On June 10, 2019, pembrolizumab was approved for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma.^1,2

Pembrolizumab was approved for use in combination with platinum and fluorouracil (5-FU) for all patients and as a single agent for patients with tumors expressing programmed cell death ligand 1 (PD-L1; Combined Positive Score [CPS] ≥1) as determined by a U.S. Food and Drug Administration (FDA)-approved test. The FDA also expanded the intended use for the PD-L1 IHC 22C3 pharmDx kit to include use as a companion diagnostic device for selecting patients with head and neck squamous cell carcinoma for treatment with pembrolizumab as a single agent.

Supporting Efficacy Data

Approval was based on findings in the phase III open-label KEYNOTE-048 trial (ClinicalTrials.gov identifier NCT02358031).² In the trial, 882 patients with metastatic head and neck squamous cell carcinoma who had not previously received systemic therapy for metastatic disease or with recurrent disease who were considered incurable by local therapies were randomly assigned 1:1:1 to receive pembrolizumab monotherapy (n = 300); pembrolizumab, carboplatin or cisplatin, and 5-FU (n = 276); or cetuximab, carboplatin or cisplatin, and 5-FU (n = 287). Overall survival, the major efficacy measure, was sequentially tested in the subgroup of patients with CPS ≥ 20, the subgroup with CPS ≥ 1, and the overall population.

In the overall population, median overall survival was 13.0 months in the pembrolizumab-plus-chemotherapy group vs 10.7 months in the cetuximab-plus-chemotherapy group (hazard ratio [HR] = 0.77, P = .0067) in a prespecified interim analysis. Results were similar in the CPS ≥ 20 subgroup (HR = 0.69, 95% confidence interval [CI] = 0.51–0.94) and the CPS ≥ 1 subgroup (HR = 0.71, 95% CI = 0.57–0.88).

For pembrolizumab monotherapy vs cetuximab plus chemotherapy, median overall survival was 12.3 months vs 10.3 months in the CPS ≥ 1 subgroup (HR = 0.78, P = .0171) and 14.9 months vs 10.7 months in the CPS ≥ 20 subgroup (HR = 0.61, P = .0015). No significant difference between the groups was observed among the total population. Also, no significant differences in progression-free survival were observed for either pembrolizumab-containing group compared with the cetuximab-plus-chemotherapy group in any population.

How It Works

Binding of 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 head and neck squamous cell carcinoma, the recommended dose of pembrolizumab 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. When pembrolizumab is given in combination with chemotherapy, pembrolizumab should be administered prior to chemotherapy when given on the same day. Prescribing information for the chemotherapy agents administered in combination with pembrolizumab should be consulted for recommended dosing information.

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 the 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 or  primary 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 single-agent pembrolizumab have been fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. The most common adverse events (≥ 20%) in clinical trials of pembrolizumab with chemotherapy have been fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, and stomatitis.

In the KEYNOTE-048 trial, the most common grade 3 or 4 adverse events were pneumonia and fatigue with single-agent pembrolizumab and pneumonia and fatigue with pembrolizumab plus chemotherapy. The most common grade 3 or 4 laboratory abnormalities were lymphopenia with single-agent pembrolizumab and lymphopenia and neutropenia with pembrolizumab plus chemotherapy. Adverse events led to discontinuation of pembrolizumab in the monotherapy arm in 12% of patients. Adverse events led to discontinuation of pembrolizumab in the combination group in 16% of patients.

Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis; immune-mediated colitis; immune-mediated hepatitis (and hepatotoxicity in combination with axitinib); immune-mediated endocrinopathies; 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. Patients should be monitored for hepatic, renal, and thyroid function and for hyperglycemia. Patients should be advised not to breastfeed while receiving pembrolizumab. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves pembrolizumab for first-line treatment of head and neck squamous cell carcinoma. Available at www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-first-line-treatment-head-and-neck-squamous-cell-carcinoma. Accessed August 26, 2019.

2. Keytruda (pembrolizumab) for injection, for intravenous use, Merck & Co, June 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514s052lbl.pdf. Accessed August 26, 2019.