Pembrolizumab

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN, some fatal), exfoliative dermatitis, and bullous pemphigoid may occur with pembrolizumab. Monitor for suspected severe skin reactions and exclude other causes. Based on the severity of the dermatologic toxicity, withhold or permanently discontinue pembrolizumab and administer corticosteroids. Withhold pembrolizumab for signs/symptoms of SJS or TEN and refer for specialized care for assessment and management. Permanently discontinue pembrolizumab if SJS or TEN is confirmed.

Type 1 diabetes mellitus has occurred (including diabetic ketoacidosis). Monitor closely for hyperglycemia and other signs/symptoms of diabetes. Insulin therapy may be required; if severe hyperglycemia is observed, administer antihyperglycemics and withhold pembrolizumab treatment until glucose control has been accomplished.

Immune-mediated colitis has occurred, including cases of grade 2 to 4 colitis. The median time to onset of colitis was 3.5 months (range: 10 days to 16.2 months) and the median duration was 1.3 months (range: 1 day to over 8 months). In many patients, colitis was managed with high-dose systemic corticosteroids for a median duration of 7 days (range: 1 day to 5.3 months), followed by a corticosteroid taper. Most patients with colitis experienced resolution. May require treatment interruption, systemic corticosteroid therapy, and/or permanent discontinuation. Monitor for signs and symptoms of colitis; administer systemic corticosteroids for grade 2 or higher colitis.

Immune-mediated hepatitis occurred (grades 2 to 4 hepatitis). The median onset for hepatitis was 1.3 months (range: 8 days to 21.4 months); the median duration was 1.8 months (range: 8 days to over 20 months). Hepatitis resolved in most patients. Administer corticosteroids (prednisone 0.5 to 1 mg/kg/day [or equivalent] for grade 2 hepatitis, and prednisone 1 to 2 mg/kg/day [or equivalent] for grade 3 or higher, each followed by a taper), and withhold or discontinue therapy based on the severity of liver enzyme elevations. Systemic corticosteroids were used to manage immune-mediated hepatitis in many patients; the median duration of high-dose corticosteroid therapy was 5 days (range: 1 to 26 days), followed by a taper. Monitor for liver function changes. May require treatment interruption, systemic corticosteroids (for grade 2 or higher toxicity), and/or permanent discontinuation.

Hypersensitivity and anaphylaxis have been observed (rare).

Immune-mediated hypophysitis occurred (grades 2, 3, and 4). The median time to onset was 3.7 months (range: 1 day to 12 months) and the median duration was 4.7 months (range: 8 days to over 12 months). Most cases were managed with systemic corticosteroids. Nearly half of patients with hypophysitis experienced resolution. Monitor for signs/symptoms of hypophysitis (eg, hypopituitarism, adrenal insufficiency). May require treatment interruption, systemic corticosteroids and hormone replacement therapy (as clinically indicated), and/or permanent discontinuation.

Infusion-related reactions (including severe and life-threatening cases) have occurred. Monitor for signs/symptoms of a reaction (eg, rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever). Interrupt infusion and permanently discontinue for severe (grade 3) or life-threatening (grade 4) infusion-related reactions.

Immune-mediated nephritis has occurred. The onset for autoimmune nephritis was 5.1 months (range: 12 days to 12.8 months) and the median duration was 3.3 months (range: 12 days to over 9 months). Grade 2 or higher nephritis should be managed with systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg/day [or equivalent], followed by a taper). Most patients required systemic corticosteroids. The median duration of corticosteroid use was 15 days (range: 3 days to 4 months), followed by a taper. Nephritis resolved in over half of affected patients. Monitor for renal function changes. May require treatment interruption, systemic corticosteroids (for grade 2 or higher toxicity), and/or permanent discontinuation.

Immune-mediated pneumonitis has been observed, including fatal cases. The median time to development was 3.3 months (range: 2 days to ~19 months) and the median duration was 1.5 months (range: 1 day to over 17 months). Many patients required initial management with high-dose systemic corticosteroids; the median duration of initial corticosteroid therapy was 8 days (range: 1 day to ~10 months) followed by a corticosteroid taper. Pneumonitis resolved in half of the affected patients. May require treatment interruption, corticosteroid therapy (prednisone 1 to 2 mg/kg /day [or equivalent] followed by a taper, for grade 2 or higher pneumonitis), and/or permanent discontinuation. Monitor for signs and symptoms of pneumonitis; if pneumonitis is suspected, evaluate with radiographic imaging and administer systemic corticosteroids for grade 2 or higher pneumonitis. Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation.

