1. Fuerst, Mark L.

Article Content

SCOTTSDALE, AZ-A combination of radiation therapy and checkpoint inhibitor immunotherapy shows promise in improving survival for patients with locally advanced head and neck squamous cell carcinoma, with acceptable toxicity. The combination of radiation and the programmed death-1 (PD-1) inhibitor pembrolizumab may offer a new treatment option for patients who are ineligible for cisplatin chemotherapy, according to a new study.

Head  Neck Cancer. H... - Click to enlarge in new windowHead & Neck Cancer. Head & Neck Cancer

Cisplatin plus radiation therapy is a standard definitive treatment of locally advanced head and neck squamous cell carcinoma. However, contraindications to cisplatin are common, potentially in more than one-third of patients, said lead author Jared Weiss, MD, Associate Professor of Medicine at the University of North Carolina Lineberger Comprehensive Cancer Center at the 2020 Multidisciplinary Head and Neck Cancers Symposium.


The single-arm trial was designed specifically for patients who normally would receive platinum chemotherapy together with radiation but may not be able to tolerate its side effects, most often due to preexisting hearing problems that place patients at risk of permanent hearing loss. Preexisting kidney damage and nerve damage also tend to be aggravated by cisplatin and place patients at risk for permanent side effects.


"That is a common dilemma in the exam room because cisplatin, while effective, tends to be particularly toxic for patients and can lead to permanent side effects for some. I will have patients I want to treat with platinum chemotherapy, but I also want to align treatment with their values. Is the patient willing to accept a risk of deafness or exacerbated ringing in their ears? These are not acceptable consequences for most people," said Weiss.


Extensive data shows the potential synergy of pembrolizumab with radiotherapy. "Radiation elicits and promotes tumor-directed immune-stimulation, which may potentiate anti-PD-1 therapy. For the first time, we report the efficacy of combined pembrolizumab and radiotherapy in locally advanced head and neck squamous cell carcinoma," said Weiss.


Research Findings

The single-arm, phase II trial included 29 patients with locally advanced head and neck squamous cell carcinoma (Abstract LBA1). All patients would have ideally received cisplatin with their radiation but were ineligible for platinum chemotherapy. Patients were treated with three cycles of pembrolizumab and concurrent radiation therapy over 6 weeks, followed by three additional cycles of immunotherapy.


The primary progression-free survival (PFS) endpoint has exceeded the hypothesized 16 months. With a median follow-up of 21 months, median PFS has not been reached. The rates of 1-year PFS and overall survival (OS) were 76 percent and 86 percent, respectively. Estimated 2-year PFS was 71 percent and estimated 2-year OS was 75 percent. For patients with p16+ oropharynx cancer, the 1-year PFS and OS rates were 88 percent and 94 percent, respectively. For the other patients, the rates were 58 percent and 75 percent, respectively. Median OS has not been reached.


Toxicities were mostly consistent with radiation therapy alone. Most toxicities were mild (grade 1-2) with the exception of grade 3-4 lymphopenia, which affected 59 percent of patients. Evaluation by flow cytometry revealed a relative decline in CD4 cells and B cells, but not CD8 cells. There was a relative preservation of T lymphocytes with reduction in other cell types.


Upon treatment, frequencies of transitional B cells and tissue-like memory B cells increased while resting memory B cells decreased. Patients with progression had greater percentages of baseline naive B cells and fewer marginal zone B cells. Programmed death-ligand1 (PD-L1) did not distinguish patients with or without progression.


"This toxicity profile is better than what patients generally experience with cisplatin and radiation. It was more consistent with what we see from radiation therapy alone, with the exception of a high rate of lymphopenia that warrants additional study," said Weiss.


A combination of PD-1 and PD-L1 blockade following chemoradiotherapy has improved survival in lung cancer. This trial is one of the first to show its potential efficacy for head and neck cancers.


"There are convincing arguments that radiation sensitizes patients to immunotherapy and can enhance its effects. And the opposite direction also seems to be true-radiation therapy needs a functional immune system to work, and our hope was that pembrolizumab might be a radiation sensitizer for these patients," said Weiss.


Unlike chemoradiation therapy, the combination of radiation and pembrolizumab pairs two active modalities that can be curative by themselves.


"If you look back to the historic studies, radiation alone often cures patients with this disease. Some of the first patients treated with pembrolizumab for recurrent/metastatic cancer are still alive many years out, with no evidence of disease," noted Weiss. "And so, our concept was that, in addition to whatever synergy the immunotherapy might provide with radiation, we also conceived of it in a more straightforward way as a 'second shot on goal' toward cure."


In conclusion, Weiss said: "Concurrent pembrolizumab and radiotherapy has demonstrated promising PFS and OS in locally advanced head and neck squamous cell carcinoma, regardless of p16 status or anatomic location, with a favorable toxicity profile and deserves evaluation in a randomized trial. The observed changes in B-cell markers deserve further study both as potential biomarkers of treatment response and as therapeutic targets."


A phase III study of this combination therapy is expected. Multiple, ongoing trials of combinations of checkpoint inhibitors and radiotherapy are looking at platinum-ineligible patients or combinations with standard-of-care cisplatin and radiotherapy in platinum-eligible patients.


Mark L. Fuerst is a contributing writer.