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Refer to Table 5 under Dosage & Administration for recommended treatment modifications and management of immune-mediated adverse reactions.
Immune-mediated pneumonitis: Immune-mediated pneumonitis or interstitial lung disease, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI [see Adverse Reactions]. Patients should be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmed with radiographic imaging and other infectious and disease-related etiologies excluded, and managed as recommended in Dosage & Administration [see Dosage & Administration].
Pneumonitis and radiation pneumonitis: Radiation pneumonitis is frequently observed in patients receiving radiation therapy to the lung and the clinical presentation of pneumonitis and radiation pneumonitis is very similar. In the PACIFIC Study, in patients who had completed treatment with concurrent chemoradiation within 1 to 42 days prior to initiation of the trial, pneumonitis and radiation pneumonitis occurred in patients receiving IMFINZI. Pneumonitis or radiation pneumonitis occurred in 161 (33.9%) patients in the IMFINZI-treated group and 58 (24.8%) in the placebo group; including Grade 3 in 16 (3.4%) patients on IMFINZI vs. 7 (3.0%) patients on placebo and Grade 5 in 5 (1.1%) patients on IMFINZI vs. 4 (1.7%) patients on placebo. The median time to onset in the IMFINZI-treated group was 55 days (range: 1-406 days) vs. 55 days (range: 1-255 days) in the placebo group.
In patients receiving IMFINZI monotherapy, immune-mediated pneumonitis occurred in 92 (3.1%) patients, including Grade 3 in 25 (0.8%) patients, Grade 4 in 2 (<0.1%) patients, and Grade 5 in 6 (0.2%) patients. The median time to onset was 55 days (range: 2-785 days). Sixty-nine of the 92 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day), 2 patients also received infliximab and 1 patient also received cyclosporine. IMFINZI was discontinued in 38 patients. Resolution occurred in 53 patients. Immune-mediated pneumonitis occurred more frequently in patients in the PACIFIC Study who had completed treatment with concurrent chemoradiation within 1 to 42 days prior to initiation of the study (9.9%), compared to the other patients in the combined safety database (1.8%).
In the PACIFIC Study, in patients with locally advanced, unresectable NSCLC (n=475 in the IMFINZI arm, and n=234 in the placebo arm) who had completed treatment with concurrent chemoradiation within 1 to 42 days prior to initiation of the study, immune-mediated pneumonitis occurred in 47 (9.9%) patients in the IMFINZI-treated group and 14 (6.0%) patients in the placebo group, including Grade 3 in 9 (1.9%) patients on IMFINZI vs. 6 (2.6%) patients on placebo and Grade 5 in 4 (0.8%) patients on IMFINZI vs. 3 (1.3%) patients on placebo. The median time to onset in the IMFINZI-treated group was 46 days (range: 2-342 days) vs. 57 days (range: 26-253 days) in the placebo group. In the IMFINZI-treated group 30 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and 2 patients also received infliximab. In the placebo group 12 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and 1 patient also received cyclophosphamide and tacrolimus. Resolution occurred for 29 patients in the IMFINZI treated group vs 6 in placebo.
Immune-mediated hepatitis: Immune-mediated hepatitis, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI [see Adverse Reactions]. Patients should be monitored for abnormal liver tests prior to and periodically during treatment with IMFINZI. Immune-mediated hepatitis should be managed as recommended in Dosage & Administration [see Dosage & Administration].
In patients receiving IMFINZI monotherapy, immune-mediated hepatitis occurred in 67 (2.2%) patients, including Grade 3 in 35 (1.2%) patients, Grade 4 in 6 (0.2%) and Grade 5 in 4 (0.1%) patients. The median time to onset was 36 days (range: 3-333 days). Forty-four of the 67 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Three patients also received mycophenolate treatment. IMFINZI was discontinued in 9 patients. Resolution occurred in 29 patients.
