JEMPERLI is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance, and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed in WARNINGS AND PRECAUTIONS may not include all possible severe and fatal immune‑mediated reactions.

Immune-mediated adverse reactions, which can be severe or fatal, can occur in any organ system or tissue. Immune‑mediated adverse reactions can occur at any time after starting a PD-1/PD-L1–blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1–blocking antibodies, they can also manifest after discontinuation of PD-1/PD-L1–blocking antibodies.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD‑1/PD‑L1–blocking antibodies. Monitor closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function tests 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 JEMPERLI depending on severity [see Dosage and Administration (2.3)]. In general, if JEMPERLI requires interruption or discontinuation, administer systemic corticosteroids (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 reaction is not controlled with corticosteroids.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies, dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

JEMPERLI can cause immune-mediated pneumonitis, which can be fatal. 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 2.3% (14/605) of patients receiving JEMPERLI, including Grade 2 (1.3%), Grade 3 (0.8%) and Grade 4 (0.2%) pneumonitis. Pneumonitis led to discontinuation of JEMPERLI in 1.3% of patients.

Systemic corticosteroids were required in 79% (11/14) of patients with pneumonitis. Pneumonitis resolved in 11 of the 14 patients. JEMPERLI was withheld for 9 patients. Five patients reinitiated JEMPERLI after symptom improvement; of these, 2 patients had recurrence of pneumonitis.

Immune-Mediated Colitis

JEMPERLI 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.

Immune-mediated colitis occurred in 1.3% (8/605) of patients receiving JEMPERLI, including Grade 2 (0.7%) and Grade 3 (0.7%) adverse reactions. Colitis led to discontinuation of JEMPERLI in 1 (0.2%) patient.

Systemic corticosteroids were required in 75% (6/8) of patients with colitis. Colitis resolved in 5 of the 8 patients. Of the 4 patients in whom JEMPERLI was withheld for colitis, all reinitiated treatment with JEMPERLI; of these, 1 patient had recurrence of colitis.

Immune-Mediated Hepatitis

JEMPERLI can cause immune-mediated hepatitis, which can be fatal.

Immune-mediated hepatitis occurred in 0.5% (3/605) of patients receiving JEMPERLI, all were Grade 3. Hepatitis led to discontinuation of JEMPERLI in 1 (0.2%) patient. Systemic corticosteroids were required in 2 patients with hepatitis and the events resolved in 2 of the 3 patients.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency: JEMPERLI 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 JEMPERLI depending on severity [see Dosage and Administration (2.3)].

Adrenal insufficiency occurred in 1.2% (7/605) patients receiving JEMPERLI, including Grade 2 (0.5%) and Grade 3 (0.7%). Adrenal insufficiency resulted in discontinuation in 1 (0.2%) patient and resolved in 4 of the 7 patients. Of the 4 patients in whom JEMPERLI was withheld for adrenal insufficiency, all reinitiated treatment with JEMPERLI. Systemic corticosteroids were required in 5 of the 7 patients with adrenal insufficiency.

Hypophysitis: JEMPERLI 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 hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue JEMPERLI depending on severity [see Dosage and Administration (2.3)].

JEMPERLI in Combination with Carboplatin and Paclitaxel: Hypophysitis (Grade 3) occurred in 0.4% (1/241) of patients receiving JEMPERLI in combination with carboplatin and paclitaxel. Systemic corticosteroids were required, and the event resolved. JEMPERLI was withheld and the patient reinitiated treatment.

JEMPERLI as a Single Agent: Hypophysitis (Grade 2) occurred in 0.2% (1/605) of patients receiving JEMPERLI as a single agent. Systemic corticosteroids were required, and the event did not resolve. JEMPERLI was withheld and the patient reinitiated treatment.

Thyroid Disorders: JEMPERLI can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate thyroid hormone replacement or medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue JEMPERLI depending on severity [see Dosage and Administration (2.3)].

Thyroiditis: Thyroiditis occurred in 0.5% (3/605) of patients receiving JEMPERLI; all were Grade 2. Systemic corticosteroids were required in 1 of 3 patients and anti-thyroid therapy was required for 2 of 3 patients with thyroiditis. JEMPERLI was withheld for 1 patient and the patient reinitiated treatment. None of the events of thyroiditis resolved; there were no discontinuations of JEMPERLI due to thyroiditis.

