Future of Immunotherapy in Head and Neck Cancer May Be in Combinations

Ezra Cohen, MD

Immunotherapy has become a key player in head and neck cancer with the approvals of pembrolizumab (Keytruda) and nivolumab (Opdivo) this past year. Researchers are hoping to build on the success of the KEYNOTE-012 and CheckMate-141 trials, which led to the approvals of pembrolizumab and nivolumab, respectively, by examining anti—PD-1/PD-L1 agents in the frontline and as a part of combination regimens.

The promise of immune-based approaches was discussed during an OncLive^® Peer Exchange panel, A New Era for Treatment of Advanced Head and Neck Cancer, which was moderated by Ezra Cohen, MD, associate director, professor of Medicine, Moores Cancer Center, UC San Diego.

During the panel, Tanguy Y. Seiwert, MD, from the University of Chicago Medicine, said that the combination of checkpoint inhibitors and chemotherapy may hold promise in head and neck cancer, as indicated by success in other tumor types.

“I think there’s something intriguing with chemotherapy. We only have data on it in other diseases, like in lung cancer. But consistently, in multiple diseases, adding chemotherapy to checkpoint inhibition seems to increase response rates above the chemotherapy threshold,” Seiwert said.

Clinical trials must be conducted though, added Seiwert, as questions remain surrounding the tolerability of immunotherapy in combination with chemotherapy or in combination with radiotherapy in head and neck cancer.

Currently, the KEYNOTE-048 trial (NCT02358031) is evaluating the safety and efficacy of pembrolizumab as a first-line treatment alone or in combination with chemotherapy in patients with recurrent or metastatic head and neck squamous cell carcinoma. Primary outcomes of this ongoing trial are progression-free survival per RECIST 1.1 and overall survival in patients with PD-L1—positive expression.

Another anti—PD-L1 agent, durvalumab (Imfinzi), is being investigated in head and neck cancer. The KESTREL (NCT02551159) trial is looking at this agent in the first-line setting. It is a phase III randomized, open-label, multicenter, global study of durvalumab alone or in combination with the CTLA-4 inhibitor tremelimumab versus standard of care for patients with recurrent or metastatic disease who have not had prior treatment.

Additionally, there may be a place for immunotherapy in the adjuvant setting, said Seiwert. “Disease burden might be important for immunotherapy. And it may be a good thing to explore, actually, when we have minimal residual disease—so, very small amounts of disease. Maybe in the adjuvant setting, there’s an additional opportunity,” said Seiwert, “I think that may be an additional opportunity where maybe checkpoint inhibition is the most effective in your small amounts of disease.”

As more data emerges, the understanding of immunotherapy in this disease will mature. Following its success in becoming the standard of care for head and neck cancer, the future of this therapeutic option is multifaceted, but clinical trials will be the only route in which to determine that, Seiwert concludes.

Kevin Harrington, MD, PhD, from The Royal Marsden NHS Foundation, added that immunotherapy as part of a combination may be curative in this disease. He said that combining radiation with checkpoint inhibition could influence mechanisms to make abscopal responses more predictable and resistant.

“Of course, the idea of bringing these therapies together and engendering an immunologically relevant and immunogenic cell death by radiation would allow us not to treat macroscopic metastatic disease, but better still, at the time of first treatment, to get rid of micrometastatic disease that may subsequently lead to metastatic failure,” said Harrington.

Combinations of radiochemotherapy in this disease type have proven challenging, specifically with EGFR inhibitors, such as cetuximab (Erbitux), which was associated with immune-related adverse events, however, combinations with immunotherapy could be a potentially rewarding route, said Viktor Grünwald, MD, PhD, Hannover Medical School, Germany.

“There are some safety hints that it may not be a piece of cake to get through radiotherapy,” said Grünwald, “But, I think it really has a lot of promise combining radiochemotherapy with immunotherapy, and it could be a future way in how we succeed to treat early forms of localized disease in this cancer.”