5.1Severe and Fatal Immune-Mediated Adverse Reactions
IMJUDO is a monoclonal antibody that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, thereby removing inhibition of the immune response. In combination with durvalumab, a PD-L1 inhibitor, these drugs have the potential for induction of immune-mediated adverse reactions. Immune-mediated adverse reactions listed herein 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 IMJUDO in combination with durvalumab. While immune-mediated adverse reactions usually manifest during treatment, immune-mediated adverse reactions can also manifest after discontinuation of IMJUDO and/or durvalumab. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of IMJUDO in combination with durvalumab.
Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and before each dose. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue IMJUDO and durvalumab depending on severity [see Dosage and Administration (2.2) ] .
In general, if combination of IMJUDO and durvalumab 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 corticosteroid therapy.
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 IMJUDO in combination with durvalumab can cause immune-mediated pneumonitis, which may be fatal. IMJUDO with Durvalumab Immune-mediated pneumonitis occurred in 1.3% (5/388) of patients receiving IMJUDO in combination with durvalumab, including fatal (0.3%) and Grade 3 (0.2%) adverse reactions.
Events resolved in 3 of the 5 patients and resulted in permanent discontinuation in 1 patient. Systemic corticosteroids were required in all patients; of these, 4 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient (1/5) required other immunosuppressants. IMJUDO with Durvalumab and Platinum-Based Chemotherapy Immune-mediated pneumonitis occurred in 3.5% (21/596) of patients receiving IMJUDO in combination with durvalumab and platinum-based chemotherapy, including fatal (0.5%) and Grade 3 (1%) adverse reactions.
Events resolved in 11 of the 21 patients and resulted in permanent discontinuation in 7 patients. Systemic corticosteroids were required in all patients with immune-mediated pneumonitis, while 1 patient (1/21) required other immunosuppressants . Immune-Mediated Colitis IMJUDO in combination with durvalumab and platinum-based chemotherapy can cause immune-mediated colitis, which may be fatal. IMJUDO in combination with durvalumab can cause immune-mediated colitis that is frequently associated with diarrhea.
Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. IMJUDO with Durvalumab Immune-mediated colitis or diarrhea occurred in 6% (23/388) of patients receiving IMJUDO in combination with durvalumab, including Grade 3 (3.6%) adverse reactions.
Events resolved in 22 of the 23 patients and resulted in permanent discontinuation in 5 patients. All patients received systemic corticosteroids, and 20 of the 23 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Three patients also received other immunosuppressants. Intestinal perforation has been observed in other studies of IMJUDO in combination with durvalumab.
IMJUDO with Durvalumab and Platinum-Based Chemotherapy Immune-mediated colitis occurred in 6.5% (39/596) of patients receiving IMJUDO in combination with durvalumab and platinum-based chemotherapy, including fatal (0.2%) and Grade 3 (2.5%) adverse reactions. Events resolved in 33 of the 39 patients and resulted in permanent discontinuation in 11 patients. Systemic corticosteroids were required in all patients with immune-mediated colitis, while 4 patients (4/39) required other immunosuppressants.
Intestinal perforation and large intestine perforation were reported in 0.1% of patients receiving IMJUDO in combination with durvalumab. Immune-Mediated Hepatitis IMJUDO in combination with durvalumab can cause immune-mediated hepatitis, which may be fatal. IMJUDO with Durvalumab Immune-mediated hepatitis occurred in 7.5% (29/388) of patients receiving IMJUDO in combination with durvalumab, including fatal (0.8%), Grade 4 (0.3%), and Grade 3 (4.1%) adverse reactions.
Events resolved in 12 of the 29 patients and resulted in permanent discontinuation in 9 patients. Systemic corticosteroids were required in all 29 patients and all 29 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Eight patients (8/29) required other immunosuppressants. IMJUDO with Durvalumab and Platinum-Based Chemotherapy Immune-mediated hepatitis occurred in 3.9% (23/596) of patients receiving IMJUDO in combination with durvalumab and platinum-based chemotherapy, including fatal (0.3%), Grade 4 (0.5%), and Grade 3 (2%) adverse reactions.
Events resolved in 12 of the 23 patients and resulted in permanent discontinuation in 27 patients. Systemic corticosteroids were required in all patients with immune-mediated hepatitis, while 2 patients (2/23) required use of other immunosuppressants. Immune-Mediated Endocrinopathies Adrenal Insufficiency : IMJUDO in combination with durvalumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated.
Withhold or permanently discontinue IMJUDO in combination with durvalumab based on the severity [see Dosage and Administration (2.2) ]. IMJUDO with Durvalumab Immune-mediated adrenal insufficiency occurred in 1.5% (6/388) of patients receiving IMJUDO in combination with durvalumab, including Grade 3 (0.3%) adverse reactions. Events resolved in 2 of the 6 patients. Systemic corticosteroids were required in al
