5.1Severe and Fatal Immune-Mediated Adverse Reactions
ZYNYZ is a monoclonal antibody that belongs to a class of drugs that binds to either the programmed death receptor-1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response with the potential for breaking of peripheral tolerance and induction of immune-mediated adverse reactions. Important immune‑mediated adverse reactions listed under Warnings and Precautions may not be inclusive of all possible severe and fatal immune-mediated reactions.
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1–blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1–blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1–blocking antibodies.
Immune-mediated adverse reactions affecting more than one body system can occur simultaneously. Early identification and management of immune‐mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1–blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.
In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue ZYNYZ depending on severity [see Dosage and Administration ( 2.2 )] . In general, if ZYNYZ requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less.
Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroids. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.
Immune-Mediated Pneumonitis ZYNYZ can cause immune-mediated pneumonitis. In patients treated with other PD-1/PD-L1–blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.1% (14/452) of patients receiving ZYNYZ, including 1 (0.2%) patient with fatal pneumonitis, Grade 3 (0.9%), and Grade 2 (1.3%). Pneumonitis led to permanent discontinuation of ZYNYZ in 1 patient and withholding of ZYNYZ in 1.1% of patients.
Systemic corticosteroids were required in 71% (10/14) of patients with pneumonitis. Pneumonitis resolved in 11 of the 14 patients. Of the 5 patients in whom ZYNYZ was withheld for pneumonitis, 4 reinitiated ZYNYZ after symptom improvement; of these, 1 had recurrence of pneumonitis. Immune-Mediated Colitis ZYNYZ can cause immune-mediated colitis. Cytomegalovirus infection/reactivation have occurred in patients with corticosteroid-refractory immune-mediated colitis treated with PD-1/PD-L1–blocking antibodies.
In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. ZYNYZ as a Single Agent: Immune-mediated colitis occurred in 2.7% (12/452) of patients receiving ZYNYZ, including Grade 4 (0.2%), Grade 3 (0.4%), and Grade 2 (1.1%). Colitis led to permanent discontinuation of ZYNYZ in 0.9% of patients and withholding of ZYNYZ in 1.3% of patients. Systemic corticosteroids were required in 75% (9/12) of patients.
Colitis resolved in 8 of the 12 patients. Of the 6 patients in whom ZYNYZ was withheld for colitis, 1 reinitiated ZYNYZ after symptom improvement; this patient did not have recurrence of colitis. ZYNYZ in Combination with Carboplatin and Paclitaxel: Immune-mediated colitis occurred in 10% (16/154) of patients receiving ZYNYZ in combination with carboplatin and paclitaxel, including Grade 4 (0.6%), Grade 3 (2.6%), and Grade 2 (3.2%).
Colitis led to permanent discontinuation of ZYNYZ in 2 patients and withholding of ZYNYZ in 2 patients. Systemic corticosteroids were required in 94% (15/16) of patients. Colitis resolved in 15 of the 16 patients. Of the 2 patients in whom ZYNYZ was withheld for colitis, both reinitiated ZYNYZ after symptom improvement; neither patient had a recurrence of colitis. Immune-Mediated Hepatitis ZYNYZ can cause immune-mediated hepatitis.
Immune-mediated hepatitis occurred in 3.5% (16/452) of patients receiving ZYNYZ, including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (0.9%). Hepatitis led to permanent discontinuation of ZYNYZ in 1.5% of patients and withholding of ZYNYZ in 1.1% of patients. Systemic corticosteroids were required in 81% (13/16) of patients. Hepatitis resolved in 9 of the 16 patients. Of the 5 patients in whom ZYNYZ was withheld for hepatitis, 3 reinitiated ZYNYZ after symptom improvement; of these, 1 had recurrence of hepatitis.
Immune-Mediated Endocrinopathies Adrenal Insufficiency ZYNYZ can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment per institutional guidelines, including hormone replacement as clinically indicated. Withhold or permanently discontinue ZYNYZ depending on severity [see Dosage and Administration ( 2.2 )] . ZYNYZ as a Single Agent: Adrenal insufficiency occurred in 0.9% (4/452) of patients receiving ZYNYZ, including Grade 3 (0.4%) and Grade 2 (0.4%).
Adrenal insufficiency did not lead to permanent discontinuation of ZYNYZ. ZYNYZ was withheld for 1 patient with adrenal insufficiency. All patients required systemic corticosteroids. Adrenal insufficiency resolved in 1 of the 4 patients. ZYNYZ in Combination with Carboplatin and Paclitaxel: Adrenal insufficiency occurred in 5.8% (9/154) of patients receiving ZYNYZ in combination with carboplatin and paclitaxel, including Grade 3 and Grade 2 (1.9% each).
Adrenal insufficiency led to permanent discontinuation of ZYNYZ in 1 patient and withholding of ZYNYZ in 3 patients. All patients required systemic corticosteroids. Adrenal insufficiency resolved in 4 of the 9 patients. Hypophysitis ZYNYZ can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitaris
