permanent discontinuation of adjuvant IMFINZI due to an adverse reaction occurred in 5% of patients. The most frequent (≥0.5%) adverse reactions that led to permanent discontinuation of adjuvant IMFINZI were nephritis (0.8%), fatigue (0.5%), diarrhea (0.5%), decreased appetite (0.5%) and pneumonitis (0.5%).

Gastric or Gastroesophageal Junction Adenocarcinoma (GC/GEJC)

Neoadjuvant and Adjuvant Treatment of Resectable GC/GEJC – MATTERHORN

The safety of IMFINZI with FLOT as neoadjuvant and adjuvant treatment, followed by single-agent IMFINZI, was evaluated in MATTERHORN, a randomized, double-blind, placebo-controlled, multicenter study of patients with resectable GC/GEJC (Stage II to Stage IVA [AJCC, 8th edition]) [see Clinical Studies (14.7 )] .

Safety data are available for the 944 patients who received IMFINZI with FLOT (n=475) or placebo with FLOT (n=469).

The median duration of exposure to IMFINZI 1,500 mg every 4 weeks in the neoadjuvant phase was 8 weeks (range: 1.4 to 8.7 weeks). The median duration of exposure to IMFINZI 1,500 mg every 4 weeks in the adjuvant phase was 48 weeks (range: 1.9 to 50.1 weeks).

The most common adverse reactions (occurring in ≥ 20% of patients) were diarrhea, nausea, peripheral neuropathy, fatigue, alopecia, decreased appetite, rash, abdominal pain, vomiting, musculoskeletal pain, pyrexia, and stomatitis.

Table 25 summarizes the adverse reactions that occurred in ≥ 10% of patients treated with IMFINZI in combination with FLOT chemotherapy.

Table 25: Adverse Reactions Occurring in ≥ 10% of Patients in the MATTERHORN study
Adverse Reaction	IMFINZI with FLOT Chemotherapy N=475		Placebo with FLOT Chemotherapy N=469
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Gastrointestinal disorders
Diarrhea Includes multiple similar terms.	64	8	59	7
Nausea	51	2.5	51	1.5
Vomiting	26	2.1	26	3
Abdominal pain	27	2.3	29	1.3
Stomatitis	20	1.1	15	0.6
Constipation	16	0	17	0.9
Dysphagia	10	1.5	8	1.5
Nervous system disorders
Peripheral neuropathy	51	3.6	47	2.3
Dysgeusia	19	0	15	0
General disorders and administration site conditions
Fatigue	47	5	45	5
Pyrexia	20	0.8	16	1.3
Skin and subcutaneous tissue disorders
Alopecia	31	0	32	0
Rash	30	1.5	20	0.4
Pruritus	11	0	5	0
Metabolism and nutrition disorders
Decreased appetite	31	3.2	30	2.1
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	21	1.5	19	0.6
Infections and infestations
COVID-19	19	1.7	16	0.6
Pneumonia	11	3.8	10	4.3
Investigations
Weight decreased	15	2.1	19	3.4
Vascular disorders
Hemorrhage	14	2.5	15	2.8
Respiratory, thoracic and mediastinal disorders
Cough	10	0	10	0

Table 26 summarizes the laboratory abnormalities in patients treated with IMFINZI in combination with FLOT chemotherapy.

Table 26: Laboratory Abnormalities (> 20%) That Worsened from Baseline in Patients with Disease Who Received IMFINZI with FLOT Chemotherapy in MATTERHORN
Laboratory Abnormality Graded per NCI CTCAE v5.0	IMFINZI with FLOT Chemotherapy The denominator used to calculate the rate varied from 444 to 472 based on the number of patients with a baseline value and at least one post-treatment value.		Placebo with FLOT Chemotherapy The denominator used to calculate the rate varied from 443 to 468 based on the number of patients with a baseline value and at least one post-treatment value.
Laboratory Abnormality Graded per NCI CTCAE v5.0	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Hematology
Decreased leukocytes	75	14	79	17
Decreased neutrophils	70	41	74	44
Decreased hemoglobin	68	7	73	8
Decreased lymphocytes	49	13	45	13
Decreased platelets	47	1.1	46	1.9
Chemistry
Increased AST	72	6	69	6
Increased ALT	70	7	65	6
Increased GGT	57	10	51	6
Increased lipase	55	16	55	15
Increased alkaline phosphatase	53	3.2	51	1.5
Decreased calcium	45	0.8	47	2.6
Increased amylase	42	6	39	4.5
Decreased potassium	39	8	40	8
Decreased sodium	33	4.4	32	4.7
Decreased albumin	31	1.5	31	0.2
Increased potassium	22	0.6	26	1.3

Adverse Reactions by Phase of Treatment

Table 27 summarizes safety profile by Phase of treatment.

Table 27: Safety Profile by Phase of Treatment
IMFINZI with FLOT Chemotherapy	Placebo with FLOT Chemotherapy
Neoadjuvant Phase
Number of Patients	475	469
Serious Adverse Reactions	21%	18%
Deaths during Treatment-emergent period	1.9%	1.7%
Permanent discontinuation of IMFINZI or Placebo	2.5%	2.1%
No surgery due to Adverse Reaction	0.6%	0.4%
Delay in surgery due to Adverse Reaction	2.3%	2.6%
Adjuvant Phase
Number of Patients	365	351
Serious Adverse Reactions	29%	26%
Deaths during Treatment-emergent period	2.2%	2.6%
Permanent discontinuation of IMFINZI or Placebo	7%	4.6%
Adjuvant Phase (IMFINZI as a single-agent)
Number of Patients	345	331
Serious Adverse Reactions	14%	15%
Deaths during Treatment-emergent period	1.7%	2.4%
Permanent discontinuation of IMFINZI or Placebo	6%	2.7%

Serious adverse reactions (≥2%) in the IMFINZI arm were diarrhea (2.5%) during the neoadjuvant phase, and pneumonia (2.5%) in the adjuvant phase.

Deaths (≥2 patients) in the IMFINZI arm were septic shock (0.6%) and acute coronary syndrome (0.4%) during the neoadjuvant phase; gastrointestinal perforation (0.5%) and COVID-19 (0.5%) during adjuvant phase; and gastrointestinal perforation (0.6%) and COVID-19 (0.6%) in the single-agent adjuvant phase.

Permanent discontinuation of IMFINZI (≥2 patients) due an adverse reaction in the IMFINZI arm were nephritis (0.4%) during the neoadjuvant phase; hepatitis (1.1%), pneumonitis (1.1%), rash (0.8%), musculoskeletal pain (0.5%), and renal failure (0.5%) during adjuvant phase; and hepatitis (0.9%), pneumonitis (0.9%), musculoskeletal pain (0.6%), and renal failure (0.6%) during the single-agent adjuvant phase.

State of Maine (MCO) Coverage for Imfinzi

State Medicaid - State Medicaid

State Medicaid - AIDS Drug Assistance Program