Nivolumab for Patients With High-Risk Oral Leukoplakia
Authors: Hanna Glenn J. , Villa Alessandro , Nandi Shuvro P. , Shi Ruichao , ONeill Anne , Liu Mofei , Quinn Charles T. , Treister Nathaniel S. , Sroussi Herve Y. , Vacharotayangul Piamkamon , Goguen Laura A. , Annino Donald J. , Rettig Eleni M. , Jo Vickie Y. , Wong Kristine S. , Lizotte Patrick , Paweletz Cloud P. , Uppaluri Ravindra , Haddad Robert I. , Cohen Ezra E. W. , Alexandrov Ludmil B. , William William N. , Lippman Scott M. , Woo Sook-bin 
Published: November 2023

ImportanceProliferative verrucous leukoplakia (PVL) is an aggressive oral precancerous disease characterized by a high risk of transformation to invasive oral squamous cell carcinoma (OSCC), and no therapies have been shown to affect its natural history. A recent study of the PVL immune landscape revealed a cytotoxic T-cell–rich microenvironment, providing strong rationale to investigate immune checkpoint therapy.ObjectiveTo determine the safety and clinical activity of anti–programmed cell death 1 protein (PD-1) therapy to treat high-risk PVL.Design, Setting, and ParticipantsThis nonrandomized, open-label, phase 2 clinical trial was conducted from January 2019 to December 2021 at a single academic medical center; median (range) follow-up was 21.1 (5.4-43.6) months. Participants were a population-based sample of patients with PVL (multifocal, contiguous, or a single lesion ≥4 cm with any degree of dysplasia).InterventionPatients underwent pretreatment biopsy (1-3 sites) and then received 4 doses of nivolumab (480 mg intravenously) every 28 days, followed by rebiopsy and intraoral photographs at each visit.Main Outcomes and MeasuresThe primary end point was the change in composite score (size and degree of dysplasia) from before to after treatment (major response [MR]: &amp;gt;80% decrease in score; partial response: 40%-80% decrease). Secondary analyses included immune-related adverse events, cancer-free survival (CFS), PD-1 ligand 1 (PD-L1) expression, 9p21.3 deletion, and other exploratory immunologic and genomic associations of response.ResultsA total of 33 patients were enrolled (median [range] age, 63 [32-80] years; 18 [55%] were female), including 8 (24%) with previously resected early-stage OSCC. Twelve patients (36%) (95% CI, 20.4%-54.8%) had a response by composite score (3 MRs [9%]), 4 had progressive disease (&amp;gt;10% composite score increase, or cancer). Nine patients (27%) developed OSCC during the trial, with a 2-year CFS of 73% (95% CI, 53%-86%). Two patients (6%) discontinued because of toxic effects; 7 (21%) experienced grade 3 to 4 immune-related adverse events. PD-L1 combined positive scores were not associated with response or CFS. Of 20 whole-exome sequenced patients, all 6 patients who had progression to OSCC after nivolumab treatment exhibited 9p21.3 somatic copy-number loss on pretreatment biopsy, while only 4 of the 14 patients (29%) who did not develop OSCC had 9p21.3 loss.Conclusions and RelevanceThis immune checkpoint therapy precancer nonrandomized clinical trial met its prespecified response end point, suggesting potential clinical activity for nivolumab in high-risk PVL. Findings identified immunogenomic associations to inform future trials in this precancerous disease with unmet medical need that has been difficult to study.Trial RegistrationClinicalTrials.gov Identifier: NCT03692325