xRead - An Update on Immunotherapy in Head and Neck Cancer (November 2025)

Clinical Review & Education Review

Immunotherapy in Head and Neck Squamous Cell Carcinoma

has been shown to improve survival in phase 3 trials of resectable non–small cell lung cancer. 68 When a neoadjuvant ICI plus chemo therapy was investigated in patients with HNSCC in a pilot phase 2 trial of neoadjuvant camrelizumab combined with nab-paclitaxel and cisplatin, 17 of 27 patients who proceeded to surgical therapy achieved a high pathologic response rate, with only 2 patients hav ing treatment-related grade 3 or 4 adverse events. 69 Combination approaches with ICIs and stereotactic body radiation therapy (SBRT) targeting gross tumor—while avoiding elective radiation to benign lymph nodes—were shown to enhance antitumor immunity and fa cilitate tumor clearance in preclinical studies. 70 A study by Darragh etal 71 administered hypofractionated SBRT in combination with neo adjuvant durvalumab (anti–PD-L1) with 89% major pathologic or complete pathologic response rates in the group of patients that re ceived the highest dose of SBRT (24 Gy in 3 fractions). None of these patients required adjuvant radiation or chemoradiation therapy, despite all enrolled patients having stage III or IV HPV-unrelated HNSCC. The Neoadjuvant Immuno-Radiotherapy Trial 72 wasanad ditional early-phase clinical trial with inclusion of HPV-related HN SCC that demonstrated impressive response rates in patients who received neoadjuvant nivolumab and SBRT. As many trials are un derway evaluating combination approaches of ICI therapy prior to surgery, some studies are revisiting an induction therapy approach by exploring the role of induction ICI with chemotherapy prior to definitive radiotherapy or chemoradiotherapy in LA HNSCC. 73,74 As results from these early-phase combination approaches with ICI therapy in the neoadjuvant setting continue to mature, continued encouraging results will warrant further investigation in phase 3 trials. Conclusions Immunotherapy has ushered in a new era of oncologic care for pa tients with HNSCC. While ICIs found initial success in trials for pa tients with R/M HNSCC, several subsequent phase 3 trials have yielded disappointing results of ICIs in the curative setting in com bination with concurrent chemoradiotherapy. 30,31 The negative sur vival signal seen in concomitant ICI therapy with chemoradiation has led to trials evaluating sequential administration of ICI either in the neoadjuvant or adjuvant phase of treatment. Based on promising response rates in early-phase trials, several phase 3 trials are cur rently underway to investigate whether ICI therapy with curative in tent can improve survival in the difficult to treat LA HNSCC popu lation. Further work is required to identify robust biomarkers of both response and resistance to immunotherapy to guide optimal treat ment algorithms and to target subpopulations likely to benefit most from ICI therapy.

sponse rates of concomitant administration of nivolumab and ipili mumab in the neoadjuvant setting.

Future Directions As HNSCC is composed of a diverse, heterogenous group of can cers with varying molecular and anatomic features that have dis tinct local tumor microenvironments, responses to ICI will be vari able. The multiple phase 3 negative trials to date were all notably conducted on a molecularly unselected patient population of LA HN SCC. Subgroup analyses from the JAVELIN Head and Neck 100 30 and KEYNOTE 412 trials 31 suggested a potential survival benefit in pa tients whose tumors expressed high levels of PD-L1. In addition, sub group analyses in the IMvoke010 trial 33 showed a trend toward a benefit with ICI in patients who underwent primary surgery and pa tients with HPV-positive disease. Selecting patients for further therapy after definitive treatment based on molecular and patho logic biomarkers may be critical and will be important to explore on subgroup analyses in the ongoing trials. Overall, these findings suggest that designing well-powered trials focusing on specific, mo lecularly selected groups of patients, including via integration of circulating tumor DNA as a marker of minimal residual disease, may be beneficial in fully realizing the benefits of ICI therapy. 59 Identifying molecular biomarkers beyond PD-L1 of response to ICI therapy may help further tailor ICI administration. Specific bio markers that have been evaluated include tumor mutational bur den, the immune composition of the tumor microenvironment, and interferon-γ and interferon-γ–related gene signatures. 60-64 While investigating markers associated with response is crucial to stratify patients who are more likely to respond to ICI, understanding the mechanisms of resistance to immunotherapy can be equally reveal ing. Various mechanisms of resistance have been identified in pre clinical and correlative studies, including T cell dysfunction, lack of intratumor immune infiltration, oncogenic tumor signaling path ways, deficiency of tumor neoantigens or downregulation of antigen presentation, and presence of immunosuppressive T and my eloid cell subsets within the tumor microenvironment. 65-67 Identi fying these mechanisms of resistance, specific to patients with HNSCC, may provide not only important prognostic information but also opportunities for identifying optimal and novel combina torial approaches with ICI to enhance response. While fundamental work continues to elucidate novel resis tance pathways to identify potential combinatorial partners to ICI therapy, there have been continuing efforts to combine ICI with es tablished treatment modalities in the neoadjuvant setting. Specifi cally, combining ICI with chemotherapy in the neoadjuvant setting

2 . Thompson-Harvey A, Yetukuri M, Hansen AR, et al. Rising incidence of late-stage head and neck cancer in the United States. Cancer . 2020;126(5): 1090-1101. doi:10.1002/cncr.32583 3 . Gormley M, Creaney G, Schache A, Ingarfield K, Conway DI. Reviewing the epidemiology of head and neck cancer: definitions, trends and risk factors. BrDent J . 2022;233(9):780-786. doi:10. 1038/s41415-022-5166-x 4 . Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with

ARTICLE INFORMATION Accepted for Publication: January 1, 2025.

receiving personal fees from Merck, Daiichi Sankyo, and Regeneron during the conduct of the study. No other disclosures were reported. REFERENCES 1 . Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin . 2018;68(6):394-424. doi:10.3322/ caac.21492

Published Online: March 6, 2025. doi:10.1001/jamaoto.2024.5254

Conflict of Interest Disclosures: DrHanna reported receiving grants from Astellas, Bicara, Bristol Myers Squibb, Coherus, ImmunityBio, Gateway, KSQ Therapeutics, Kura Oncology, Regeneron, Replimune, and Secura Bio and personal fees from Bicara and Kura Oncology outside the submitted work. Dr Uppaluri reported

526 JAMA Otolaryngology–Head & Neck Surgery May 2025 Volume 151, Number 5 (Reprinted)

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