Immune-mediated colitis: Immune-mediated colitis or diarrhea, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI [see Adverse Reactions]. Patients should be monitored for signs and symptoms of colitis or diarrhea and managed as recommended in Dosage & Administration [see Dosage & Administration].
In patients receiving IMFINZI monotherapy, immune-mediated colitis or diarrhea occurred in 58 (1.9%) patients, including Grade 3 in 9 (0.3%) patients and Grade 4 in 2 (<0.1%) patients. The median time to onset was 70 days (range: 1-394 days). Thirty-eight of the 58 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient also received infliximab treatment and one patient also received mycophenolate treatment. IMFINZI was discontinued in 9 patients. Resolution occurred in 43 patients.
Immune-mediated endocrinopathies: Immune-mediated hypothyroidism/hyperthyroidism/thyroiditis: Immune-mediated hypothyroidism, hyperthyroidism or thyroiditis have occurred in patients receiving IMFINZI [see Adverse Reactions]. Patients should be monitored for abnormal thyroid function tests prior to and periodically during treatment and managed as recommended in Dosage & Administration [see Dosage & Administration].
Immune-mediated hypothyroidism: In patients receiving IMFINZI monotherapy, immune-mediated hypothyroidism occurred in 245 (8.2%) patients, including Grade 3 in 4 (0.1%) patients. The median time to onset was 85 days (range: 1-562 days). Of the 245 patients, 240 patients received hormone replacement therapy, 6 patients received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day) for immune-mediated hypothyroidism followed by hormone replacement. No patients discontinued IMFINZI due to immune-mediated hypothyroidism. Immune-mediated hypothyroidism was preceded by immune-mediated hyperthyroidism in 20 patients or immune-mediated thyroiditis in 3 patients.
Immune-mediated hyperthyroidism: In patients receiving IMFINZI monotherapy, immune-mediated hyperthyroidism occurred in 50 (1.7%) patients, there were no Grade 3 or 4 cases. The median time to onset was 43 days (range: 1-253 days). Forty-six of the 50 patients received medical therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker), 11 patients received systemic corticosteroids and 4 of the 11 patients received high-dose systemic corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient discontinued IMFINZI due to immune-mediated hyperthyroidism. Resolution occurred in 39 patients.
Immune-mediated thyroiditis: In patients receiving IMFINZI monotherapy, immune-mediated thyroiditis occurred in 12 (0.4%) patients, including Grade 3 in 2 (<0.1%) patients. The median time to onset was 49 days (range: 14-106 days). Of the 12 patients, 10 patients received hormone replacement therapy, 1 patient received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day). One patient discontinued IMFINZI due to immune-mediated thyroiditis.
Immune-mediated adrenal insufficiency: Immune-mediated adrenal insufficiency occurred in patients receiving IMFINZI [see Adverse Reactions]. Patients should be monitored for clinical signs and symptoms of adrenal insufficiency. For symptomatic adrenal insufficiency, patients should be managed as recommended in Dosage & Administration [see Dosage & Administration].
In patients receiving IMFINZI monotherapy, immune-mediated adrenal insufficiency occurred in 14 (0.5%) patients, including Grade 3 in 3 (<0.1%) patients. The median time to onset was 146 days (range: 20-547 days). All 14 patients received systemic corticosteroids; 4 of the 14 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). No patients discontinued IMFINZI due to immune-mediated adrenal insufficiency. Resolution occurred in 3 patients.
Immune-mediated type 1 diabetes mellitus: Immune-mediated type 1 diabetes mellitus, which can present with diabetic ketoacidosis, occurred in patients receiving IMFINZI [see Adverse Reactions]. Patients should be monitored for clinical signs and symptoms of type 1 diabetes mellitus. For symptomatic type 1 diabetes mellitus, patients should be managed as recommended in Dosage & Administration [see Dosage & Administration].
