FDA Approves Keytruda Regimens to Treat Head and Neck Squamous Cell Carcinoma

The Food and Drug Administration approved Keytruda (pembrolizumab) monotherapy and in combination with chemotherapy for the front-line treatments of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma, according to Merck — the drug’s manufacturer.

In particular, the approval for the monotherapy is indicated for patients with a composite positive score for PD-L1 expression of one or more, and the combination with platinum and fluorouracil (FU) for this patient population was irrespective of PD-L1 expression.

"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," Dr. Barbara Burtness, professor of medicine at Yale School of Medicine and co-director of the Development Therapeutics Research Program at Yale Cancer Center, said in a press release. "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."

The agency based its approval on findings from the open-label, randomized phase 3 KEYNOTE-048 trial — designed to evaluate whether Keytruda could prolong survival and slow disease progression compared with the EXTREME regimen (platinum-based chemotherapy with cisplatin or carboplatin, 5-FU, and Erbitux [cetuximab]) in the recurrent or metastatic setting.

In total, 882 patients were randomized to receive either standard EXTREME treatment (300 patients), single-agent Keytruda (301 patients) and Keytruda plus platinum-based chemotherapy with 5-FU (281 patients). Treatment was administered until unacceptable toxicity or progressive disease.

The primary endpoints were progression-free survival and overall survival in patients whose composite positive score for PD-L1 expression was 20 or more, one or more and in all patients enrolled. The data cutoff date was June 13, 2018, with a minimum follow-up of 17 months.

Single-agent Keytruda led to a 22% reduction in the risk of disease progression or death compared with the standard EXTREME regimen in patients with PD-L1—positive tumors. When in combination with chemotherapy the PD-1 inhibitor led to a 23% reduction in the risk of disease progression or death.

In patients with a composite positive score for PD-L1 expression of 20 or more, the median overall survival was 14.9 months compared with 10.7 months in those who received Keytruda alone versus EXTREME respectively, and the two-year overall survival rate was 38% versus 22%. There was no difference in progression-free survival between the two arms.

In addition, the overall response rates were 23.3% and 36.1% with Keytruda and standard therapy, respectively; however, the median duration of response was longer with the PD-1 inhibitor at 20.9 months versus 4.5 months.

For those with a composite positive score for PD-L1 expression of one or more, the median overall survival for Keytruda monotherapy compared with EXTREME was 12.3 months versus 10.3 months, respectively, and the two-year overall survival rates were 30% versus 19%.

The overall response rate was 19.1% with Keytruda and 34.9% with standard therapy; however, the median duration of response was again longer with Keytruda at 20.9 months and 4.5 months, respectively. Again, there was no difference in progression-free survival between the two groups.

Keytruda was well tolerated with a safety profile that was consistent with prior studies. The rates of grade 3 to 5 treatment-related side effects were 17% for those treated with Keytruda monotherapy, 69% for patients who received standard treatment and 71% for those in the Keytruda/chemotherapy arm.

"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," Dr. Jonathan Cheng, vice president of clinical research at Merck Research Laboratories, said in the release.

"This approval is an important advance in the management of this devastating cancer,” he added. “The results of KEYNOTE-048, which support this approval, demonstrated that Keytruda monotherapy for patients whose tumors expressed PD-L1 (composite positive score) 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."