The ASCO Post asked for comment from Glenn J. Hanna, MD, Director of the Center for Salivary and Rare Head and Neck Cancers, Dana-Farber Cancer Institute, and Assistant Professor of Medicine at Harvard Medical School. Dr. Hanna said it is important to put the findings of KEYNOTE-412¹ into context with similar trials. In particular, the similarly designed JAVELIN-100 trial of the anti–PD-L1 agent avelumab also failed to meet its primary endpoint of progression-free survival,² he noted.

Glenn J. Hanna, MD

“When we step back and take a 30,000-foot view, we’re talking about two large, very well done randomized international phase III trials asking whether we can add immunotherapy to chemoradiation, with immunotherapy continued as maintenance, to improve outcomes. What we are learning is that maybe the ‘kitchen sink approach’ is not the best. Rather, what might make more sense is to sequence drugs,” Dr. Hanna said.

To this end, he said that neoadjuvant studies of immunotherapy followed by chemoradiation “look compelling,” as do studies evaluating chemoradiation alone followed by adjuvant immunotherapy. “I believe our focus is shifting to a sequential approach as opposed to a concurrent approach.”

Dr. Hanna had some thoughts as to why the regimens of KEYNOTE-412 and JAVELIN-100 were not effective. “You’re giving an immune checkpoint inhibitor in the setting of an ablative environment with myelosuppressive chemotherapy along with radiotherapy, doing a number on your T cells. Maybe this is not the right point to introduce immunotherapy on top of radiotherapy,” he said.

Immunology Perspective

Sherene Loi, MD, PhD

Sherene Loi, MD, PhD, of the Peter MacCallum Cancer Centre, Melbourne, elaborated on the mechanisms by which radiotherapy might alter the body’s immune response to checkpoint inhibition. Dr. Loi was invited to discuss KEYNOTE-412 and several other immunotherapy trials at the Presidential Symposium from the perspective of an immunologist.

Combinations of radiotherapy and anti–PD-1/L1 agents have been shown preclinically to induce immunogenic cell death, and this can be affected by dose and fractionation. Radiation to head and neck tumors targets bilateral lymph nodes, and lymphocytes are very sensitive to radiation. Radiotherapy is associated with peripheral lymphopenia, which can have effects on immunosurveillance, and this might be enhanced with modern techniques delivering high doses that can affect peripheral lymphocyte pools. “This, combined with targeting draining lymph nodes, may not be optimal for developing an immune response,” she explained. 

However, is there a possibility that a PD-L1–enriched population might derive some benefit from combinations as evaluated in KEYNOTE-412? This subset did have better outcomes than the intent-to-treat population receiving pembrolizumab, Dr. Hanna acknowledged, pointing to “a slight separation of the curve and a trend toward fewer events.” This suggests there could be a “population buried in here” for whom a combination strategy could be beneficial. That aside, he believes the signal is not strong enough for additional studies of this combinatorial approach to move forward.

The better question is whether anti–PD-L1 agents can be positioned either in the neoadjuvant or adjuvant setting to make a difference. The phase II/III ECOG-ACRIN 3161, for example, is evaluating chemoradiation followed by adjuvant checkpoint blockade in human papillomavirus–positive immediate-risk patients. This and similar studies are probably the way of the future in head and neck cancer, he said. 

DISCLOSURE: Dr. Hanna reported financial relationships with Bristol Myers Squibb, Bicara, Exicure, Gateway for Cancer Research, GSK, NantKwest, Regeneron, Sanofi Genzyme, Coherus, Maverick, and Merck. Dr. Loi reported no conflicts of interest. 

REFERENCES

1. Machiels JP, Tao Y, Burtness B, et al: Primary results of the phase 3 KEYNOTE-412 study: Pembrolizumab plus chemoradiation therapy (CRT) vs placebo plus CRT for locally advanced head and neck squamous cell carcinoma. ESMO Congress 2022. Abstract LBA5. Presented September 11, 2022.

2. Cohen EE, Ferris RL, Psyrri A, et al: Primary results of the phase III JAVELIN Head & Neck 100 trial: Avelumab plus chemoradiotherapy followed by avelumab maintenance vs CRT in patients with locally advanced squamous cell carcinoma of the head and neck. ESMO Congress 2022. Abstract 910O. Presented September 19, 2020.