In patients receiving IMFINZI monotherapy, Grade 3 immune-mediated type 1 diabetes mellitus occurred in 1 (<0.1%) patient. The time to onset was 43 days. This patient required long-term insulin therapy and IMFINZI was permanently discontinued due to immune-mediated type 1 diabetes mellitus.
Immune-mediated hypophysitis/hypopituitarism: Immune-mediated hypophysitis or hypopituitarism occurred in patients receiving IMFINZI [see Adverse Reactions]. Patients should be monitored for clinical signs and symptoms of hypophysitis or hypopituitarism. For symptomatic hypophysitis or hypopituitarism, patients should be managed as recommended in Dosage & Administration [see Dosage & Administration].
In patients receiving IMFINZI monotherapy, immune-mediated hypophysitis/hypopituitarism occurred in 2 (<0.1%) patients both Grade 3. The time to onset for the events was 44 days and 50 days. Both patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and one patient discontinued IMFINZI due to immune-mediated hypophysitis/hypopituitarism.
Immune-mediated nephritis: Immune-mediated nephritis, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI [see Adverse Reactions]. Patients should be monitored for abnormal renal function tests prior to and periodically during treatment with IMFINZI and managed as recommended in Dosage & Administration [see Dosage & Administration].
In patients receiving IMFINZI monotherapy, immune-mediated nephritis occurred in 14 (0.5%) patients, including Grade 3 in 2 (<0.1%) patients. The median time to onset was 71 days (range: 4-393 days). Nine patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and 1 patient also received mycophenolate. IMFINZI was discontinued in 5 patients. Resolution occurred in 8 patients.
Immune-mediated rash: Immune-mediated rash or dermatitis (including pemphigoid), defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI [see Adverse Reactions]. Patients should be monitored for signs and symptoms of rash or dermatitis and managed as recommended in Dosage & Administration [see Dosage & Administration].
In patients receiving IMFINZI monotherapy, immune-mediated rash or dermatitis (including pemphigoid) occurred in 50 (1.7%) patients, including Grade 3 in 12 (0.4%) patients. The median time to onset was 43 days (range: 4-333 days). Twenty-four of the 50 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). IMFINZI was discontinued in 3 patients. Resolution occurred in 31 patients.
Other immune-mediated adverse reactions: Given the mechanism of action of IMFINZI, other potential immune-mediated adverse reactions may occur. Patients should be monitored for signs and symptoms and managed as recommended in Dosage & Administration [see Dosage & Administration]. Other immune-mediated adverse reactions are myasthenia gravis, myocarditis, myositis, polymyositis and immune thrombocytopenia, pancreatitis and encephalitis.
Infusion-related reactions: Patients should be monitored for signs and symptoms of infusion-related reactions. Severe infusion-related reactions have been reported in patients receiving IMFINZI [see Adverse Reactions].
In patients receiving IMFINZI monotherapy, infusion-related reactions occurred in 49 (1.6%) patients, including Grade 3 in 5 (0.2%) patients. There were no Grade 4 or 5 events.
Embryo-Fetal Toxicity: Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of durvalumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased premature delivery, fetal loss and premature neonatal death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI and for at least 3 months after the last dose of IMFINZI [see Use in Pregnancy & Lactation].
Use in Children: The safety and effectiveness of IMFINZI have not been established in pediatric patients.
Use in the Elderly: Of the 476 patients treated with IMFINZI in the PACIFIC study, 45% were 65 years or older, while 7.6% were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients. The PACIFIC study did not include sufficient numbers of patients aged 75 years and over to determine whether they respond differently from younger patients.
Of the 265 patients with ES-SCLC treated with IMFINZI in combination with chemotherapy, 101 (38%) patients were 65 years or older and 19 (7.2%) patients were 75 years or older. There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients.
Of the 338 patients with BTC treated with IMFINZI in combination with chemotherapy in the TOPAZ-1 study, 158 (47%) patients were 65 years or older and 38 (11%) patients were 75 years or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients.
