New Horizons in Immunotherapy for Head and Neck Cancer

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Immunotherapy is a new treatment paradigm in recurrent metastatic head and neck cancer, according to Nabil F. Saba, MD. At a symposium hosted by the Winship Cancer Institute and Emory University—Updates in the Management of Head and Neck Cancer—Dr. Saba discussed current research and new developments in the field.1

The concept of the immune system being able to control cancer has been the subject of debate for over a century, but the idea has recently been corroborated with developments in epidemiology and molecular biology, noted Dr. Saba, Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine and Director of the Head and Neck Medical Oncology Program at the Winship Cancer Institute. He said the concept is simple: A tumor cell can be completely eliminated by the immune system, or it can enter into a state of equilibrium with the immune system, called immune editing. The interaction of the cancer cells with the tumor microenvironment leads to the cancer cells’ using a subset of immune cells for its own protection from the immune system, which we call immune-escape.

Single-Agent Checkpoint Inhibitors

Standard approaches in immune therapy have mostly involved checkpoint inhibitors. They include antibodies that inhibit programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4). Those agents include nivolumab (Opdivo), pembrolizumab (Keytruda), avelumab (Bavencio), durvalumab (Imfinzi), tremelimumab, and ipilimumab (Yervoy); so far, only nivolumab and pembrolizumab have received approval by the U.S. Food and Drug Administration in the treatment of patients with head and neck cancer who have failed to respond to platinum-based chemotherapy.

Nabil F. Saba, MD

Nabil F. Saba, MD

The only randomized phase III trial conducted in recurrent or metastatic head and neck squamous cell carcinoma that has shown a survival advantage using these agents over chemotherapy is CheckMate 141.2 In this trial, nivolumab doubled the 1-year survival rate compared with investigator’s choice therapy (36% vs 17%). Nivolumab was clearly favored over chemotherapy in all subgroups, regardless of age, performance status, tobacco use, and prior lines of therapy; and the improvement was demonstrated regardless of PD-L1 expression or p16 status (a test for human papillomavirus [HPV]). Side-effect profile and quality-of-life measures also favored nivolumab over chemotherapy.

“Not only do we have a class of agents that seem to be improving the survival of patients who are heavily treated, but they also seem to result in preservation of quality of life.”

For medical oncologists, the paradigm for using systemic therapy has shifted. “Whereas with cytotoxic chemotherapy, the question was, ‘Can we justify giving chemotherapy?’ with these better tolerated agents, the question we’re now asking is, ‘Can we justify denying these agents to patients?’” he said.

Another question of interest is whether patients can continue with checkpoint inhibition after disease progression on single-agent checkpoint inhibitors. Recently, CheckMate 141 investigators analyzed 57 patients treated after disease progression on nivolumab, compared with 82 patients not treated after disease progression. The data suggest that treatment beyond first disease progression with nivolumab is feasible and tolerable, with a safety profile similar to that of the overall nivolumab population. (This information was presented at the 2017 American Association for Cancer Research meeting in Washington, DC.)

“This isn’t a clinical trial, however. It’s a subset analysis of a study, so we can’t say this is practice-changing, but it is important to realize that some patients who got treated beyond progression did tolerate the treatment and continued to benefit from it,” reported Dr. Saba. “So the answer to this question is ‘yes’; there probably is a subgroup of patients who could continue their treatment beyond progression.”

Beyond Single Agents

In first-line recurrent/metastatic disease, trials of single agents and combination trials are continuing to accrue. According to Dr. Saba, there is interest in utilizing these agents in early-stage disease prior to surgery, in the adjuvant and maintenance settings, as well as in combination with other immunotherapeutic agents.

Completed trials using combinations of different checkpoint inhibitors in the recurrent/metastatic disease setting include the phase II CONDOR and the phase III EAGLE trials, the results of which are hopefully expected in the near future. The KESTREL trial compared durvalumab with or without tremelimumab vs the EXTREME regimen (platinum-based therapy plus cetuximab [Erbitux]) in the first-line head and neck squamous cell carcinoma setting. The study will yield much anticipated results for patients treated in the first-line setting,” Dr. Saba noted.

Immunotherapy for Head and Neck Cancer

  • Nivolumab (Opdivo) and pembrolizumab (Keytruda) are the only two checkpoint inhibitors with FDA approval for treatment of patients with head and neck cancer.
  • Preventing infection with the human papillomavirus (HPV) through a vaccine should prevent the development of HPV-related head and neck cancer.
  • More effort is needed to increase uptake of HPV vaccination, which is one of the most effective ways to use the immune system to prevent HPV-related head and neck cancer.

The KEYNOTE-048 trial is the only trial combining a checkpoint inhibitor (pembrolizumab) with chemotherapy (EXTREME regimen) in the first line; results from this trial are also hopefully expected at the 2017 meeting of the European Society for Medical Oncology. CheckMate 651 and CheckMate 714 targeting patients in the first-line and platinum refractory settings continue to accrue. “The field is moving in a direction that explores combination therapies in the first-line recurrent/metastatic setting, earlier stages, in addition to refractory cases,” he added.

According to Dr. Saba, a major question that investigators are now asking is how to predict response to these agents. “Numerous factors may affect why patients do or do not respond to these therapies, including factors influencing the innate immunity, the tumor microenvironment, and host factors such as the microbiome,” he said. KEYNOTE-0123 and CheckMate 141 examined the ability of PD-L1 expression to predict outcome and showed that tumor PD-L1 expression in the tumor itself as well as its microenvironment, was associated with improved response to checkpoint inhibitors. “The expression of these biomarkers in tumor associated inflammatory cells seem also to correlate with outcome,” stated Dr. Saba.

Finally, we need to bank on one of the most effective and simplest ways of using the immune system to fight cancer of the head and neck that is related to the human papillomavirus (HPV), which is responsible for a large proportion of new head and neck cancer cases. Prevention of HPV infection through a vaccine should prevent the development of this type of cancer. “However, HPV vaccination rates remain very low, especially for men,” admitted Dr. Saba. “We clearly need to make more efforts along those lines.” ■

Disclosure: Dr. Saba reported no conflicts of interest.


1. Saba NF: The new horizon in immunotherapy for head and neck cancer. 2017 Winship Cancer Institute of Emory University Updates in the Management of Head and Neck Cancer Symposium. Presented April 22, 2017.

2. Ferris RL, et al: Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375:1856-1867, 2016.

3. Chow LQ, et al: Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma. J Clin Oncol. September 19, 2016 (early release online).