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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 Precautions section reflect exposure to IMFINZI as a single agent in a total of 1889 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 trial (ATLANTIC Study) that enrolled 444 patients with advanced solid tumors, including NSCLC. In these trials, 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 in combination with chemotherapy in 265 patients from the CASPIAN study (a randomized, open-label study in patients with ES-SCLC), 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 300 mg in 388 patients in HIMALAYA. In the HIMALAYA study patients received IMFINZI 1,500 mg in combination with tremelimumab 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 Precautions section reflect exposure to IMFINZI 1,500 mg in combination with tremelimumab 75 mg and histology-based platinum chemotherapy regimens in 330 patients in POSEIDON [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions] and 266 patients with ES-SCLC in CASPIAN who received up to four cycles of platinum-etoposide plus IMFINZI 1,500 mg with tremelimumab 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 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, 8th edition]); squamous or non-squamous) [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
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 12 summarizes the adverse reactions that occurred in (≥ 10%) patients treated with IMFINZI in combination with chemotherapy. (See Table 12.)
Click on icon to see table/diagram/imageTable 13 summarizes the laboratory abnormalities in patients treated with IMFINZI in combination with chemotherapy. (See Table 13.)
Click on icon to see table/diagram/imageNeoadjuvant 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 Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
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 14 summarizes the adverse reactions that occurred in at least 10% of patients treated with IMFINZI. (See Table 14.)
Click on icon to see table/diagram/imageOther 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 15 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI. (See Table 15.)
Click on icon to see table/diagram/imageMetastatic NSCLC - POSEIDON: The safety of IMFINZI in combination with tremelimumab 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 (≥ 30 kg body weight received 75 mg and < 30 kg body weight received 1 mg/kg) and histology-based platinum chemotherapy regimens [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. Of these patients, 66% received the maximum 5 doses of tremelimumab 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 Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
The median age of patients who received IMFINZI in combination with tremelimumab 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 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 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 due to an adverse reaction occurred in 17% of the patients. Adverse reactions which resulted in permanent discontinuation of IMFINZI or tremelimumab in > 2% of patients included pneumonia.
Dosage interruption or delay of IMFINZI and tremelimumab due to an adverse reaction occurred in 41% of patients. Adverse reactions which required dosage interruption or delay of IMFINZI and tremelimumab 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 16 summarizes the adverse reactions in POSEIDON. (See Table 16.)
Click on icon to see table/diagram/imageTable 17 summarizes the laboratory abnormalities in POSEIDON. (See Table 17.)
Click on icon to see table/diagram/imageSmall Cell Lung Cancer: 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 Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. 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 18 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy. (See Table 18.)
Click on icon to see table/diagram/imageTable 19 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI plus chemotherapy. (See Table 19.)
Click on icon to see table/diagram/imageBiliary 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 Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
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 20 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy. (See Table 20.)
Click on icon to see table/diagram/imageTable 21 summarizes the laboratory abnormalities in patients treated with IMFINZI plus chemotherapy. (See Table 21.)
Click on icon to see table/diagram/imageHepatocellular Carcinoma: Unresectable HCC - HIMALAYA: The safety of IMFINZI in combination with tremelimumab was evaluated in a total of 388 patients with uHCC in HIMALAYA, a randomized, open-label, multicenter study [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. Patients received IMFINZI 1,500 mg administered as a single intravenous infusion in combination with tremelimumab 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. 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, 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 22 summarizes the adverse reactions that occurred in patients treated with IMFINZI in combination with tremelimumab in the HIMALAYA study. (See Table 22.)
Click on icon to see table/diagram/imageTable 23 summarizes the laboratory abnormalities that occurred in patients treated with IMFINZI in combination with tremelimumab in the HIMALAYA study. (See Table 23.)
Click on icon to see table/diagram/imageEndometrial 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 Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. 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 24 and 25 summarize adverse reactions and laboratory abnormalities in DUO-E, respectively. (See Table 24.)
Click on icon to see table/diagram/imageClinically 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 25 summarizes the laboratory abnormalities that occurred in patients treated with IMFINZI with carboplatin and paclitaxel followed by IMFINZI as a single agent. (See Table 25.)
Click on icon to see table/diagram/image
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