MADRID-Pembrolizumab provides a 19 percent reduction in the risk of death over standard of care for recurrent or metastatic head and neck squamous cell carcinoma, according to a new study. However, the immunotherapy did not reach the pre-specified efficacy boundary. The data was recently presented at the ESMO 2017 Congress (LBA45_PR).
"Even though the study did not meet its primary endpoint, I still think it is a positive trial," said lead investigator Ezra Cohen, MD, Associate Director of the UC San Diego Moores Cancer Center in La Jolla, Calif. "It reinforces that pembrolizumab should continue to be offered as an important option for all patients with this devastating disease."
He pointed out that the 19 percent improvement in overall survival (OS) was a clinically meaningful difference for this population who only lived 7-8 months, on average, after initiating treatment with the anti-PD-1 agent. Also, 12.5 percent of patients in the standard of care arm received subsequent immunotherapy, potentially impacting OS, he said. "Post-study crossover in the standard of care arm appears to have confounded the OS analysis."
The PD-1 pathway has been implicated in tumor immune escape. Pembrolizumab provides anti-tumor activity and a manageable safety profile in recurrent or metastatic head and neck cancer, said Cohen. The drug has been shown to increase PD-L1 expression on tumor cells and infiltrating immune cells associated with improved response in recurrent or metastatic head and neck cancer. Pembrolizumab received accelerated approval by the FDA for treating recurrent or metastatic head and neck cancer patients who had progressed after platinum-containing chemotherapy.
Trial Details
The KEYNOTE-040 trial was a global, open-label, phase III study that included 495 patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx who had a recurrence or progressive disease following a platinum-based chemotherapy. The patients were randomized to receive either pembrolizumab (247 patients) 200 mg every 3 weeks or standard-of-care treatment (248 patients), which was the investigator's choice of either methotrexate, docetaxel, or cetuximab.
Pembrolizumab prolonged OS in the intention-to-treat population, but the difference did not achieve statistical significance (HR 0.81). There was no difference in progression-free survival between the two groups, each about 2 months.
However, for a subset of patients who had PD-L1-expressing tumors, pembrolizumab was associated with dramatic and significantly improved outcomes. Specifically, among patients with combined tumor and immune cell PD-L1-expression (CPS) of at least 1 percent, median OS was 8.7 months with pembrolizumab versus 7.1 months with standard treatments (HR 0.75), and among patients with PD-L1 expression in more than 50 percent of their cancer cells, median OS was 11.6 months versus 7.9 months, respectively (HR 0.54). All complete responses with pembrolizumab were observed in the CPS of at least 1 percent population.
The overall response rate was higher with pembrolizumab (14.6%) than with standard of care (10.1%). The median duration of response was also higher with pembrolizumab (18.4 months) than with standard-of-care treatments (5 months).
Pembrolizumab measured up well in terms of side effects. "In almost every category, it had a better side-effect profile, meaning a lower incidence of toxicity versus standard treatments," said Cohen. "The exception is hypothyroidism, which occurred in 13 percent of those treated with pembrolizumab versus only 1 percent of those given other treatments."
The incidence of treatment-related adverse events of any grade was lower with pembrolizumab (63%) than with standard of care (83.8%). Grade 3-5 drug-related adverse events occurred in 13.4 percent of pembrolizumab-treated patients and 36.3 percent of those who received standard of care; 1.6 percent and 0.9 percent, respectively, died of drug-related adverse events.
Implications for Practice
Overall, Cohen said the KEYNOTE-040 trial reinforces what is already known about anti-PD-1 therapy in head and neck cancer. "From a clinician's perspective, I would feel the same in any country. This is a meaningful therapy that improves survival," he said.
"Keynote-040 did not reach its primary endpoint of OS; however, pembrolizumab was superior to investigator's choice in terms of toxicity, an important consideration in treatment decisions for these poor-prognosis patients with recurrent or metastatic platinum-refractory head and neck squamous cell carcinoma," commented Amanda Psyrri, MD, from the University of Athens Medical School and Attikon University Hospital in Athens, Greece. "As the authors point out, subsequent immunotherapy in the standard-of-care arm may have confounded OS analysis.
"The magnitude of treatment effect was greater in patients with PD-L1 combined positive score of at least 1 percent, especially those with CPS of at least 50 percent, suggesting that pembrolizumab may represent the preferable treatment option for this subset of patients," she continued.
Pembrolizumab is continuing to be explored in this patient population with several ongoing phase III studies, said Cohen. KEYNOTE-048 is investigating pembrolizumab monotherapy versus pembrolizumab plus platinum plus 5-FU versus cetuximab plus platinum plus 5-FU as first-line therapy for recurrent or metastatic head and neck cancer. KEYNOTE-412 is examining pembrolizumab plus chemoradiation versus placebo plus chemoradiation for locally advanced head and neck cancer.
Staff contributed to this article.