Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Untreated Oral Cavity Squamous Cell Carcinoma

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 PARTICIPANTSIn this randomized phase 2 clinical trial conducted at 1 academic center, 29 patients with untreated squamous cell carcinoma of the oral cavity (ՆT2, 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.

Clinical benefit of neoadjuvant anti‐PD‐1/PD‐L1 utilization among different tumors

“…Further, 313 articles were excluded when assessing the eligibility according to the inclusion criteria. Eventually, 20 eligible articles were included in this meta‐analysis 20–39 . The procedure is demonstrated in Figure 1.…”

“…PD‐1/PD‐L1 inhibitors like atezolizumab and pembrolizumab showed superior efficacy in clinical utilization 12,14–19 . Some studies try to uncover the clinical value of the utilization of PD‐1/PD‐L1 inhibitors in neoadjuvant therapy 20–39 . To evaluate the efficacy and safety of the therapy, this meta‐analysis pooled and analyzed the data of these trials.…”

Importance of the PD-1/PD-L1 Axis for Malignant Transformation and Risk Assessment of Oral Leukoplakia

“…In some of these patients PD-1 blocking leads to long lasting responses [ 2 ]. Recently, the clinical use of checkpoint inhibitors is shifting towards early stages of OSCC treatment with the first results of successful neoadjuvant PD-1 inhibition being published [ 3 , 4 ] and currently evaluated in a large prospective study (KEYNOTE-689 study; NCT03765918).…”

Current Trends and Future Prospects of Molecular Targeted Therapy in Head and Neck Squamous Cell Carcinoma

“…Currently, cetuximab, which is an anti-EGFR antibody, and nivolumab and pembrolizumab, which are anti-PD-1 antibodies, have been approved and treated as molecular targeted therapeutic agents that can be used for oral cancer [ 57 ]. In addition, clinical trials of molecular targeted therapeutic agents such as ipilimumab, which is an anti-CTLA-4 antibody [ 58 ], and avelumab and atezolizumab, which are anti-PD-L1 antibodies [ 59 ], have been performed. However, which agent should be used and how much effect can be expected differ from each patient when using these molecular targeted therapeutic agents, and it is considered that there is no response to these agents at all.…”