Late in 2018, pembrolizumab was granted accelerated approval in the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma.1,2
Supporting Efficacy Data
Approval was based on Cancer Immunotherapy Trials Network protocol 9 (CITN-09), also known as KEYNOTE-017 (ClinicalTrials.gov identifier NCT02267603),2 a multicenter, open-label trial that enrolled 50 patients with recurrent locally advanced or metastatic Merkel cell carcinoma who had not received prior systemic therapy for advanced disease. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible for the trial. Patients received pembrolizumab at 2 mg/kg every 3 weeks. The major efficacy outcome measures were overall response rate and response duration, assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors version 1.1.
Among the 50 patients, the median age was 71 years (with 80% at least 65 years), 68% were male, 90% were white, all had an Eastern Cooperative Oncology Group performance status of 0 or 1, 14% had stage IIIB disease and 86% had stage IV disease, and 84% had prior surgery and 70% had prior radiation therapy.
The overall response rate was 56%, with a complete response observed in 24% of patients. The median response duration was not reached (range = 5.9 to 34.5+ months). Among the 28 patients with responses, 96% had a response duration of more than 6 months, and 54% had a response duration of more than 12 months.
How It Works
Binding of programmed cell death ligand 1 (PD-L1) and PD-L2 to the programmed cell death protein 1 (PD-1) receptor found on T cells inhibits T-cell proliferation and cytokine production. Pembrolizumab is an anti–PD-1 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response. Upregulation of PD-L1/PD-L2 is observed in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance. In syngeneic mouse models, inhibition of PD-1 activity resulted in decreased tumor growth.
How It Is Used
The recommended dose of pembrolizumab in Merkel cell carcinoma is 200 mg every 3 weeks for adults and 2 mg/kg (up to 200 mg) every 3 weeks for pediatric patients; it is given as an intravenous infusion over 30 minutes. Treatment should continue until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
No dose reductions in pembrolizumab are recommended. Treatment should be withheld or discontinued to manage adverse reactions. Pembrolizumab infusion should be interrupted or slowed for grade 1 or 2 infusion-related reactions and permanently discontinued for grade 3 or 4 reactions. Specific management guidelines for immune-mediated adverse events are provided in the product labeling.
Pembrolizumab treatment should be withheld for the following, primarily immune-mediated, adverse reactions: grade 2 pneumonitis; grade 2 or 3 colitis; immune-mediated hepatitis in patients with hepatocellular carcinoma and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal (ULN) if baseline up to 2 times ULN, AST or ALT > 3 times baseline if baseline ≥ 2 times ULN, total bilirubin > 2.0 mg/dL if baseline less than 1.5 mg/dL, or total bilirubin > 3.0 mg/dL regardless of baseline level; immune-mediated hepatitis in patients without hepatocellular carcinoma with AST or ALT greater than 3 but no more than 5 ULN or total bilirubin greater than 1.5 but no more than 3 times ULN: grade 3 or 4 endocrinopathies; grade 4 hematologic toxicity in patients with classical Hodgkin lymphoma or primary mediastinal large B-cell lymphoma; grade 2 nephritis; grade 3 skin reactions or suspected Stevens-Johnson syndrome or toxic epidermal necrolysis; and any other grade 2 or 3 immune-mediated adverse reaction, based on severity and type. Treatment can be resumed when adverse reactions recover to grade 0 or 1.
Adverse reactions for which pembrolizumab should be permanently discontinued include grade 3 or 4 or recurrent grade 2 pneumonitis; grade 4 colitis; among patients with hepatocellular carcinoma who have immune-related hepatitis, ALT or AST > 10 times ULN, Child-Pugh score ≥ 9, gastrointestinal bleeding suggestive of portal hypertension, new onset of clinically detectable ascites, or encephalopathy; among patients with immune-mediated hepatitis without hepatocellular carcinoma and in patients without liver metastases, AST or ALT > 5 times ULN or total bilirubin > 3 times ULN; or in patients with liver metastasis and grade 2 AST or ALT at baseline, an increase in AST or ALT of 50% or more relative to baseline that persists for at least 1 week; grade 3 or 4 nephritis; grade 4 skin reactions or confirmed Stevens-Johnson syndrome or toxic epidermal necrolysis; other immune-mediated reactions of grade 3 based on the severity and type of reaction or grade 4 reactions; recurrent immune-mediated adverse reactions including recurrent grade 2 pneumonitis and other recurrent grade 3 or 4 events; inability to taper corticosteroid treatment; and persistent grade 2 or 3 adverse reactions (excluding endocrinopathy).
The most common adverse events reported in at least 20% of patients who received pembrolizumab as a single agent in clinical trials were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Among the 50 patients with Merkel cell carcinoma enrolled in KEYNOTE-017, the median duration of exposure to pembrolizumab was 6.6 months. Adverse events in patients with Merkel cell carcinoma were similar to those in patients with melanoma or non–small cell lung cancer. Grade 3 or 4 laboratory abnormalities that occurred at a higher incidence in patients with Merkel cell carcinoma were elevated AST (11%) and hyperglycemia (19%).
Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies (including hypophysitis, thyroid disorders, and type 1 diabetes), nephritis, skin adverse reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; and embryofetal toxicity. Treatment of patients with multiple myeloma with a PD-1– or PD-L1–blocking antibody in combination with a thalidomide analog plus dexamethasone is not recommended outside of controlled clinical trials. Patients should be monitored for hepatic, renal, and thyroid function as well as for hyperglycemia. Patients should be advised not to breastfeed while receiving pembrolizumab.■
1. U.S. Food and Drug Administration: FDA approves pembrolizumab for Merkel cell carcinoma. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm628867.htm. Accessed July 24, 2019.
2. Pembrolizumab (Keytruda) injection for intravenous use prescribing information. Merck and Co. December 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/125514s045lbl.pdf. Accessed July 24, 2019.