Pembrolizumab Falls Short in Phase III Head and Neck Cancer Trial

Roger Dansey, MD

Pembrolizumab (Keytruda) did not meet the primary endpoint of overall survival (OS) in patients with previously-treated recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) in the phase III KEYNOTE-040 trial, according to Merck, the manufacturer of the PD-1 inhibitor.

Investigators were evaluating pembrolizumab versus standard chemotherapy with methotrexate, docetaxel or cetuximab (Erbitux). The hazard ratio for OS with pembrolizumab was 0.82 (95% CI, 0.67-1.01; P = .03).

In a press release, Roger Dansey, MD, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories, said the company would release the full results “at an upcoming medical meeting.”

The FDA granted accelerated approval to pembrolizumab in August 2016 for patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy based on results from the open-label phase Ib KEYNOTE-012 trial. Full approval was contingent on results from confirmatory trials, such as KEYNOTE-040.

The accelerated approval was specifically based on an efficacy analysis of 174 patients treated with a prior platinum-based agent. In this assessment, the overall response rate (ORR) with pembrolizumab was 16% (95% CI, 11-22), which included a complete response (CR) 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 2 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 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 progression-free survival (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 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.

Merck noted in its release that the researchers did not observe any new safety signals in KEYNOTE-040.

The company did not say what significance, if any, these results might have for KEYNOTE-048, a phase III trial comparing pembrolizumab with platinum-based chemotherapy plus 5-FU and cetuximab, or in combination with platinum-based therapy and 5-FU as a frontline treatment for patients with recurrent or metastatic HNSCC.

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).