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

Abstract

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.

Figure 1.. Trial Flow Diagram

Figure 2.. Summary of Response in Both Treatment Arms

A, The y-axis represents percent pathologic response. B, The y-axis represents percent unidirectional tumor response.

Figure 3.. Clinical and Pathologic Features of Response

A, Pretreatment image shows a cT2 squamous cell carcinoma of the right oral tongue. B, Fifteen days following cycle 1 of preoperative immunotherapy, image at the time of surgery demonstrates near-complete clinical regression of primary lesion (no residual squamous cell carcinoma identified on pathologic analysis). C, Original magnification ×200, and D, original magnification ×400 histopathologic images at the time of surgery following neoadjuvant immunotherapy in another patient with a robust response demonstrate evidence of robust T-cell infiltrate with evidence of regressed tumor, giant cell reaction, and acellular keratin. C and D, Hematoxylin-eosin.