FDA Approves Pembrolizumab Regimens for HNSCC

The FDA approved pembrolizumab (Keytruda) alone or in combination with platinum 5-fluorouacil (5-FU) chemotherapy for the frontline treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) whose tumors are PD-L1 positive with a combined positive score (CPS) ≥1 according to Merck, the manufacturer of the immunotherapy agent.

The approval was based off findings from the phase III KEYNOTE-048 trial, where single-agent pembrolizumab led to a significant improvement in overall survival (OS) compared to standard chemotherapy for patients whose tumors were PD-L1 positive with a CPS ≥20 and CPS ≥1. The immunotherapy agent also improved OS in the general population, too.

“This approval is a very exciting milestone in the treatment of head and neck cancer and has the potential to transform the way we treat patients with this debilitating disease by offering important new therapeutic options,” said Barbara Burtness, MD, professor of medicine, Yale School of Medicine and co-director, Development Therapeutics Research Program, Yale Cancer Center, in a statement. “Metastatic or recurrent head and neck cancer has been an area of significant unmet need, so it is encouraging to have immunotherapy regimens available for patients in the first-line setting.”

In the trial, single-agent pembrolizumab led to a 22% reduction in the risk of disease progression or death compared with the standard EXTREME regimen, which comprises cetuximab (Erbitux) with carboplatin or cisplatin plus 5-FU, in patients with PD-L1—positive tumors (HR, 0.78; 95% CI, 0.64-0.96; P = .0171). When in combination with chemotherapy in the overall KEYNOTE-048 population, the PD-1 inhibitor led to a 23% reduction in the risk of disease progression or death (HR, 0.77; 95% CI, 0.63-0.93; P = .0067).

Patients enrolled on KEYNOTE-048 had squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx. They did not have prior chemotherapy or systemic therapy, had a good ECOG performance status and tissue available for PD-L1 testing. Participants were stratified by PD-L1 expression, p16 status, and ECOG performance status.

Each patient was randomized to one of the following arms:

• 200 mg of pembrolizumab every 3 weeks;
• 200 mg of pembrolizumab every 3 weeks, and carboplatin AUC 5 mg/mL/min every 3 weeks or 100 mg/m² every 3 weeks and 1,000 mg/m² of FU a day as a continuous IV infusion over 96 hours every 3 weeks; or
• 400 mg/m²/day of cetuximab as the initial dose, then 250 mg/m² once weekly, carboplatin AUC 5mg/mL/min IV every 3 weeks or 100 mg/m² every 3 weeks or 100 mg/m² every 3 weeks and 1,000 mg/m²/day of FU as a continuous intravenous infusion over 96 hours every three weeks (maximum of six cycles of platinum and FU)

Overall, pembrolizumab was well tolerated. The combination of pembrolizumab and chemotherapy had a comparable safety profile to EXTREME. The rates of grade 3 to 5 treatment-related adverse events (TRAEs) were 17% for those treated with pembrolizumab monotherapy and 69% for patients who received standard treatment. In the pembrolizumab/chemotherapy group, the rate of grade 3 to 5 TRAEs was 71%.

“Head and neck squamous cell carcinoma has historically presented many challenges to physicians and patients, including limited treatment options and physical and functional issues caused by the disease and its treatment,” said Jonathan Cheng, MD, vice president, clinical research, Merck Research Laboratories. “This approval is an important advance in the management of this devastating cancer. The results of KEYNOTE-048, which support this approval, demonstrated that Keytruda monotherapy for patients whose tumors expressed PD-L1 CPS greater than or equal to one and Keytruda in combination with chemotherapy regardless of PD-L1 expression significantly prolonged survival for patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma in the first-line setting.”

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