Immune-mediated hyperthyroidism, hypothyroidism, and thyroiditis have occurred. The median onset for hyperthyroidism was 1.4 months (range: 1 day to ~22 months) and the median duration was 2.1 months (range: 3 days to over 15 months). Hyperthyroidism resolved in nearly three-fourths of affected patients. Hypothyroidism occurred with a median onset of 3.5 months (range: 1 day to 19 months) and median duration was not reached (range: 2 days to over 27 months). Hypothyroidism resolved in one-fifth of affected patients. The incidence of new or worsening hypothyroidism was higher in patients with squamous cell cancer of the head and neck. Monitor for changes in thyroid function (at baseline, periodically during treatment, and as clinically indicated) and for signs/symptoms of thyroid disorders. Administer thionamides and beta-blockers for hyperthyroidism as appropriate; may require treatment interruption and/or permanent discontinuation. Isolated hypothyroidism may be managed with replacement therapy. Thyroiditis occurred with a median onset of 1.2 months (range 0.5 to 3.5 months).

Other clinically relevant immune-mediated disorders have been observed (may involve any organ system), including rash, exfoliative dermatitis, bullous pemphigoid, uveitis, arthritis, vasculitis, myositis, Guillain-Barré syndrome, pancreatitis, hemolytic anemia, serum sickness, myasthenia gravis, myelitis, myocarditis, and partial seizures (in a patient with inflammatory foci in brain parenchyma). If an immune-mediated adverse event is suspected, evaluate appropriately to confirm or exclude other causes; withhold treatment and administer systemic corticosteroids based on severity of reaction. Upon resolution to grade 0 or 1, initiate corticosteroid taper (continue tapering over at least 1 month). When reaction remains at grade 1 or less during taper may reinitiate pembrolizumab. Immune-mediated adverse reactions that do not resolve with systemic corticosteroids may be managed with other systemic immunosuppressants (based on limited data). Discontinue permanently for severe or grade 3 immune-mediated adverse event that is recurrent or life-threatening. Disease-related concerns:

Anti-PD-1 monoclonal antibodies generate an immune response that may aggravate underlying autoimmune disorders or prior immune-related adverse events. A retrospective study analyzed the safety and efficacy of treatment with anti-PD-1 monoclonal antibodies (eg, pembrolizumab, nivolumab) in melanoma patients with preexisting autoimmune disease or prior significant ipilimumab-mediated adverse immune events. Results showed that while immune toxicities associated with this class of therapy did occur, most reactions were mild and easily manageable and did not require permanent drug therapy discontinuation. A significant percentage of patients achieved clinical response with anti-PD-1 monoclonal antibody therapy, despite baseline autoimmunity or prior ipilimumab-related adverse events (Menzies 2017).

Patients who received allogeneic hematopoietic stem cell transplant (HSCT) following discontinuation of pembrolizumab therapy experienced immune-mediated complications (some fatal) including graft versus host disease (GVHD) and severe sinusoidal obstructive syndrome (SOS; formerly called veno-occlusive disease) following reduced-intensity conditioning. Fatal hyperacute GVHD post HSCT has also been reported in lymphoma patients who received an anti PD-1 antibody prior to transplant. These complications may occur despite intervening therapy between pembrolizumab and HSCT. Monitor closely for early signs/symptoms of transplant-related complications (eg, hyperacute GVHD, severe [grade 3 to 4] acute GVHD, steroid-requiring febrile syndrome, SOS, and other immune-mediated adverse reactions) and manage promptly.

An increase in mortality was noted in 2 clinical studies in patients with multiple myeloma who received pembrolizumab in combination with a thalidomide analogue and dexamethasone. Causes of death in the experimental arm (containing pembrolizumab, dexamethasone, and a thalidomide analogue [pomalidomide or lenalidomide]) included myocarditis, Stevens-Johnson syndrome, MI, pericardial hemorrhage, cardiac failure, respiratory tract infection, neutropenic sepsis, sepsis, multiple organ dysfunction, respiratory failure, intestinal ischemia, cardiopulmonary arrest, suicide, pulmonary embolism, cardiac arrest, pneumonia, sudden death, and large intestine perforation. Multiple myeloma is not an approved indication for PD-1 or PD-L1 blocking antibodies; pembrolizumab should not be used to treat multiple myeloma in combination with a thalidomide analogue and dexamethasone unless as part of a clinical trial.

Solid organ transplant rejection has been reported in postmarketing surveillance. Pembrolizumab may increase the risk of rejection; consider benefit versus risk of pembrolizumab treatment in solid organ transplant patients. Other warnings/precautions:

Select patients for metastatic gastric cancer and non-small cell lung cancer (NSCLC) single agent treatment based on PD-L1 expression. If PD-L1 expression is not detected in a gastric cancer archived specimen, evaluate feasibility of obtaining a tumor biopsy to test for PD-L1 expression. Information on tests to detect PD-L1 expression in gastric cancer or NSCLC may be found at http://www.fda.gov/companiondiagnostics.