650O A phase II study of nivolumab for high-risk oral leukoplakia

Spatial PD‐L1, immune‐cell microenvironment, and genomic copy‐number alteration patterns and drivers of invasive‐disease transition in prospective oral precancer cohort

“…precancers can exhibit features of an inflamed phenotype with adaptive immune resistance, suggesting a possible role for PD-L1mediated mechanisms of immune evasion contributing to oral tumorigenesis and an opportunity for PD-1/PD-L1-targeting for immune interception in high risk OPC subgroups. The clinical relevance of our findings can be further highlighted by the recently reported results of a phase 2 study demonstrating activity of the PD-1 inhibitor nivolumab in patients with the high-risk oral proliferative verrucous leukoplakia precancer,46 thus supporting further evaluation of this strategy in larger cohorts. The inferior OCFS in PD-L1high, immune-cold OPCs observed here also support the development of (added) T-cell recruitment strategies for cancer prevention.…”

Single-cell and spatial dissection of precancerous lesions underlying the initiation process of oral squamous cell carcinoma

“…There is an ongoing phase IIa clinical trial exploring the potential of metformin to target PI3K/mTOR signaling in oral premalignant lesions 47 . For anti-PD-1 therapies in OSCC prevention, we should mention that in September 2022, the Hanna team published their latest results on the therapeutic effect of nivolumab (an anti-PD-1 antibody) in high-risk OLK, with a favorable overall cancer-free-survival of 37% 48 . While effort is required for further assessment of the safety and effectiveness of these therapies in OSCC prevention, these studies paved the way for OSCC intervention at an early stage.…”

Immunotherapy in Prepatients—Preventing or Promoting a Malignant Transformation?

“…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.…”

“…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 …”