Pembrolizumab (Keytruda) is making inroads into head and neck cancer, with encouraging results in heavily pre-treated patients with recurrent or metastatic squamous cell carcinoma of the head and neck, according to a report on the expansion-cohort ­KEYNOTE-012 study presented at the 2015 ASCO Annual Meeting.¹

In these poor-prognosis patients who were heavily pretreated, pembrolizumab achieved tumor shrinkage in 57%, and 24.8% had a partial or complete response. Responses were seen in both human papillomavirus (HPV)-positive and HPV-negative tumors.

‘Remarkable’ Efficacy

“The efficacy we saw was remarkable. This is the largest experience with immunotherapy in head and neck cancer. Pembrolizumab was roughly twice as effective when measured by response as we have seen with cetuximab [Erbitux], our only approved targeted therapy for head and neck cancer. Responses are durable, which has not been seen before in head and neck cancer and pembrolizumab seems to be broadly active regardless of HPV status, PD-L1 status, or prior treatment,” said lead author Tanguy Y. Seiwert, MD, Assistant Professor of Medicine and Associate Program Leader for Head and Neck Cancer at the University of Chicago.

He noted that recent data suggest that cetuximab and other EGFR inhibitors may be less effective against HPV-positive tumors, so the fact that robust activity were seen in this group is ­encouraging.

“Furthermore the side effect profile was favorable. We have high hopes that immunotherapy will change the way we treat head and neck cancer,” Dr. Seiwert said.

Pembrolizumab is the first anti–programmed cell death protein 1 (PD-1) therapy to be approved by the U.S. Food and Drug Administration. It is approved in advanced melanoma and is now being studied in other solid tumors.

Recurrent/metastatic head and neck cancer has a poor prognosis, associated with a median overall survival of 10 to 13 months in the first-line setting and 6 months in previously treated patients, which represent the majority of patients in KEYNOTE-012. The current standard of care is platinum-based doublet chemotherapy with or without cetuximab. Second-line options are methotrexate, taxanes, and cetuximab. These therapies have downsides: Chemotherapy is associated with significant side effects, and only 10% to 13% of patients respond to single-agent cetuximab.

Study Details

This expansion cohort enrolled 132 patients with recurrent or metastatic squamous cell carcinoma of the head and neck, irrespective of PD-L1 or HPV status. All patients received fixed-dose pembrolizumab (infusion of 200 mg every 3 weeks) for 24 months or until disease progression or intolerable toxicity. About 59% had been previously treated with two or more therapies for recurrent or metastatic head and neck cancer.

Tumor shrinkage was reported in 56%. The overall objective response rate was 24.8%: 27.2% in HPV-negative patients and 20.6% in HPV-positive patients. About 25% of patients had stable disease, for a disease control rate of about 50%, which Dr. Seiwert called “very promising” as many patients with prolonged stable disease may ultimately also benefit from immunotherapy, Dr. Seiwert said.

The duration of response in responders was excellent, he continued; 86% of responding patients remained in response at the time of his presentation.

“Pembrolizumab was well tolerated, better than with chemotherapy or radiation,” Dr. Seiwert said. About 60% of patients had any adverse events, but were mostly mild: 15% had mild, low grade (grade 1/2) side effects included hypothyroidism (9.1%), decreased appetite (7.6%), and rash (7.6%).

Serious side effects (grade 3/4) were reported in fewer than 10% of patients. Few patients experienced serious immune-related adverse events, which included pneumonitis and  colitis (one patient).

Looking Ahead

Dr. Seiwert noted that longer follow-up is needed to assess survival. “Studies of other immunotherapies have shown that patients who have disease stabilization or even experience disease progression initially on these therapies may ultimately derive significant benefit that can translate to longer survival,” he said.

Furthermore, it may be possible to predict who is most likely to benefit from pembrolizumab using PD-L1 as a biomarker, Dr. Seiwart noted. Analysis of PD-L1 status and response is ongoing.

Dr. Seiwert is the lead author of another study presented at the meeting, suggesting that an interferon-gamma expression signature is another promising biomarker that might predict the benefit of pembrolizumab in PD-L1–positive head and neck cancer, with high accuracy including a 95% negative preditive, and 40% positive predictive value, however additional validation is needed.²

Pembrolizumab is currently being compared with standard treatment in two ongoing phase III studies in patients with recurrent/metastatic head and neck cancer. ■

Disclosure: The study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc. Dr. Seiwert reported receiving honoraria from Bayer/Onyx, Merck, and Novartis and research funding via his institution from Boehringer Ingelheim and Genentech/Roche. For full disclosures of the study authors visit abstract.asco.org.

References

1. Seiwert T, Haddad RI, Gupta S, et al: Antitumor activity and safety of pembrolizumab in patients with advanced squamous cell carcinoma of the head and neck (SCCHN). 2015 ASCO Annual Meeting. Abstract LBA6008. Presented June 1, 2015.

2. Seiwert T, Burtness B, Weiss J, et al: Inflamed-phenotype gene expression signatures to predict benefit from the anti-PD-1 antibody pembrolizumab in PD-L1+ head and neck cancer patients. 2015 ASCO Annual Meeting. Abstract 6017. Presented May 30, 2015.