Adjuvant nivolumab in addition to postoperative radiation therapy in locally advanced head and neck cancer: Results of the phase II NadiHN trial.

6092 Background: The benefit of adding immune checkpoint inhibition to standard postoperative adjuvant radiotherapy in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) with an intermediate risk of recurrence remains unclear. Methods: The phase II, open-label, randomized, multicenter national NadiHN trial (EudraCT 2016-004787-20) enrolled participants with resected locally advanced HNSCC (R0 resection with ≥5 mm margins; no extracapsular nodal extension). Patients were stratified by primary site (oropharyngeal vs non-oropharyngeal), p16 status (for oropharyngeal tumors), centrally assessed PD-L1 tumor cell (TC) score (≥1% vs <1%), and center, and were randomized 1:1 to receive nivolumab before, during, and after postoperative radiotherapy (PORT) or PORT alone. Nivolumab (10 cycles of 240 mg q2w, followed by 10 cycles of 480 mg q4w) started 2 weeks prior to PORT. The primary endpoint was disease-free survival (DFS) in the intention-to-treat population. The planned sample size of 176 patients was designed to provide 80% power to detect a significant DFS improvement (log-rank test). Key secondary endpoints included overall survival (OS) and safety. Enrollment remained below target. During the trial, an adaptive interim analysis was implemented and led to early study termination upon Data Monitoring Committee recommendation due to futility. Results: Between 2017 and 2022, 84 participants were randomized (42 per arm). After a median follow-up of 37.3 months, median DFS was not reached in either group. The 2-year DFS rate was numerically higher with nivolumab + PORT (80%) than with PORT alone (69%), but the difference was not statistically significant (HR 0.934; 95% CI 0.408–2.140; p = 0.7301). Censoring deaths without documented recurrence yielded similar results. OS also did not differ significantly (HR 2.618; 95% CI 0.892–7.684; p = 0.0827). Grade ≥3 treatment-emergent adverse events occurred in 80.6% of patients in the nivolumab arm and 52.5% in the control arm. One treatment-related death occurred in the nivolumab + PORT arm. Conclusions: Interpretation of the trial is limited by early termination, small sample size, and fewer-than-expected DFS events. Adjuvant nivolumab added to standard PORT numerically—but not significantly—improved DFS in locally advanced HNSCC. Signals of potential benefit were observed in the PD-L1–positive subgroup (2y-DFS 82.4 vs. 76.2%) and lymph-node–positive subgroups (2y-DFS 84.2% vs. 70.7%). No new safety signals were identified. Funding: The trial was sponsored by the University Hospital Bonn with financial support from Bristol Myers Squibb. Clinical trial information: EudraCT 2016-004787-20.