On June 10, the U.S. Food and Drug Administration (FDA) approved the anti–programmed cell death protein 1 immunotherapy pembrolizumab (Keytruda) for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma. Pembrolizumab was approved for use in combination with platinum and fluorouracil (5-FU) for all patients, and as a single agent for patients whose tumors express programmed cell death ligand 1 (PD-L1; combined positive score [CPS] ≥ 1) as determined by an 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.
Approval was based on KEYNOTE-048, a randomized, multicenter, three-arm, open-label, active-controlled trial conducted in 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.
Patients were randomly assigned 1:1:1 to receive one of the following treatments: pembrolizumab as a single agent; pembrolizumab, carboplatin or cisplatin, and 5-FU; or cetuximab, carboplatin or cisplatin, and 5-FU. Randomization was stratified by tumor PD-L1 expression (tumor proportion score [TPS] ≥ 50% or < 50%), human papillomavirus status according to p16 IHC (positive or negative), and ECOG performance status (0 vs 1). PD-L1 expression (TPS and CPS) was determined using the PD-L1 IHC 22C3 pharmDx kit.
Overall survival—sequentially tested in the subgroup of patients with a CPS ≥ 20 head and neck squamous cell carcinoma, the subgroup of patients with a CPS ≥ 1 head and neck squamous cell carcinoma, and the overall population—was the major efficacy measure.
The trial demonstrated a statistically significant improvement in overall survival in the overall population for patients who received pembrolizumab plus chemotherapy compared with cetuximab plus chemotherapy at a prespecified interim analysis. The median overall survival was 13.0 months for the pembrolizumab plus chemotherapy arm and 10.7 months for the cetuximab plus chemotherapy arm (hazard ratio [HR] = 0.77; 95% confidence interval [CI] = 0.63–0.93; P = .0067). Results were similar in the CPS ≥ 20 (HR = 0.69; 95% CI = 0.51–0.94) and CPS ≥ 1 subgroups (HR = 0.71; 95% CI = 0.57–0.88).
The trial also demonstrated statistically significant improvements in overall survival for the subgroups of patients with PD-L1 CPS ≥ 1 and PD-L1 CPS ≥ 20 head and neck squamous cell carcinoma who were randomly assigned to pembrolizumab as a single agent compared with cetuximab plus chemotherapy. In the CPS ≥ 1 subgroup, the median overall survival was 12.3 months for the pembrolizumab arm and 10.3 months for the cetuximab-plus-chemotherapy arm (HR = 0.78; 95% CI = 0.64–0.96; P = .0171). For the CPS ≥ 20 subgroup, the median overall survival was 14.9 months for the pembrolizumab arm and 10.7 months for the cetuximab plus chemotherapy arm (HR = 0.61; 95% CI = 0.45–0.83; P = .0015). At the time of the interim analysis, there was no significant difference in overall survival between the single-agent pembrolizumab arm and the cetuximab-plus-chemotherapy arm for the overall population.
There were no significant differences in progression-free survival for either pembrolizumab-containing arm compared with the cetuximab-plus-chemotherapy arm in any population.
The most common adverse reactions reported in at least 20% of patients who received pembrolizumab as a single agent in KEYNOTE-048 were fatigue, constipation, and rash. The most common adverse reactions reported in at least 20% of patients who received pembrolizumab in combination with chemotherapy were nausea, fatigue, constipation, vomiting, mucosal inflammation, diarrhea, decreased appetite, stomatitis, and cough.
The recommended pembrolizumab dose for head and neck squamous cell carcinoma 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. ■