Pembrolizumab Plus Radiotherapy Worthy of Further Study in Locally Advanced Squamous Cell Head and Neck Cancer

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The combination of the checkpoint inhibitor pembrolizumab and definitive radiation therapy appears to be a safe and feasible option for patients with locally advanced head and neck cancer who are not eligible for cisplatin, according to data presented at the 2020 Multidisciplinary Head and Neck Cancers Symposium.1

The 1-year progression-free and overall survival rates with the combination treatment were 76% and 86%, respectively, and the 2-year estimated survival rate is 75%. Results of the single-arm, phase II study also showed that both clinician- and patient-graded adverse events were consistent with radiotherapy alone, with the exception of lymphopenia. Finally, investigators observed changes in B-cell markers that could serve as potential biomarkers of treatment response or even therapeutic targets.

“There is an emerging literature on both immunosuppressive and promoting roles of B cells with immunotherapy that makes these changes provocative and worthy of further study,” said Jared Weiss, MD, Associate Professor and Associate Director for Finance at the University of North Carolina School of Medicine, Chapel Hill. “Multiple ongoing studies will further elucidate the role of checkpoint blockades together with definitive radiation therapy, but if those results are similar to these, a phase III study of pembrolizumab and radiotherapy for platinum-ineligible patients is warranted.”

“If ongoing studies show similar results, a phase III study of pembrolizumab and radiotherapy for platinum-ineligible patients is warranted.”
— Jared Weiss, MD

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As Dr. Weiss reported, the combination of cisplatin and definitive-dose radiotherapy is a standard treatment of locally advanced head and neck cancer, but contraindications to cisplatin are common in everyday clinical practice and occur in more than one-third of patients. Although cetuximab is an alternative therapy approved by the U.S. Food and Drug Administration, added Dr. Weiss, recent data have called into question the extent of its efficacy, particularly in the human papillomavirus (HPV) positive population. And, in certain geographic regions of the United States, anaphylaxis can be a problem.

In addition, said Dr. Weiss, radiation elicits and promotes tumor-directed immune stimulation, which may potentiate anti–programmed cell death protein 1 therapy. Pembrolizumab has already been shown to be active in patients with head and neck cancer, with a potentially curative response observed in a small percentage.

“Adding pembrolizumab to a definitive strategy can be conceived of as the addition of an active drug, but it’s also a second shot on goal because there is durable control with the drug alone,” said Dr. Weiss.

Study Details

For this single-arm, multi-institution, phase II study, Dr. Weiss and colleagues enrolled 29 patients with locally advanced squamous cell head and neck cancer who were platinum-ineligible, defined by the provider and standard organ measures. Patients with American Joint Committee on Cancer (AJCC) version 7 stage III or IV disease were included in the study; they received radiotherapy concurrently with 3 cycles of pembrolizumab (200 mg every 3 weeks followed by 3 adjuvant cycles). The primary endpoint was progression-free survival of at least 16 months.

Survival Outcomes and Toxicity

As Dr. Weiss reported, because the chief inclusion criterion was platinum ineligibility, this patient population was sicker than those in typical phase II studies. More than two-thirds of patients were platinum-ineligible due to preexisting otopathy, said Dr. Weiss, who noted that patients were restaged from the AJCC 7th edition to the 8th edition to more accurately reflect biologic and anatomic risk.

“I feel very strongly that nonrandomized, phase II data can have meaning,” said Dr. Weiss. “If we want to interpret these data accurately, we need a frank assessment of the risk level of patients actually accrued.”

Due to HPV-positive, low-risk oropharyngeal cancer, 8 of the 29 patients were restaged from stage III or IV to stage I and II, and 21 of 29 retained stage III or IV status.

With a median follow-up of 21 months, the study met its primary endpoint. The 1-year progression-free survival rate was 76% and projected to 2-year progression-free survival is 71%. The 1-year overall survival rate was 86%, and the 2-year estimated survival rate is 75%. Findings showed that patients with p16-positive oropharyngeal cancer fared even better: 1-year progression-free and overall survival rates were 88% and 94%, respectively, for p16-positive disease.

The toxicity of the combined regimen was also acceptable, said Dr. Weiss. Of note, most toxicities were mild (grade 1 and 2), with the exception of grade 3 and 4 lymphopenia, which affected 59% of patients. “The toxicity profile was consistent with safety data of radiotherapy alone, but the high rate of lymphopenia warrants additional study,” he commented.

According to Dr. Weiss, lymphopenia has been reported with pembrolizumab monotherapy and in a study of cisplatin, pembrolizumab, and radiotherapy. The investigators sought to characterize this adverse event with existing samples; they found that lymphocyte counts reached their nadir at week 4 with partial recovery at week 20 and no further recovery at week 40. Flow cytometry on peripheral blood showed a relative decline in CD4 cells and B cells but a relative preservation of CD8 cells.


  • Concurrent pembrolizumab and radiotherapy demonstrated promising progression-free and overall survival in locally advanced squamous cell head and neck cancer, regardless of p16 status or anatomic location, with a favorable toxicity profile.
  • Changes in B-cell markers could serve as potential biomarkers of treatment response and/or therapeutic targets.

Potential Biomarkers

Although absolute lymphocyte count alone or its change did not predict for early disease progression, said Dr. Weiss, a comparison of early progressors and nonprogressors found that those with progressive disease had higher baseline-naive B-cell levels in peripheral blood and lower circulating marginal zone B cells.

Analysis of changes over time within B cells identified a relative increase in tissue-like memory B cells, increased transitional B cells, and decreased resting memory cells. Dr. Weiss called these changes “provocative” and “worthy of further study” as potential biomarkers of treatment response and therapeutic targets. 

DISCLOSURE: Dr. Weiss has served as a consultant for AbbVie, Azitra, Blueprint, Eli Lilly, EMD Serono, G1 Therapeutics, and Jounce Therapeutics. He has received research grants from AstraZeneca, Merck, and Pfizer; honoraria from Inivata; and owns stock in Nektar and options in Vesselon.


1. Weiss J, Vincent B, Deal A, et al: Progression-free survival, overall survival, and immunophenotyping outcomes for patients with stage III-IV head and neck cancer and cisplatin contraindication treated with definitive radiotherapy plus pembrolizumab. 2020 Multidisciplinary Head and Neck Cancers Symposium. Abstract LBA-1. Presented February 28, 2020.


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