Hypothyroidism: JEMPERLI in Combination with Carboplatin and Paclitaxel: Hypothyroidism occurred in 12% (30/241) of patients receiving JEMPERLI in combination with carboplatin and paclitaxel, all of which were Grade 2. Hypothyroidism led to discontinuation of JEMPERLI in 1 patient and resolved in 23% (7/30) of patients. JEMPERLI was withheld for 5 patients and all reinitiated treatment with JEMPERLI. Thyroid hormone replacement was required for 27 of the 30 patients with hypothyroidism.

JEMPERLI as a Single Agent: Hypothyroidism occurred in 8% (46/605) of patients receiving JEMPERLI as a single agent, all of which were Grade 2. Hypothyroidism did not lead to discontinuation of JEMPERLI and resolved in 37% (17/46) of patients. JEMPERLI was withheld for 2 patients and both reinitiated treatment. Thyroid hormone replacement therapy was required for 45 of the 46 patients with hypothyroidism.

Hyperthyroidism: JEMPERLI in Combination with Carboplatin and Paclitaxel: Hyperthyroidism occurred in 3.3% (8/241) of patients receiving JEMPERLI in combination with carboplatin and paclitaxel, including Grade 2 (2.9%) and Grade 3 (0.4%). Hyperthyroidism did not lead to discontinuation of JEMPERLI and resolved in 75% (6/8) of patients. JEMPERLI was withheld for 1 patient and the patient reinitiated treatment. Anti-thyroid therapy was required for 2 of the 8 patients while systemic corticosteroids were required for 1 of the 8 patients with hyperthyroidism.

JEMPERLI as a Single Agent: Hyperthyroidism occurred in 2.3% (14/605) of patients receiving JEMPERLI as a single agent, including Grade 2 (2.1%) and Grade 3 (0.2%). Hyperthyroidism did not lead to discontinuation of JEMPERLI and resolved in 71% (10/14) of the 14 patients. JEMPERLI was withheld for 2 patients and both reinitiated treatment. Anti-thyroid therapy was required for 10 of the 14 patients with hyperthyroidism.

Type 1 Diabetes Mellitus, Which Can Present with Diabetic Ketoacidosis: JEMPERLI can cause type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue JEMPERLI depending on severity [see Dosage and Administration (2.3)].

JEMPERLI in Combination with Carboplatin and Paclitaxel: Type 1 diabetes mellitus (Grade 3) occurred in 0.4% (1/241) of patients receiving JEMPERLI in combination with carboplatin and paclitaxel. Type 1 diabetes mellitus led to withholding JEMPERLI; the patient reinitiated treatment and required long-term insulin therapy.

JEMPERLI as a Single Agent: Type 1 diabetes mellitus occurred in 0.2% (1/605) of patients receiving JEMPERLI as a single agent, which was Grade 3. Type 1 diabetes mellitus did not result in treatment discontinuation and did not resolve.

Immune-Mediated Nephritis with Renal Dysfunction

JEMPERLI can cause immune-mediated nephritis, which can be fatal. Nephritis, including tubulointerstitial nephritis, occurred in 0.5% (3/605) of patients receiving JEMPERLI; all were Grade 2. Nephritis led to discontinuation of JEMPERLI in 1 (0.2%) patient and resolved in all patients. JEMPERLI was withheld for 1 patient and the patient reinitiated treatment. Systemic corticosteroids were required in 2 of the 3 patients experiencing nephritis.

Immune-Mediated Dermatologic Adverse Reactions

JEMPERLI can cause immune-mediated rash or dermatitis. Bullous and exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS), have occurred with PD‑1/PD‑L1–blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes. Withhold or permanently discontinue JEMPERLI depending on severity [see Dosage and Administration (2.3)].

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred in <1% of the 605 patients treated with JEMPERLI or were reported with the use of other PD-1/PD-L1–blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis, Guillain‑Barré syndrome, nerve paresis, autoimmune neuropathy.

Cardiac/Vascular: Myocarditis, pericarditis, vasculitis.

Ocular: Uveitis, iritis, other ocular inflammatory toxicities. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune‑mediated adverse reactions, consider a Vogt‑Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Gastrointestinal: Pancreatitis, including increases in serum amylase and lipase levels, gastritis, duodenitis.

Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatica.

Endocrine: Hypoparathyroidism.

Other (Hematologic/Immune): Autoimmune hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection, other transplant (including corneal graft) rejection.