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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 Precautions reflect exposure to IMFINZI in 1889 patients from the PACIFIC study (a randomized, placebo-controlled study that enrolled 475 patients with Stage III NSCLC), and Study 1108 (an open-label, single-arm, multicohort study that enrolled 970 patients with advanced solid tumours), and additional open-label, single-arm trial that enrolled 444 patients with metastatic lung cancer, indications for which durvalumab is not approved. 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 1500 mg every 3 or 4 weeks.
The data described in this section reflect exposure to IMFINZI in patients with Stage III NSCLC enrolled in the PACIFIC study and in patients with ES-SCLC enrolled in the CASPIAN study and in patients with BTC enrolled in the TOPAZ-1 study and in patients with endometrial cancer enrolled in the DUO-E study.
Summary of the safety profile: IMFINZI in combination with chemotherapy: The safety of IMFINZI in combination with chemotherapy is based on pooled data in 838 patients from 3 studies (TOPAZ-1, CASPIAN and DUO-E). The most common (>10%) adverse reactions were neutropenia (47.3%), anaemia (44.9%), fatigue (38.8%), nausea (38.4%), thrombocytopenia (28.0%), alopecia (27.4%), constipation (25.9%), decreased appetite (21.2%), neuropathy peripheral (21.2%), abdominal pain (20.3%), diarrhoea (19.1%), rash (18.5%), vomiting (18.0%), leukopenia (17.2%), pyrexia (13.4%), arthralgia (12.4%), cough/productive cough (12.4%), pruritus (11.8%), hypothyroidism (11.0%), aspartate aminotransferase increased/alanine aminotransferase increased (10.7%) and oedema peripheral (10.1%). The most common (>2%) NCI CTCAE Grade ≥3 adverse reactions were neutropenia (30.7%), anaemia (17.1%), thrombocytopenia (9.9%), leukopenia (6.4%), fatigue (4.5%), febrile neutropenia (2.9%), aspartate aminotransferase increased/alanine aminotransferase increased (2.1%) and pneumonia (2.0%).
IMFINZI was discontinued due to adverse reactions in 3.6% of patients. The most common adverse reactions leading to treatment discontinuation were anaemia (0.5%), rash (0.5%) and fatigue (0.5%).
IMFINZI was delayed or interrupted due to adverse reactions in 31.0% of patients. The most common adverse reactions leading to dose delay or interruption were neutropenia (15.0%), thrombocytopenia (6.8%), anaemia (5.1%) and leukopenia (2.9%).
IMFINZI in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib 300 mg twice daily.
The safety of IMFINZI given in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib 300 mg twice daily is based on data in 238 patients with endometrial cancer. The most common (>20%) adverse reactions were anaemia (61.8%), nausea (54.6%), fatigue (54.2%), neuropathy peripheral (51.7%), alopecia (50.8%), neutropenia (39.5%), constipation (32.8%), thrombocytopenia (29.8%), diarrhoea (28.2%), vomiting (25.6%), arthralgia (24.4%), rash (23.5%), abdominal pain (23.5%), decreased appetite (23.1%) and leukopenia (20.2%).
The most common (>2%) NCI CTCAE Grade ≥3 adverse reactions were neutropenia (25.2%), anaemia (23.5%), leukopenia (6.7%), thrombocytopenia (5.9%), fatigue (5.5%), febrile neutropenia (3.4%), nausea (2.9%), aspartate aminotransferase increased/alanine aminotransferase increased (2.9%) and neuropathy peripheral (2.5%).
IMFINZI was discontinued in 4.6% of patients. The most common adverse reaction leading to treatment discontinuation was pneumonitis (1.7%).
IMFINZI was interrupted in 38.2% of patients. The most common adverse reactions leading to dose interruption were anaemia (13.4%), thrombocytopenia (11.8%), neutropenia (10.1%), leukopenia (2.9%), hypothyroidism (2.1%) and upper respiratory tract infection (2.1%).
Non-Small Cell Lung Cancer: AEGEAN Study: 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 [AJC, 8th edition]; squamous or non-squamous) [see Pharmacology: 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 11 summarizes the adverse reactions that occurred in (≥ 10%) patients treated with IMFINZI in combination with chemotherapy. (See Table 11.)
Click on icon to see table/diagram/imageTable 12 summarizes the laboratory abnormalities in patients treated with IMFINZI in combination with chemotherapy. (See Table 12.)
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%).
PACIFIC Study: 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: 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 13 summarizes the adverse reactions that occurred in at least 10% of patients treated with IMFINZI. (See Table 13.)
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 14 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI. (See Table 14.)
Click on icon to see table/diagram/imageSmall Cell Lung Cancer: 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 1500 mg in combination with chemotherapy every 3 weeks for 4 cycles followed by IMFINZI 1500 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: 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 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 15 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy. (See Table 15.)
Click on icon to see table/diagram/imageTable 16 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI plus chemotherapy. (See Table 16.)
Click on icon to see table/diagram/imageBiliary Tract Cancer: 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: 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), 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 17 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy. (See Table 17.)
Click on icon to see table/diagram/imageTable 18 summarizes the laboratory abnormalities in patients treated with IMFINZI plus chemotherapy. (See Table 18.)
Click on icon to see table/diagram/imageEndometrial Cancer (DUO-E): Adverse reactions known to occur with durvalumab, chemotherapy or olaparib given alone, may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical trials with combination therapy. Refer to the local prescribing information for chemotherapy and olaparib. (See Tables 19 and 20.)
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