On June 24, 2020, pembrolizumab was approved for treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma that is not curable by surgery or radiation.1,2
Supporting Efficacy Data
Approval was based on findings in the multicenter, multicohort, open-label KEYNOTE-629 trial (Clinical Trials.gov identifier NCT03284424).2 The trial excluded patients who had previously received therapy with a PD-1, PD-L1, or anti–CTLA-4 antibody and those with autoimmune disease or a medical condition that required immunosuppression. A total of 105 patients received pembrolizumab at 200 mg intravenously (IV) every 3 weeks until disease progression, unacceptable toxicity, or a maximum of 24 months. Assessment of tumor status was performed every 6 weeks during the first year and every 9 weeks during the second year.
Pembrolizumab has warnings/precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation before and after pembrolizumab treatment, and embryofetal toxicity.
Median patient age was 72 years (range = 29–95 years; 71% ≥ 65 years), 76% were male, 71% were White and 25% were of unknown race, and all had an Eastern Cooperative Oncology Group performance status of 0 (34%) or 1. Overall, 45% had locally recurrent cutaneous squamous cell carcinoma alone, 24% had metastatic cutaneous squamous cell carcinoma alone, and 31% had both locally recurrent and metastatic cutaneous squamous cell carcinoma; 87% had received one or more prior lines of therapy; and 74% had received prior radiation therapy.
The major efficacy outcome measures were objective response rate and response duration as assessed by blinded independent central review according to Response Evaluation Criteria in Solid Tumors version 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
An objective response was observed in 36 patients (34%, 95% confidence interval = 24%–44%), with a complete response in 4% of patients. A median response duration was not reached (range = 2.7 to 13.1+ months), with 69% of responders having a response of at least 6 months.
How It Works
Binding of PD-L1 and PD-L2 to the PD-1 receptor found on T cells inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands is observed in some tumors and signaling through this pathway can contribute to the inhibition of active T-cell tumor immune surveillance. 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 ligands, thereby releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response. In syngeneic mouse models, inhibition of PD-1 activity resulted in decreased tumor growth.
How It Is Used
In the current indication, the recommended dose of pembrolizumab is 200 mg every 3 weeks or 400 mg every 6 weeks via 30-minute IV infusion, with treatment continued until disease progression, unacceptable toxicity, or for up to 24 months. Determination of the efficacy and safety of pembrolizumab at a dosage of 400 mg every 6 weeks for cutaneous squamous cell carcinoma is primarily based on the modeling of dose/exposure efficacy and safety relationships and observed pharmacokinetic data in patients with melanoma.
No dose reductions of 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 warnings/precautions section of product labeling.
Product labeling provides recommended dosing modifications—including withholding, resuming, and discontinuing treatment—for the following adverse reactions: immune-mediated pneumonitis, colitis, hepatitis (in patients with and without hepatocellular carcinoma); endocrinopathies, nephritis, skin adverse reactions, and other immune-mediated adverse reactions; liver enzyme elevations in patients with renal cell carcinoma receiving combination therapy; hematologic toxicity in patients with classical Hodgkin lymphoma or primary mediastinal large B-cell lymphoma; inability to taper corticosteroid treatment; persistent grade 2 or 3 adverse reactions (excluding endocrinopathy); and infusion-related reactions.
Among the 105 patients with cutaneous squamous cell carcinoma receiving pembrolizumab in the KEYNOTE-629 trial, the median duration of exposure to treatment was 5.8 months (range = 1 day to 16.1 months). Product labeling provides no specific data on adverse events or laboratory abnormalities in the cutaneous squamous cell carcinoma population. It states that adverse reactions occurring in patients with cutaneous squamous cell carcinoma were similar to those occurring in 2,799 patients with melanoma or non–small cell lung cancer treated with pembrolizumab as a single agent. Grade 3 or 4 laboratory abnormalities that occurred at a higher incidence included lymphopenia (11%).
The most common adverse events of any grade (at least 20% of patients) observed with the administration of pembrolizumab as a single agent in clinical trials have been fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions.
Pembrolizumab has warnings/precautions for immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis (and hepatotoxicity in combination with axitinib), immune-mediated endocrinopathies (including hypophysitis, thyroid disorders, and type 1 diabetes), immune-mediated nephritis, immune-mediated skin adverse reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis) and other immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation before and after pembrolizumab treatment, 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 and for hyperglycemia. Patients should be advised not to breastfeed while receiving pembrolizumab.
1. U.S. Food and Drug Administration: FDA approves pembrolizumab for cutaneous squamous cell carcinoma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab--cutaneous-squamous-cell-carcinoma. Accessed July 23, 2020.
2. U.S. Food and Drug Administration: Highlights of prescribing information for Keytruda (pembrolizumab) injection, Merck & Co, June 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s092lbl.pdf. Accessed July 23, 2020.