Sequencing Immunotherapy and Hypofractionated Radiotherapy in Frail Patients with Locally Advanced Head and Neck Squamous Cell Carcinoma

(1) Background: Hypofractionated radiotherapy and immunotherapy (IT) are possible treatment options for HNSCC patients unsuitable for standard curative treatment, yet no high-level evidence supports their combined use. We aim to report on the clinical outcome of a single-center cohort of HNSCC patients treated with a hypofractionated radiotherapy (hypoRT) regimen in combination with IT alone or chemo-immunotherapy (CT-IT). (2) Methods: We enrolled a cohort of elderly and frail HNSCC patients unsuitable for standard curative treatment, deemed candidates to undergo hypoRT in a sequential strategy (time interval < 6 months), followed or preceded by IT alone (hypoRT_IT) or CT-IT. We selected our sample using the Geriatric 8 (G8) score and the Charlson Comorbidity Index (CCI). (3) Results: At a median follow-up of 11 months (IQR 5–20), the median locoregional control (LRC) was 12 months (95% CI 7.0–17.1) with a 1-year progression-free survival rate of 63%. For the hypoRT-IT group, the median overall survival was 12 months (95% CI 0–24). No grade (G) 4–5 in-field acute side effects were observed, while one case of G3 oral mucositis and two cases of G3 radiation dermatitis were reported. (4) Conclusions: A sequential combination of checkpoint inhibitors and hypoRT may provide clinical benefit with acceptable toxicity in frail and elderly patients with advanced HNSCC unfit for standard therapy.