FDA Approves Pembrolizumab for Head and Neck Cancer

Roger M. Perlmutter, MD, PhD

The FDA has granted an accelerated approval to pembrolizumab (Keytruda) as a treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) following progression on a platinum-based chemotherapy, based on objective response rates (ORR) in the phase Ib KEYNOTE-012 study.

Merck, the developer of the PD-1 inhibitor, announced the approval, which was based on an efficacy analysis of 174 patients treated with a prior platinum-based agent. In this assessment, the ORR with pembrolizumab was 16% (95% CI, 11-22), which included a complete response rate of 5%. Responses lasted for ≥6 months for 82% of patients.

Pembrolizumab was approved regardless of PD-L1 staining, and at a fixed dose of 200 mg every 3 weeks. In data from the KEYNOTE-012 presented at the 2016 ASCO Annual Meeting for 192 patients, pembrolizumab had an ORR of 18% and a stable disease rate of 17% in patients with recurrent/metastatic HNSCC.

In the KEYNOTE-012 trial, 192 total patients with recurrent/metastatic HNSCC received two doses of pembrolizumab. In the first arm, patients with PD-L1-postive HNSCC received the PD-1 inhibitor at 10-mg/kg (n = 60). In the second group, patients received pembrolizumab at 200 mg every 3 weeks regardless of PD-L1 status (n = 132).

The median age of patients was 60 years (range, 20-84), and the majority were males (83%). Overall, the median number of prior therapies was 2, with 45% having received ≥3 lines of systemic therapy. Fifty-seven percent of patients had received prior platinum therapy and cetuximab. The ECOG performance status was primarily 1 (70%) and most patients had M1 disease (88%).

At a data cutoff of April 26, 2016, 4% of patients had experienced a complete response (CR) and 14% had a partial response. Sixty percent of patients experienced a decrease in target lesion size, and 65% of responders remained on therapy. The median duration of response was not yet reached, with 71% of responses lasting 12 months.

In patients treated with a prior platinum-based agent (n = 174), the ORR was 17% (95% CI, 12-23), with a CR rate of 5% in the data presented at ASCO. In this group, 53 patients received the 10 mg/kg dose and 121 got the 200 mg dose of pembrolizumab. The median duration of response had not yet been reached and was similar across both doses of pembrolizumab.

Of the full 192 patients, those with HPV-positive disease had an ORR of 24% and in those with HPV-negative disease the response rate was 16%. There were 4 CRs in each of the HPV groups. In patients treated with prior cetuximab and platinum therapy (n = 110), the ORR was 15% (95% CI, 9-23) and the CR rate was 5%.

Median PFS was 2.0 months with pembrolizumab (95% CI, 1.9-2.1). The 6-month PFS rate was 25% and the 12-month rate was 17%. Median overall survival (OS) across evaluable patients was 8.0 months (95% CI, 6-10). The 6-month OS rate was 58%. At 12 months, 38% of patients remained alive.

Treatment-related adverse events (AEs) were experienced by 64% of the 192 patients enrolled. Grade 3/4 AEs occurred in 13% of patients. Overall, 6% of patients discontinued therapy due to treatment-related AEs. The most common treatment-related AEs were fatigue (22%), hypothyroidism (10%), rash (10%), pruritus (8%), decreased appetite (8%), pyrexia (6%), and nausea (6%). Treatment-related grade 3/4 AEs included ALT and AST increase, fatigue, decreased appetite, hyponatremia, pneumonitis, facial swelling, and hypothyroidism.

“Head and neck cancer is a complex disease that historically has been associated with high recurrence rates and poor long-term outcomes, highlighting the critical need for new treatment options,” Tanguy Seiwert, MD, associate director of the Head and Neck Cancer Program and assistant professor of medicine at The University of Chicago, said in a statement. “The approval of Keytruda for previously treated patients with recurrent or metastatic head and neck squamous cell carcinoma is an important step forward in treating this disease.”

A full approval is contingent upon confirmatory results from a larger study. Currently, the phase III KEYNOTE-040 study is comparing pembrolizumab with methotrexate, docetaxel, or cetuximab in 466 patients with recurrent or metastatic head and neck cancer. The primary completion date for this study is January 2017, and the study has fully accrued. (NCT02252042).

In a second phase III study, pembrolizumab is being explored as a frontline treatment for patients with recurrent or metastatic HNSCC. The PD-1 inhibitor is being compared with platinum-based chemotherapy plus 5-FU and cetuximab or in combination with platinum-based therapy and 5-FU. This study plans to enroll 780 patients, with an estimated primary completion date of November 2017 (NCT02358031).

Mehra R, Seiwert TY, Mahipal A, et al. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): Pooled analyses after long-term follow-up in KEYNOTE-012. J Clin Oncol. 2016;34 (suppl; abstr 6012).

“Today’s approval represents a meaningful advance for the oncology community, as well as for our head and neck cancer clinical program,” Roger M. Perlmutter, MD, president, Merck Research Laboratories, said in a statement. “Together with prior approvals in the treatment of other tumor types, today’s action by the FDA underscores our tireless commitment to addressing the unmet needs of patients suffering from a broad range of cancers.”