Pathologic Response After Neoadjuvant Chemoimmunotherapy in Head and Neck Squamous Cell Carcinoma

Importance Treatment outcomes for locally advanced head and neck squamous cell carcinoma (HNSCC) remain suboptimal, and strategies to improve response to therapy are needed. Neoadjuvant immunotherapy has shown promise, but pathologic response rates remain modest with single-agent regimens. Objective To compare rates of pathologic response between neoadjuvant immunotherapy (NAI) and neoadjuvant chemoimmunotherapy (NACI) in patients with resectable HNSCC treated in an off-trial setting. Design, Setting, and Participants This was a single-center retrospective cohort study of adult patients with pathologically confirmed HNSCC of the aerodigestive tract who received at least 1 cycle of NAI or NACI followed by definitive surgery at a large, urban tertiary academic referral center from July 19, 2024, to March 4, 2026. Patients with locoregional recurrence were included if treated with curative intent. Propensity score–adjusted analyses were performed to account for baseline differences between treatment groups. Data were analyzed from March 5 to June 17, 2026. Exposure NAI and NACI, typically administered over 2 cycles, before surgery. Main Outcomes and Measures Pathologic response in the surgical specimen, categorized as pathologic complete response (pCR), major pathologic response (MPR; ≤10% viable tumor), or partial response. Deep pathologic response was defined as pCR or MPR. Results Among 86 participants (mean [SD] age, 63 [12] years; 27 female [31%] and 59 male [69%]), 25 (29%; 95% CI, 21%-39%) achieved pCR and 15 (17%; 95% CI, 11%-27%) achieved MPR. pCR or MPR occurred in 39 of 58 NACI recipients (67%; 95% CI, 54%-78%) compared with 1 of 28 NAI recipients (3.6%; 95% CI, 0.6%-17.7%). In propensity score–adjusted analysis, NACI was associated with higher odds of pCR or MPR (odds ratio [OR], 29.1; 95% CI, 6.7-274.7). Treatment was generally well tolerated, with few adverse event−related delays to surgery. Conclusions and Relevance In this cohort study, neoadjuvant chemoimmunotherapy was associated with substantially higher rates of pCR and MPR compared with immunotherapy alone in resectable HNSCC. These findings support the potential role of combination regimens in improving tumor response, although prospective trials are needed to determine effects on survival.