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Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Untreated Oral Cavity Squamous Cell Carcinoma: A Phase 2 Open-Label Randomized Clinical Trial

Authors: Schoenfeld, Jonathan D; Hanna, Glenn J; Jo, Vickie Y; Rawal, Bhupendra; Chen, Yu-Hui; Catalano, Paul S; Lako, Ana; Ciantra, Zoe; Weirather, Jason L; Criscitiello, Shana; Luoma, Adrienne; Chau, Nicole; Lorch, Jochen; Kass, Jason I; Annino, Donald; Goguen, Laura; Desai, Anupam; Ross, Brendan; Shah, Hina J; Jacene, Heather A; Margalit, Danielle N; Tishler, Roy B; Wucherpfennig, Kai W; Rodig, Scott J; Uppaluri, Ravindra; Haddad, Robert I

Online: https://jamanetwork.com/journals/jamaoncology/article-abstract/2769892

Issue: JAMA Oncol. 2020 Oct 1;6(10):1563-1570.


Importance Novel approaches are needed to improve outcomes in patients with squamous cell carcinoma of the oral cavity. Neoadjuvant immunotherapy given prior to surgery and combining programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibitors are 2 strategies to enhance antitumor immune responses that could be of benefit. Design, Setting, and Participants In this randomized phase 2 clinical trial conducted at 1 academic center, 29 patients with untreated squamous cell carcinoma of the oral cavity (≥T2, or clinically node positive) were enrolled between 2016 to 2019. Interventions Treatment was administered with nivolumab, 3 mg/kg, weeks 1 and 3, or nivolumab and ipilimumab (ipilimumab, 1 mg/kg, given week 1 only). Patients had surgery 3 to 7 days following cycle 2. Main Outcomes and Measures Safety and volumetric response determined using bidirectional measurements. Secondary end points included pathologic and objective response, progression-free survival (PFS), and overall survival. Multiplex immunofluorescence was used to evaluate primary tumor immune markers. Results Fourteen patients were randomized to nivolumab (N) and 15 patients to nivolumab/ipilimumab (N+I) (mean [SD] age, 62 [12] years; 18 men [62%] and 11 women [38%]). The most common subsite was oral tongue (n = 16). Baseline clinical staging included patients with T2 (n = 20) or greater (n = 9) T stage and 17 patients (59%) with node-positive disease. Median time from cycle 1 to surgery was 19 days (range, 7-21 days); there were no surgical delays. There were toxic effects at least possibly related to study treatment in 21 patients, including grade 3 to 4 events in 2 (N), and 5 (N+I) patients. One patient died of conditions thought unrelated to study treatment (postoperative flap failure, stroke). There was evidence of response in both the N and N+I arms (volumetric response 50%, 53%; pathologic downstaging 53%, 69%; RECIST response 13%, 38%; and pathologic response 54%, 73%, respectively). Four patients had major/complete pathologic response greater than 90% (N, n = 1; N+I, n = 3). With 14.2 months median follow-up, 1-year progression-free survival was 85% and overall survival was 89%. Conclusions and Relevance Treatment with N and N+I was feasible prior to surgical resection. We observed promising rates of response in both arms, supporting further neoadjuvant studies with these agents. Trial Registration ClinicalTrials.gov Identifier: NCT02919683.