Induction Nivolumab Before Chemoradiation in High-Risk Human Papillomavirus–Driven Oropharynx Cancers: IMMUNEBOOST-HPV, a Multicenter Randomized Phase II Trial

PURPOSE Patients with human papillomavirus (HPV)–positive oropharyngeal cancer (OPC) and advanced stage and/or significant smoking history are at higher risk of relapse. Induction immunotherapy before chemoradiation (CRT) may improve outcomes. This randomized phase II trial assessed the feasibility and safety of induction nivolumab before CRT in this high-risk population. METHODS Eligible patients had HPV-positive OPC with either T4 and/or N2/N3 disease or a smoking history >10 pack-years. Patients were randomly assigned 1:2 to receive either standard CRT (70 Gy with cisplatin, control arm [CA], n = 20) or two infusions of nivolumab followed by CRT (experimental arm [EA], n = 41). The primary end point was the rate of patients who received full treatment in due time (FTDT), defined as (1) two nivolumab infusions on days 1 and 13-17, (2) CRT started between days 27-37 after the first nivolumab infusion, (3) no radiotherapy break ≥7 days, (4) >95% of theoretical/prescribed RT dose, and (5) cisplatin dose received ≥200 mg/m 2 . If two patients or less in the EA failed FTDT, the strategy would be considered feasible. Secondary end points included oncologic outcomes and toxicity. RESULTS Between July 2019 and September 2021, 62 patients were randomly assigned. Median follow-up was 37.5 months. The primary end point was not met: four of 41 patients in EA received <200 mg/m 2 cisplatin. Grade 4 to 5 acute adverse events occurred only in EA, in seven patients. The 2-year cumulative incidence (95% CI) of relapse was 7.3% (1.9 to 18.0) in EA versus 15.0% (3.6 to 34.0) in CA. CONCLUSION Induction nivolumab before CRT did not meet the predefined feasibility threshold because of reduced cisplatin dosing after toxicity in 10% of patients. The relapse incidence was numerically lower in the EA but this finding is exploratory and requires confirmation.