KEYTRUDA(R) (pembrolizumab): Additional Indication
Merck is pleased to announce that KEYTRUDA has been approved by the FDA for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
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PD-L1 diagnostic testing is not required prior to initiating treatment with KEYTRUDA in these patients |
FDA=Food and Drug Administration; PD-L1=programmed death ligand 1.
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Selected Safety Information for KEYTRUDA® (pembrolizumab) injection 100 mg |
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Immune-mediated adverse reactions, which may be severe or fatal, can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered if appropriate. For more information regarding immune-mediated adverse reactions, please read the additional Selected Safety Information below. |
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KEYNOTE-028/KEYNOTE-158
Third-line or Greater Treatment of SCLC
The efficacy of KEYTRUDA was investigated in 83 patients with SCLC who had disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy enrolled in one of two multicenter, multi-cohort, non-randomized, open label trials: KEYNOTE-028 (NCT02054806), Cohort C1, or KEYNOTE-158 (NCT02628067), Cohort G. The trials excluded patients with autoimmune disease or a medical condition that required immunosuppression.
Patients received either KEYTRUDA 200 mg intravenously every 3 weeks (n=64) or 10 mg/kg intravenously every 2 weeks (n=19). Treatment with KEYTRUDA continued until documented disease progression, unacceptable toxicity, or a maximum of 24 months. Patients with initial radiographic disease progression could receive additional doses of KEYTRUDA during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status.
Assessment of tumor status was performed every 8 weeks for the first 6 months in KEYNOTE-028, every 9 weeks for the first 12 months in KEYNOTE-158, and every 12 weeks thereafter for both studies. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR) as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
The study population characteristics were: median age of 62 years (range: 24 to 84); 40% age 65 or older; 64% male; 63% White, 25% Asian, and 2% Black; 30% Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 and 69% ECOG PS of 1; 7% had M0 disease and 93% had M1 disease; and 16% had a history of brain metastases. Sixty-four percent received two prior lines of therapy and 36% received three or more lines of therapy; 60% received prior thoracic radiation therapy; 51% received prior radiation therapy to the brain.
Efficacy results are summarized below.
Efficacy Results in Patients with Small Cell Lung Cancer
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Endpoint |
KEYTRUDA n=83 |
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Objective response rate |
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ORR (95% CI) |
19% (11, 29) |
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Complete response rate |
2% |
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Partial response rate |
17% |
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Duration of Response |
n=16 |
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Range (months) |
4.1, 35.8+ |
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% with duration ≥6 months |
94% |
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% with duration ≥12 months |
63% |
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% with duration ≥18 months |
56% |
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+Denotes ongoing response |
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CI=confidence interval. |
Recommended Dosage for SCLC
The recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Selected Safety Information for KEYTRUDA® (pembrolizumab) injection 100 mg (continued)
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Immune-Mediated Pneumonitis |
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KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 8.2% (65/790) of non–small cell lung cancer (NSCLC) patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis. |
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Immune-Mediated Colitis |
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KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis. |
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Immune-Mediated Hepatitis |
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KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA. |
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Immune-Mediated Endocrinopathies |
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KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients. |
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Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid function (prior to and periodically during treatment), and hyperglycemia. For hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia. |
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Immune-Mediated Nephritis and Renal Dysfunction |
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KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis. |
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Immune-Mediated Skin Reactions |
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Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA. |
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Other Immune-Mediated Adverse Reactions |
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Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction. |
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The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use. |
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Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients. |
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Infusion-Related Reactions |
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KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA. |
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Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) |
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Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions. |
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In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients. |
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Increased Mortality in Patients With Multiple Myeloma |
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In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a programmed death receptor-1 (PD-1) or PD-L1 blocking antibody in this combination is not recommended outside of controlled trials |
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Embryofetal Toxicity |
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Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose. |
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Adverse Reactions |
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The most common adverse reactions for KEYTRUDA (reported in ≥20% of patients) were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. |
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Lactation |
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Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the final dose. |
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Before prescribing KEYTRUDA® (pembrolizumab), please read the Prescribing Information.
The Medication Guide also is available.
