The combination ofa phase 2 trial suggests.
“There are convincing arguments that radiation sensitizes patients to immunotherapy and can enhance its effects,” Jared Weiss, MD, associate professor of medicine, UNC Lineberger Comprehensive Cancer, Chapel Hill, North Carolina, said in a statement.
“And the opposite direction also seems to be true – radiation therapy needs a functional immune system to work. Our hope was that pembrolizumab might be a radiation sensitizer for these patients,” he said.
Theat the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.
Both modalities have had some outstanding results in the past, observed Weiss. “If you look back to the historic studies, radiation alone often cures patients with this disease, while some of the first patients treated with pembrolizumab for recurrent/metastatic cancer are still alive many years out, with no evidence of disease,” he said.
“Our concept was that, in addition to whatever synergy the immunotherapy might provide with radiation, we also conceived of it as a ‘second shot on goal’ towards a cure, because there is durable control with drug alone,” he added.
The single-arm trial included 29 patients with locally advanced HNSCC.
Only about 10% of patients were current smokers, but more than half of the study group had a history of smoking. Of those, more than 55% had a history of 10 pack-years or more.
In slightly more than one third of patients, the primary site of the cancer was the base of the tongue. The tonsils were the primary site in slightly more than one third.
Platinum ineligibility was defined by provider and standard measures.
More than two thirds of patients were ineligible to receive cisplatin because of preexisting otopathy, including hearing impairment and tinnitus.
The combination of cisplatin and definitive-dose radiotherapy is standard treatment for locally advanced head and neck cancer, but contraindications to cisplatin are common in everyday clinical practice. Weiss noted that contraindications are present in about one third of his patients.
“We replaced standard, every-3-week cisplatin with pembrolizumab every 3 weeks,” Weiss explained, “and we hypothesized that with the ongoing effects of radiation therapy after completion, that additional adjuvant cycles could further sensitize patients [to the effects of radiation] without impairing recovery, so we added three adjuvant cycles as well,” he added.
With six cycles of an every-3-week drug, patients received 18 weeks of pembrolizumab in total.
Echoing results from the previously reported KEYNOTE-48 trial, pembrolizumab given with radiotherapy instead of chemotherapy led to an overall progression-free survival (PFS) rate of 76% at 1 year and an estimated PFS of 71% at 2 years.
At 1 year, 86% of patients were still alive, and at 2 years, an estimated 75% of patients were still alive, Weiss added.
For patients with human papillomavirus 16–positive cancer, rates of PFS and overall survival were slightly better, at 88% and 94%, respectively.
With regard to toxicities, “For the most part, this [treatment regimen] looks like radiation alone with one very notable exception, which was lymphopenia,” Weiss observed. Grade 3-4 lymphopenia affected 59% of patients.
Lymphocyte count hit bottom at week 4, he added, with only partial recovery at week 20 and no further recovery at 40 weeks. Lymphocyte count alone or any change in it was not predictive of early progression.
However, in comparing patients who experienced early disease progression to patients who did not experience progression, levels of baseline naive B cells in peripheral blood were higher and levels of circulating marginal zone B cells were lower in patients with progressive disease, Weiss reported.
Patient-reported outcomes indicated that common symptoms of treatment peaked at week 10, and there was relative recovery by week 20.
As reflected by Functional Assessment of Cancer Therapy (FACT) scores, which include social, emotional, and functional well-being, as well as the head and neck cancer scale, “we again see a nadir at 10 weeks with relative recovery at 20 weeks,” Weiss noted.
“We found that concurrent pembrolizumab with radiotherapy is a safe and feasible option for locally advanced head and neck cancer patients with cisplatin ineligibility,” Weiss concluded.
More research is being conducted in this area, and multiple ongoing studies will further elucidate the value of PD-1 or PD-L1 checkpoint blockade with definitive radiation therapy, he added.
The study was funded by Merck & Co. Weiss’ institution has received research funding from Celgene, Pfizer, Merck, AZ/Medimmmune, Amgen, Carefusion, G1 Therapeutics, Immunicum, Loxo/Lilly, and the Jimmy V Foundation. Weiss has received honoraria for consulting from AstraZeneca, EMD Serono, Genentech, Inivata, Celgene, G1 Therapeutics, Jounce Therapeutics, Abbvie, Rakuten, Nanobiotix, Azitra, Loxo/Lilly, Pfizer, and Blueprint had has stock in Nektar and Vesselon.
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