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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Schoenfeld reports research support paid to the institution: Merck, BMS, Regeneron; Consulting/Scientific Advisory Board/Travel fees: Debiopharm, BMS, Nanobiotix, Tilos, AstraZeneca, LEK, Catenion, ACI Clinical, Immunitas; Expert witness fees. Dr Hanna reports consulting/advisory for BMS, Maverick, Merck, and Sanofi Genzyme; research support to institution from BMS, Exicure, GSK, Altor NantKwest, Kite, Regeneron, Sanofi Genzyme. Dr Jo reports immediate family member employment/equity Merck. Mr Rawal reports current employment at PRA Health Sciences. Dr Luoma reports current employment at BMS. Dr Chau reports research support paid to institution: Merck, GSK, Pfizer. Dr Lorch reports Consulting: Bayer, Genentech, BMS Scientific support to institution: BMS, Novartis, Bayer, Takeda. Dr Tishler Advisory Board: Regeneron; Data Safety Monitoring Board: PSI/Oragenics. Dr Jacene reports research support to institution: GTx Inc and Siemens Healthcare and consulting for Advanced Accelerator Applications. Dr Wucherpfennig reports consulting for TCR2 Therapeutics, T-Scan Therapeutics and Nextech Invest; he receives sponsored research funding from Novartis and is a co-founder of Immunitas Therapeutics. Dr Rodig receives research support from BMS, Merck, Affimed, and KITE/Gilead. Dr Uppaluri serves on a Merck Scientific Advisory Board. Dr Haddad reports consulting for BMS, Merck, AstraZeneca, Pfizer, GSK, Genentech, Celgene, and Bayer, and Research Support from GSK, Merck, BMS, Pfizer, AstraZeneca, Genentech, and Kura.

Figures

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.