Pembrolizumab Approved by FDA for Recurrent HNSCC

Robert L. Ferris, MD, PhD

Robert L. Ferris, MD, PhD

The FDA has approved the PD-1 inhibitor pembrolizumab (Keytruda) as a second-line therapy for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) for those who have progression on a platinum chemotherapy, according to the developer of the immunotherapy, Merck.

The accelerated approval was based on the phase Ib KEYNOTE-012 study, in which pembrolizumab showed an objective response rate (ORR) of 16%. The complete response (CR) rate with the agent was 5% and responses lasted for ≥6 months for the majority of patients (82%). Pembrolizumab was approved at a fixed dose of 200 mg every 3 weeks regardless of PD-L1 expression.

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).

"This is an exciting day to have a new FDA-approved agent. The last one was 10 years ago," said immunotherapy expert Robert Ferris, MD, PhD, vice chair for Clinical Operations, associate director for Translational Research. "We still have a ways to go to understand resistance and how pembrolizumab should be integrated with standards of care like radiotherapy in locally advanced and chemotherapy in the first-line and against or with cetuximab in second-line head and neck cancer."

The approval was based solely on an assessment of 174 patients treated with a prior platinum-based regimen. In this group, 53 patients received the 10 mg/kg dose and 121 got the 200 mg dose of pembrolizumab. In the full 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 across the full study 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% of patients had received prior platinum therapy and cetuximab. The ECOG performance status was primarily 1 (70%) and most patients had metastatic disease (88%).

In data presented at the 2016 ASCO Annual Meeting for patients treated with a prior platinum-based agent (n = 174), the ORR was 17%, with a CR rate of 5%. The median duration of response had not yet been reached and was similar across both doses of pembrolizumab.

In data for the full study, 4% of patients had experienced a complete response (CR) and 14% had a partial response. Sixty% 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.

Median progression-free survival 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/AST increases, fatigue, decreased appetite, hypernatremia, 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 Pembrolizumab for previously treated patients with recurrent or metastatic head and neck squamous cell carcinoma is an important step forward in treating this disease.”

A second phase III study is assessing pembrolizumab 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