Neoadjuvant Nivolumab Plus Chemotherapy Followed by Response-Stratified Chemoradiation Therapy in HPV-Negative Head and Neck Cancer: The DEPEND Phase 2 Nonrandomized Clinical Trial.

Importance: Neoadjuvant immunotherapy in human papillomavirus (HPV)-negative locoregionally advanced (LA) head and neck squamous cell carcinoma (HNSCC) appears promising, yet its role in nonsurgical treatment for head and neck cancer remains undefined. Neoadjuvant nivolumab plus chemotherapy followed by response-stratified de-escalated chemoradiation therapy (CRT) in HPV-negative LA stage IVa/b HNSCC may improve treatment efficacy while reducing treatment-related toxic effects.

Objective: To determine the deep response rate and tolerability of neoadjuvant nivolumab plus chemotherapy followed by response-stratified CRT in nonvirally mediated stage IVa/b HNSCC.

Design, Setting, And Participants: In this investigator-initiated phase 2 nonrandomized clinical trial conducted at a single academic center, patients with stage IVa/b (American Joint Committee on Cancer Tumor Classification, 8th edition) HPV-negative LA HNSCC were enrolled between 2019 and 2022. Data were analyzed from February 2023 to January 2024.

Interventions: The DEPEND trial evaluated neoadjuvant nivolumab plus carboplatin and paclitaxel, followed by response-stratified CRT. Patients with 50% or greater reduction per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 received de-escalated CRT to 66 Gy with elimination of elective nodal volumes; patients with less than 50% reduction received standard CRT to 70 to 75 Gy. Adjuvant nivolumab was administered for 9 cycles.

Main Outcomes And Measures: The primary end point was deep response rate (DRR; 50% or greater shrinkage per RECIST version 1.1) following neoadjuvant nivolumab plus chemotherapy. Secondary end points included progression-free survival (PFS), overall survival (OS), locoregional control, and distant control. Exploratory end points included acute toxic effects in patients who received response-adapted de-escalated CRT.

Results: Of 36 included patients, 28 (78%) were male, and the median (range) age was 58.9 (27-77) years. All patients started treatment and were available for analysis. The median (range) follow-up was 20 (13-40) months. The primary end point was met, with a DRR following neoadjuvant nivolumab/chemotherapy of 53% (95% CI, 35-70). The objective response rate was 86% (95% CI, 71-95). A total of 19 received de-escalated CRT and 16 received standard CRT. PFS and OS at 2 years were 66% (95% CI, 34-76) and 73% (95% CI, 52-86), respectively. The most common treatment-emergent adverse events for de-escalated and standard CRT were mucositis (14 of 19 [74%] and 15 of 16 [94%], respectively), radiation dermatitis (13 of 19 [68%] and 14 of 16 [88%], respectively), and dry mouth (7 of 19 [37%] and 10 of 16 [63%], respectively).

Conclusions And Relevance: In this phase 2 nonrandomized clinical trial, neoadjuvant nivolumab/chemotherapy led to deep responses in 53% of patients with HPV-negative LA stage IVa/b HNSCC, and response-adapted de-escalated CRT led to favorable survival with lower acute toxic effects among deep responders.

Trial Registration: ClinicalTrials.gov Identifier: NCT03944915.