Neoadjuvant Nivolumab Plus Chemotherapy Followed By Response-Adaptive Therapy for HPV<sup>+</sup> Oropharyngeal Cancer
Authors: Ari J. Rosenberg, Nishant Agrawal, Aditya Juloori, John Cursio, Zhen Gooi, Elizabeth Blair, Jeffrey Chin, Daniel Ginat, Olga Pasternak-Wise, Rifat Hasina, Anna Starus, Frederick S. Jones, Evgeny Izumchenko, Ellen MacCracken, Rachelle Wolk, Nicole Cipriani, Mark W. Lingen, Alexander T. Pearson, Tanguy Y. Seiwert, Daniel J. Haraf, Everett E. Vokes
Journal: JAMA Oncology (2024)

Importance Immune checkpoint inhibitors improve survival in recurrent and/or metastatic head and neck cancer, yet their role in curative human papillomavirus−positive oropharyngeal cancer (HPV + OPC) remains undefined. Neoadjuvant nivolumab and chemotherapy followed by response-adaptive treatment in HPV + OPC may increase efficacy while reducing toxicity. Objective To determine the deep response rate and tolerability of the addition of neoadjuvant nivolumab to chemotherapy followed by response-adapted locoregional therapy (LRT) in patients with HPV + OPC. Design, Setting, and Participants This phase 2 nonrandomized clinical trial conducted at a single academic center enrolled 77 patients with locoregionally advanced HPV + OPC from 2017 to 2020. Data analyses were performed from February 10, 2021, to January 9, 2023. Interventions Addition of nivolumab to neoadjuvant nab-paclitaxel and carboplatin (studied in the first OPTIMA trial) followed by response-adapted LRT in patients with HPV + OPC stages III to IV. Main Outcomes and Measures Primary outcome was deep response rate to neoadjuvant nivolumab plus chemotherapy, defined as the proportion of tumors with 50% or greater shrinkage per the Response Evaluation Criteria in Solid Tumors 1.1. Secondary outcomes were progression-free survival (PFS) and overall survival (OS). Swallowing function, quality of life, and tissue- and blood-based biomarkers, including programmed death-ligand 1 (PD-L1) expression and circulating tumor HPV-DNA (ctHPV-DNA), were also evaluated. Results The 73 eligible patients (median [range] age, 61 [37-82] years; 6 [8.2%] female; 67 [91.8%] male) started neoadjuvant nivolumab and chemotherapy. Deep responses were observed in 51 patients (70.8%; 95% CI, 0.59-0.81). Subsequent risk- and response-adaptive therapy was assigned as follows: group A, single-modality radiotherapy alone or transoral robotic surgery (28 patients); group B, intermediate-dose chemoradiotherapy of 45 to 50 Gray (34 patients); and group C, regular-dose chemoradiotherapy of 70 to 75 Gray (10 patients). Two-year PFS and OS were 90.0% (95% CI, 0.80-0.95) and 91.4% (95% CI, 0.82-0.96), respectively. By response-adapted group, 2-year PFS and OS for group A were 96.4% and 96.4%, and group B, 88.0% and 91.0%, respectively. Lower enteral feeding rates and changes in weight, as well as improved swallowing, were observed among patients who received response-adapted LRT. Pathologic complete response rate among patients who underwent transoral robotic surgery was 67.0%. PD-L1 expression was nonsignificantly higher for deeper responses and improved PFS, and ctHPV-DNA clearance was significantly associated with improved PFS. Conclusions and Relevance This phase 2 nonrandomized clinical trial found that neoadjuvant nivolumab and chemotherapy followed by response-adapted LRT is feasible and has favorable tolerability, excellent OS, and improved functional outcomes in HPV + OPC, including among patients with high-risk disease. Moreover, addition of nivolumab may benefit high PD-L1 expressors, and sensitive dynamic biomarkers (eg, ctHPV-DNA) are useful for patient selection. Trial Registration ClinicalTrials.gov Identifier: NCT03107182