Larynx preservation via chemotherapy-free neoadjuvant sintilimab-cetuximab-SBRT and response-adapted treatment in locally advanced laryngeal cancer: A phase II, single-arm clinical trial (the NeoVOICE study).

6095 Background: The current standard of care for locally advanced laryngeal squamous cell carcinoma (LA-LSCC), including surgery and chemoradiotherapy, might cause long-term toxicities and laryngeal dysfunctions. The study aims to investigate the efficacy and safety of neoadjuvant cetuximab, sintilimab and stereotactic body radiation therapy (SBRT) treating patients with LA-LSCC for larynx preservation. Methods: In this phase II, single-arm trial, patients with LA-LSCC (cT2N1-3M0 or cT3-4aN0-3M0, AJCC 8.0 th ) were recruited. Eligible patients received SBRT (8 Gy × 3 fractions), followed by sintilimab (200mg, Q3W, 2 cycles) and cetuximab (a loading dose of 400 mg/m 2 , followed by 250 mg/m 2 , QW, 6 cycles). Further treatment was determined by a radiographic evaluation per RECIST 1.1: patients who reached CR or PR would receive intensity modulated radiation therapy (The initial IMRT dose to the primary tumor was 46 Gy in 23 fractions, with a pre-specified plan to reduce the dose to 37.8 Gy based on early tolerance data from the cohort.) or minimally invasive surgery, while ones with SD or PD would receive radical surgery. The primary endpoint was the larynx-preservation rate (LPR) at 1-year post-radiation. Results: Between July 1, 2024 and June 30, 2025, 20 patients were enrolled. 15 (75%) were clinical stage III and 5 were stage IVa. 19 finished neoadjuvant SBRT, sintilimab and cetuximab (one withdrawn due to personal reasons after SBRT), with the ORR of 100% (12 had CR and 7 had PR). Then 18 patients received sequential IMRT, with a median dose of 37.8 Gy (one refused and chose active surveillance). During the whole treatment, grade 3 TRAEs occurred in 5/20 patients (25%), including 3 cases of post-radiation pharyngitis, 1 myocarditis and 1 rash. All 3 cases of grade 3 pharyngitis occurred in the first 6 patients with 46 Gy IMRT. Following a protocol amendment, subsequent patients (n=12) received a reduced dose of 37.8 Gy. In the reduced-dose cohort, no further grade 3+ pharyngitis was observed, while the LPR remained high. After a median follow-up of 7.4 months, 3 patients failed to larynx preservation, including 2 cases with tracheotomies due to pharyngitis and 1 receiving total laryngectomy due to tumor recurrence. Based on results of EORTC QLQ-H&N35 questionnaires, compared to the baseline, most patients reported similar or improved symptoms, including pain, speech and dry mouth, at 6 months post-radiation. Conclusions: Neoadjuvant combination of immunotherapy, targeted therapy and SBRT showed excellent efficacy and tolerant toxicity for patients with LA-LSCC. Importantly, dose reduction of sequential IMRT appears to mitigate severe toxicity without compromising laryngeal preservation, outlining a promising de-escalation strategy for future practice. Clinical trial information: ChiCTR2500100185.