Background: The role of neoadjuvant immunotherapy in curative-intent head and neck squamous cell carcinoma (HNSCC) remains poorly defined. Survival for locoregionally advanced (LA) HPV negative (-) HNSCC remains poor with two-year survival of ~50%, and substantial treatment-related toxicity with standard chemoradiation (CRT). Given the activity of anti-PD1 in recurrent/metastatic HNSCC, we studied neoadjuvant nivolumab with chemotherapy and the feasibility of subsequent response-stratified CRT in HPV(-) LA HNSCC. Methods: The DEPEND trial (NCT03944915) is a phase II trial of nivolumab, paclitaxel, and carboplatin followed by response-stratified CRT for previously untreated stage IVA-B (AJCC-8th edition) HPV(-) HNSCC. The ultimate goal is to evaluate radiation volume and/or dose reduction to decrease long-term toxicities. Eligible patients received three 21-day cycles of nivolumab 360mg day 1, paclitaxel 100mg/m2 on days 1/8/15, and carboplatin AUC5 day 1. Patients with ≥50% reduction by RECIST 1.1 received response-adapted CRT to 66Gy with elimination of elective nodal volumes; < 50% reduction received standard-dose CRT to 70-75Gy. Post-CRT nivolumab 480mg every 4 weeks for 9 months was administered. The primary endpoint was deep response rate (DRR) defined as the proportion of patients with ≥50% reduction. Tumor PD-L1 immunohistochemistry was reported as combined positive score (CPS). Results: Thirty-six eligible patients started treatment between September 2019 and June 2022. Median age 59 (range 27-77), 22% female, 80% 20PYH smoking, 39% oral cavity, 19% oropharynx, 25% larynx/hypopharynx, 78% T3/4 and 78% N2/3. PD-L1 CPS ≥1 in 58%. The DRR with nivolumab/chemotherapy was 54% (95% CI 0.37-0.72), which met our statistical endpoint. The ORR was 89%. CRT stratification was as follows: Response-adapted CRT (n = 19) and standard-dose CRT (n = 16). At a median follow-up of 14 months, 2-year PFS and OS were 64% (95%CI 0.41-0.80) and 76% (95%CI 0.53-0.89), respectively. By CRT stratification, 2-year PFS was 79% and 46% in response-adapted and standard-dose CRT, and 2-year OS was 86% and 67% in response-adapted and standard-dose CRT, respectively. One patient died from disease progression during neoadjuvant therapy. 2-year distant control in response-adapted and standard-dose CRT arms was 100% and 63%, and 2-year locoregional control was 85% and 92%, respectively. PD-L1 CPS ≥1 and < 1 demonstrated DRR of 75% and 27%, respectively (p= 0.01). Conclusions: Nivolumab-based neoadjuvant chemoimmunotherapy led to deep responses, and response-adapted CRT was associated with favorable survival and locoregional control. PD-L1 expression was predictive of deep response to nivolumab-based neoadjuvant therapy. Late toxicity analysis between treatment arms is planned. Clinical trial information: NCT03944915.