On June 17, 2019, pembrolizumab was granted accelerated approval for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.^1,2

Supporting Efficacy Data

Approval was based on findings in 83 patients in cohorts from two multicenter, multicohort, open-label studies—KEYNOTE-158 (ClinicalTrials.gov identifier NCT02628067) and KEYNOTE-028 (NCT02054806).² Patients received either pembrolizumab at 200 mg every 3 weeks (n = 64) or 10 mg/kg every 2 weeks (n = 19), with treatment continued until disease progression, unacceptable toxicity, or a maximum of 24 months. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible.

Patients had a median age of 62 years (range = 24–84 years; 40% aged ≥ 65 years); 64% were male; 63% were white and25% were Asian; 99% had an Eastern Cooperative Oncology Group performance status of 0 (30%) or 1 (69%); 7% had M0 disease and 93% had M1 disease; 16% had a history of brain metastases; 64% received two prior lines of therapy and 36% received three or more lines of therapy; 60% received prior thoracic radiation therapy; and 51% received prior radiation therapy to the brain.

The objective response rate on blinded independent central review using modified Response Evaluation Criteria in Solid Tumors, version 1.1, was 19%, with complete response in 2%. Among 16 responders, response duration was ≥ 6 months in 94%, ≥ 12 months in 63%, and ≥ 18 months in 56%.

How It Works

Binding of programmed cell death ligands 1 and 2 (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-1 ligands 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

In metastatic SCLC, the recommended dose of pembrolizumab is 200 mg via intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

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; immune-mediated colitis; immune-mediated hepatitis in patients with and without hepatocellular carcinoma; immune-mediated endocrinopathies; immune-mediated nephritis; immune-mediated skin adverse reactions; hematologic toxicity in patients with classical Hodgkin lymphoma orprimary mediastinal large B-cell lymphoma; other immune-mediated adverse reactions; recurrent immune-mediated adverse reactions; inability to taper corticosteroid treatment; and persistent grade 2 or 3 adverse reactions (excluding endocrinopathy).

Safety Profile

The most common adverse events of any grade (reported in ≥ 20% of patients) in clinical trials of pembrolizumab as a single agent have been fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.

Safety was evaluated in a total of 131 patients with previously treated SCLC who received pembrolizumab in KEYNOTE-158 (n = 107) and KEYNOTE-028 (n = 24). Adverse events were similar to those occurring in patients with other solid tumors who received pembrolizumab. Common adverse events of any grade reported in ≥ 20% of patients included fatigue, decreased appetite, cough, nausea, and constipation. Adverse events led to dose interruption in 25% and permanent treatment discontinuation in 9%. Serious adverse events occurred in 31% of patients, with the most common (≥ 2%) being pneumonia and pleural effusion.

Pembrolizumab carries 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; 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 during pembrolizumab therapy. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves pembrolizumab for metastatic small cell lung cancer. Available at www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-metastatic-small-cell-lung-cancer. Accessed July 24, 2019.

2. U.S. Food and Drug Administration: Keytruda (pembrolizumab) for injection, for intravenous use. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514s053lbl.pdf. Accessed July 24, 2019.