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Pembrolizumab exhibits antitumor activity in recurrent HNSCC
Patients with recurrent metastatic head and neck squamous cell carcinoma who were resistant to platinum and cetuximab experienced clinically significant antitumor activity with pembrolizumab, according to a single-arm, phase 2 study published in Journal of Clinical Oncology.
Further, pembrolizumab (Keytruda, Merck) was associated with moderate adverse events.
“[Our study] focused on a very heavily pretreated patient population; there are no FDA–approved treatments for patients with head and neck cancer who are refractory to both platinum and cetuximab,” Joshua M. Bauml, MD, assistant professor of medicine and co-deputy director of the lung/head and neck medical oncology clinical research program at Hospital of the University of Pennsylvania, told HemOnc Today. “Their prognosis is poor, and available agents given off label have limited activity.”
Palliative chemotherapy has been the mainstay of therapy for recurrent metastatic HNSCC not amenable to curative-intent treatment, but has limited efficacy. The best median OS of 10 months was achieved with a combination of cetuximab (Erbitux, Eli Lilly), platinum and fluorouracil. After progression, methotrexate is commonly prescribed, yielding an overall response rate of about 5% and a median OS of 6 months.
Pembrolizumab — a well-tolerated anti–PD-1 antibody — exhibited durable antitumor activity in patients with locally advanced HNSCC, but had not been tested in patients with recurrent metastatic HNSCC resistant to platinum and cetuximab.
Researchers analyzed patients with recurrent metastatic HNSCC whose disease had progressed within 6 months of being treated with platinum and cetuximab. Patients received 200 mg pembrolizumab every 3 weeks and underwent imaging every 6 to 9 weeks. ORR — assessed according to PD-L1 expression and HPV status — and safety served as primary endpoints.
Among 171 patients (median age 61 years; 81% men; 89% white) treated with pembrolizumab, 75% had received two or more prior lines of therapy for metastatic disease, 82% were PD-L1 positive and 22% were HPV positive.
ORR was 16% (95% CI, 11-23) with a median duration of response of 8 months (range 2+ months to 12+ months). At the time of analysis, 75% of responses were ongoing.
Response rates were similar among all PD-L1 and HPV groups.
“Methotrexate — which is classically used as a reference regimen for such patients — has a response rate of about 5%,” Bauml said. “As such, a response rate of 16% [with pembrolizumab] is quite exciting. It is even more exciting when you consider the fact that this is a similar response rate to what was seen in [previous studies], where patients were less heavily pretreated. For a select group of patients, we are seeing that pembrolizumab has activity regardless of pretreatment status.”
Median PFS was 2.1 months and median OS was 8 months.
At the time of analysis, 64% of patients (n = 109) experienced treatment-related adverse events, and 15% (n = 26) experienced grade 3 or worse adverse events.
The most common adverse events of any grade were fatigue (18%), hypothyroidism (9%), nausea (6%), aspartate aminotransferase increase (6%) and diarrhea (6%). Seven patients (4%) stopped treatment and one patient died of treatment-related pneumonitis.
“At this point, both pembrolizumab and nivolumab [Opdivo, Bristol-Myers Squibb] are FDA approved for the treatment of recurrent metastatic head and neck cancer after platinum failure,” Bauml said. “No biomarker is required to prescribe either agent. This is not to say, however, that a biomarker is not needed. The problem is that PD-L1, given its heterogeneous and dynamic nature, is simply not an ideal biomarker. Current research efforts are underway to identify better ones, including mutational load and gene expression profiling. These are not currently clinically validated.”
Ongoing phase 3 studies of pembrolizumab in head and neck cancer in the metastatic setting will be watched closely, Bauml said.
“There is also significant interest in moving PD-1 inhibition earlier into the management of head and neck cancer, before it becomes metastatic,” Bauml added. “There are multiple ongoing trials exploring how to do that best.” – by Chuck Gormley
For more information:
Joshua Bauml, MD, can be reached at University of Pennsylvania, South Pavilion, Floor 10, 3400 Civic Center Blvd, Philadelphia, PA 19104; e-mail: joshua.bauml@uphs.upenn.edu
Disclosure: Merck funded this study. Bauml reports consultant or advisory roles with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Clovis Oncology, Genentech and Guardant Health; and research funding from Caregive Systems, Incyte, Merck and Novartis. Please see the full study for a list of all other researchers’ relevant financial disclosures.