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Original Investigation
August 27, 2020

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

Author Affiliations
  • 1Brigham and Women's Hospital, Boston, Massachusetts
  • 2Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
  • 3PRA Health Sciences, Boston, Massachusetts
  • 4Bristol-Myers Squibb, Boston, Massachusetts
  • 5Beth-Israel Deaconess Medical Center, Boston, Massachusetts
  • 6British Columbia Cancer, Vancouver, Canada
  • 7McGill Medical School, Montreal, Canada
JAMA Oncol. 2020;6(10):1563-1570. doi:10.1001/jamaoncol.2020.2955
Key Points

Question  Is neoadjuvant programmed cell death protein 1 (PD-1) or combined PD-1/cytotoxic T-lymphocyte–associated protein 4 inhibition administered prior to surgery tolerated and effective in patients with untreated squamous cell carcinoma of the oral cavity?

Findings  In this phase 2 clinical trial of 29 patients with oral cavity cancer randomized to nivolumab alone or nivolumab and ipilimumab, there were no delays to surgery, and evidence of clinical, radiologic, and pathologic responses in both arms, including 4 patients with major (>90%) or complete pathologic response—3 who were treated with nivolumab and ipilimumab.

Meaning  Both nivolumab and nivolumab plus ipilimumab are feasible in the neoadjuvant setting and result in promising rates of response.


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

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