Nivolumab for Patients With High-Risk Oral Leukoplakia

Abstract

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]: >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 (>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

Immunotherapy in Prepatients—Preventing or Promoting a Malignant Transformation?

“…In addition, toxicity warrants special attention when treating premalignant conditions due to increased potential for net harms. The 20% rate of grade 3 to 4 immune-related adverse events (irAEs) in this small trial at a highly specialized center should raise concern, since the incidence of irAEs, including potentially fatal toxic effects, can be substantial outside the carefully curated world of clinical trials …”

“…In this issue of JAMA Oncology , Hanna and colleagues present a nonrandomized controlled trial offering a glimpse into this new frontier, by treating high-risk oral proliferative verrucous leukoplakia (PVL), a condition that carries a 10% to 30% risk of transformation into oral squamous cell carcinoma (OSCC). In this industry-sponsored, single-center, single-group phase 2 trial including 33 patients, the investigators administered 4 cycles of nivolumab (480 mg every 4 weeks) to participants with high-risk PVL, defined as large lesions with dysplasia, PVL throughout the oral cavity, moderately dysplastic lesions, or erythroleukoplakia for which surgery was recommended but declined.…”

“…Recent clinical trials of adjuvant therapies, including with ICIs, are subject to several problems that limit their validity for routine clinical practice, such as underpowered post hoc subgroup analyses; combining heterogeneous subpopulations into a single study population, resulting in treatment effect point estimates just acceptable enough to garner approval in the largest population possible; and not insisting on demonstration of improved overall survival to change practice despite the potential for substantial overtreatment and life-altering toxic effects . Clinical trials of ICIs for secondary prevention of oral cancer stemming from the study published by Hanna and colleagues may be subject to related problems. Notably, this study did not exclude participants who had previously been treated for early-stage OSCC, thus enriching the study population for (1) PVLs that may, given diagnostic limitations, have truly been OSCC and (2) PVLs with demonstrated ability to undergo malignant transformation.…”

New insights into the role of the oral leukoplakia microenvironment in malignant transformation

“…Proliferative verrucous leukoplakia, a subtype with a high rate of malignant transformation, exhibited a distinct immune microenvironment compared to localized leukoplakia. CD8+ T cells and Tregs were more abundant in proliferative leukoplakia samples, often colocalizing at the dysplasia–stromal interface, with overexpression of programmed death-ligand 1 (PD-L1), a classic immune checkpoint related to the risk of malignant transformation ( 45 , 46 ), suggesting that the PD-1/PD-L1 axis blockade can be used as immunotherapy in oral precancer ( 47 ). This suggests that CD8+ and Tregs may play a role in promoting malignant transformation, potentially serving as a prognostic marker for carcinoma risk.…”

“…This role is mainly related to two components (Figure 1): Future perspectives in potentially malignant oral diseases point to improved risk prediction of malignant transformation and manipulation of the microenvironment as a therapeutic strategy. The use of immune checkpoint inhibitors, specifically anti-PD-1 immunotherapy, has been studied for the treatment of oral leukoplakia, and recently, a clinical trial in oral high-grade epithelial dysplasia was reported with promising results (47).…”