Response-Adapted Surgery after Neoadjuvant Immunochemotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma (REMATCH): A Single-Arm Phase II Trial

PURPOSE: We assessed the feasibility and efficacy of a response-adapted surgical strategy in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) achieving major tumor regression after neoadjuvant immunochemotherapy (NAICT). PATIENTS AND METHODS: This phase II, single-arm, prospective trial enrolled patients with resectable, human papillomavirus-negative stage III to IVA LA-HNSCC. All received three cycles of NAICT (penpulimab, nab-paclitaxel, and cisplatin). Pre-cycle 3 imaging and laryngoscopy guided surgery: Patients with ≥50% primary tumor regression underwent reduced-volume surgery (RVS); those with <50% regression received standard-volume surgery (SVS). All received risk-adapted adjuvant radiotherapy. The primary endpoint was 2-year disease-free survival (DFS). RESULTS: Fifty patients completed NAICT, with an objective response rate of 94% [95% confidence interval (CI), 84%-99%]. At a median follow-up of 34.0 months (IQR, 30.1-39.5), the 2-year DFS for the per-protocol cohort was 83% (95% CI, 69%-91%). The RVS group (n = 42) achieved a 2-year DFS of 90% (95% CI, 77%-96%) with 100% laryngeal preservation in laryngeal/hypopharyngeal cancers, whereas the SVS group (n = 5) had a 2-year DFS of 20% (95% CI, 0.8%-58%). Grade 3 adverse events (AE) occurred in 16% of patients related to NAICT and in 15% related to surgery; there were no grade 4 or 5 AEs. At 9 months after radiotherapy, most quality-of-life scores improved or stabilized compared with baseline. CONCLUSIONS: The REMATCH trial provides the first prospective evidence that a response-adapted surgical strategy after NAICT is feasible. Patients achieving ≥50% primary tumor regression derived promising survival and universal laryngeal preservation. These findings support the initiation of phase III randomized trials to validate this de-escalation strategy.