FDA Approves Keytruda for Metastatic or Recurrent Head and Neck Cancer

The U.S. Food and Drug Administration (FDA) has approved Keytruda (pembrolizumab) as a first-line therapy for patients with metastatic or recurrent and inoperable head and neck squamous cell carcinoma (HNSCC) whose tumors express the PD-L1 factor.

It also approved the treatment in combination with platinum chemotherapy — cisplatin or carboplatin — and fluorouracil regardless 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,” Barbara Burtness, professor of medicine at the Yale School of Medicine and co-director of the development therapeutics research program at the 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,” she added.

Keytruda is a checkpoint blockade immunotherapy, developed by Merck (known as MSD outside the U.S. and Canada), that works by targeting the PD-1 receptor, a protein found on the surface of immune cells, and preventing it from binding to another protein called PD-L1, produced by cancer cells to avoiding being killed by immune cells.

The approval — given under priority review — was based on data from the randomized, open-label KEYNOTE-048 Phase 3 trial (NCT02358031). That trial compared Keytruda alone, and Keytruda plus chemotherapy, to the EXTREME regimen — a standard of care treatment composed of platinum chemotherapy, fluorouracil, and Erbitux (cetuximab).

The trial included 882 patients with head and neck squamous cancer who had not received prior systemic therapy for relapsed or metastatic disease.

Its primary goals were overall survival and time to cancer progression or death, in the group of patients whose tumors produce PD-L1 — corresponding to a combined positive score (CPS) greater than 1 — and in all participants regardless of PD-L1 presence.

Researchers found that Keytruda extended the lives of patients producing the PD-L1 factor — particularly of those with high PD-L1 levels, measured as a CPS of 20 or higher — from 10.3 months to a median of 12.3 months. This corresponded to a reduction in the risk of death by 22%.

The rate of responses was lower with Keytruda (19%) than with chemo (35%), but its median duration was longer — 20.9 months versus 4.5 months — and more patients achieved a complete response (5% vs. 3%).

Keytruda also led to a non-inferior overall survival rate in the global population, regardless of PD-L1 expression. However, no statistically significant differences were found in the time people lived without their disease worsening between the Keytruda and chemo groups.

When given in combination with chemotherapy, Keytruda also extended participans’ lives, from 10.7 months to 13.0 months, reducing the risk of death by 33%. But survival results were particularly better among patients producing any level of the PD-L1 factor, who saw a 35% reduction in risk of death, and in those with high levels of the factor, who had a 40% reduction.

In the global population, response rates were similar among participants receiving the combination and chemo (36% in both groups), but more patients achieved a complete response — 6% versus 3%. Responses also were somewhat longer in the combination (6.7 months) than for chemo only (4.3 months).

Again, no significant differences were seen in the time patients lived without disease worsening.

Keytruda was discontinued due to adverse reactions in 12% of those given only the medication, and in 16% of those receiving the combination. The most common side effects resulting in discontinuation were sepsis, lung inflammation, and septic shock.

Other side effects resulting in treatment interruption were low levels of some cells of the immune system, lung inflammation, and low sodium concentration in the blood.

“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, vice president of clinical research at the 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 (combined 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,” Cheng said.

Ketruda was granted accelerated approval by the FDA in 2016 for the treatment of patients with HNSCC.