Pembrolizumab shows promise in metastatic head and neck cancer

MADRID — Pembrolizumab significantly reduced the risk for death compared with chemotherapy among patients with recurrent or metastatic head and neck squamous cell carcinoma, according to results of an open-label phase 3 study presented at the European Society for Medical Oncology Congress.

Although the prespecified efficacy boundary was not reached in the study, the anti-PD-1 antibody pembrolizumab (Keytruda, Merck) conferred improvements in OS, PFS and objective response rates for patients with PD-L1-expressing tumors.

“The most important thing to realize from the KEYNOTE-040 study is that, although it didn’t meet its primary endpoint, pembrolizumab clearly remains an active agent in this disease,” Ezra Cohen, MD, associate director and professor of medicine at Moores Cancer Center at UC San Diego, told HemOnc Today. “It is a clinically meaningful result.

“I believe it showed superiority to the standard of care, it produced single-agent responses, and it improved overall survival, and those differences are even further exaggerated in tumors that expressed PD-L1,” Cohen added. “The reality is that we live in a world where patients can, fortunately, get subsequent immunotherapy after coming off a clinical trial. That’s exactly what happened, and it affected the overall survival results. In no way should this deter clinicians from using the drug or in no way [should it] change current clinical management.”

The prognosis of patients with recurrent or metastatic head and neck squamous cell carcinoma is generally poor, with a median OS between 6 and 12 months, depending on patient- and disease-related factors.

In a previous phase 1B study, pembrolizumab showed antitumor activity and manageable toxicity in recurrent or metastatic head and neck squamous cell carcinoma.

Researchers with KEYNOTE-040 recruited 495 patients from 97 sites in 20 countries with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx who had recurrence or progressive disease after receiving a platinum-containing regimen.

Researchers randomly assigned 247 patients (83.8% male; median age, 60 years) to pembrolizumab 200mg every 3 weeks for 24months. The other 248 patients (82.7% male; median age, 60 years) received investigators’ choice of methotrexate (n = 65), docetaxel (n = 110) or cetuximab (n = 73).

Randomization was stratified by ECOG performance status of 0 or 1, HPV status (p16 positive vs. negative), and PD-L1 tumor proportion score (50% vs.<50%). Treatment continued until confirmed progressive disease or intolerable toxicity.

OS in the intent-to-treat population served as the primary endpoint. Key secondary endpoints included OS in patients with PD-L1 combined positive score of 1%, and PFS and ORR in the intent-to-treat and combined positive score (CPS) 1% populations. Prespecified efficacy boundary for OS in the intent to treat population was one-sided (P = .0175).

At median follow-up of 7.3months, researchers reported a higher response rate (14.6% vs. 10.1%) and more durable median response (18.4 months vs. 5 months) in the pembrolizumab group.

Further, 8.9% of patients remained on pembrolizumab compared with 0.9% on chemotherapy. Pembrolizumab prolonged OS in the intent-to-treat population (HR = 0.81), but the difference did not reach statistical significance (one-sided P = .0204).

There was no difference in PFS (2.1 months for pembrolizumab vs. 2.3 months for chemotherapy). ORR was higher with pembrolizumab (14.6% vs. 10.1%).

Pembrolizumab outcomes were significantly improved in patients with PD-L1–expressing tumors. Patients with a PD-L1 CPS at or greater than 1% had a median OS of 8.7 months with pembrolizumab vs. 7.1 months with chemotherapy. Those with a PD-L1 tumor proportion score at or greater than 50% had a median OS of 11.6 months with pembrolizumab vs. 7.9 months with chemotherapy.

Additionally, 12.5% of patients in the chemotherapy arm received subsequent immunotherapy, potentially affecting OS.

Grade 3 to grade 5 drug-related adverse events incidence was 13.4% with pembrolizumab and 36.3% with chemotherapy. Adverse events led to four deaths in the pembrolizumab group (1.6%) and two in the chemotherapy group (0.9%).

“There were patients in our study who were treated in the first line — curative-intent intent therapy containing platinum — and then recurred within 3 to 6 months,” Cohen said. “Those patients appeared to do very well with pembrolizumab alone. In fact, the hazard ratios were on the favorable side for that patient subgroup.”

Two ongoing studies — KEYNOTE-048, which compares pembrolizumab alone vs. pembrolizumab or cetuximab (Erbitux, Eli Lilly) with platinum chemotherapy and 5-flurouracil for recurrent or metastatic head and neck squamous cell carcinoma; and KEYNOTE-412, which compares pembrolizumab and chemoradiation vs. placebo and chemoradiation for locally advanced head and neck squamous cell carcinoma – could determine the extent of pembrolizumab’s use in the disease.

“I believe that we will be using immunotherapy in first-line recurrent metastatic patients probably within the next year because of the data we will see,” Cohen said. “For the locally advanced patients, that’s the next level to go to because that’s where patients with head and neck cancer present. That’s where we can really make an impact. The early data suggests it’s safe to combine immunotherapy with chemotherapy and radiation.

“What we’re going to see in the near-term are more combinations utilizing PD-1 or PD-L1 as the backbone,” Cohen added. “What we’re already seeing is very encouraging with an increase in response rate and potentially an increase in survival in uncontrolled settings. Yes, PD-1 is one mechanism of evading the immune response, but there are clearly others. If we can take advantage of modulating more than one, we may be able to increase the effectiveness of these agents and move into the earlier stages of disease, where we can have a much more dramatic impact on survival.”– by Chuck Gormley

Reference:

Cohen E, et al. Abstract LBA45. Presented at European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.

Disclosures: Merck funded this study. Cohen reports an advisory role with Merck, Human Longevity, Inc., Pfizer, AstraZeneca and Bristol-Myers Squibb, and stock ownership in Human Longevity, Inc. Please see the abstract for a list of all other researchers’ relevant financial disclosures.