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

IMPORTANCE Novel approaches aeneededu,impmve 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-Iymphocyte-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 random zed phase 2 clinical trial conducted at 1academic 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 land 3, or nivolumab and ipilimumab (ipilimumab, 1mg/kg, given week lonly). Patients had surgery 3 to 7 days following cycle 2. Al AIN 01..ITCONIE A NO Atil..IRE5 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+1) (mean [SO] 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 lto surgery was 19 days (range, 7-21days); 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+1, n = 3). With 14.2 months median follow-up, 1 -year progression -free survival was 85% and overall survival was 89%. CONCLUSIONS AND R EL E VA NC E 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.