First non-randomised study of immune checkpoint blockade in patients with precancerous disease, specifically patients with high-risk oral precancer, to mitigate progression to oral squamous cell carcinoma (OSCC), met its primary response endpoint, but few patients had complete lesion regression. Recognising the limitations and complexity of measuring treatment outcomes in cancer prevention studies, the investigators demonstrate potential clinical activity and acceptable safety with the use of immune checkpoint inhibitor in a population with high-risk precancer.

A next step would be to consider a larger, precision immunotherapy randomised study favouring cancer-free survival (CFS) as a primary outcome and stratified by prior history of early-stage treated OSCC and 9p21.3 loss according to Dr. Glenn J. Hanna of the Department of Medical Oncology, Center for Head & Neck Oncology, Dana-Farber Cancer Institute, Harvard Medical School in Boston, MA, US, and colleagues who published their findings on 16 November 2023 in the JAMA Oncology.

The authors wrote in the background that oral leukoplakia refers to a white plaque of variable cancer risk, having excluded other conditions, and affects up to 5% of the global population, but only a small proportion of leukoplakia lesions will undergo malignant transformation. Degree of epithelial dysplasia, lesion size, and tobacco history all influence the transformation rate.

Proliferative verrucous leukoplakia defines an aggressive subtype with a malignant transformation rate exceeding 10% per year, characterised by heterogeneous or verrucous lesions involving multiple oral subsites. No treatments have been shown to change the natural history of this severe oral precancerous disease.

Prior retrospective study revealed a cytotoxic T-cell–rich immune microenvironment in proliferative verrucous leukoplakia. These findings together with immunosurveillance studies in the context of lung premalignancy and of various immuno-oncology interventions in preclinical models provided strong rationale for investigating PD1/PD-L1 axis blockade in oral precancerous disease. 

The aim of this study was to determine the safety and clinical activity of anti-PD1 preventive therapy to treat high-risk proliferative verrucous leukoplakia. This non-randomised, open-label, phase II study was conducted from January 2019 to December 2021 at a single academic medical centre.

Median follow-up was 21.1 months (range, 5.4-43.6). Participants were a population-based sample of patients with proliferative verrucous leukoplakia (multifocal, contiguous, or a single lesion ≥4 cm with any degree of dysplasia). Patients underwent pretreatment biopsy (1-3 sites) and then received 4 doses of nivolumab 480 mg intravenously every 28 days, followed by re-biopsy and intraoral photographs at each visit.

The primary endpoint was the change in composite score (size and degree of dysplasia) from before to after treatment with major response (MR) defined as >80% decrease in score and partial response defined as 40-80% decrease. Secondary analyses included immune-related adverse events, CFS, PD-L1 expression, 9p21.3 deletion, and other exploratory immunologic and genomic associations of response.

A total of 33 patients were enrolled. Median age was 63 years (range, 32-80), 18 patients were female (55%), including 8 (24%) with previously resected early-stage OSCC. Twelve patients (36%; 95% confidence interval [CI] 20.4%-54.8%) had a response by composite score of which 3 MRs (9%), and 4 had progressive disease (>10% composite score increase, or cancer). Nine patients (27%) developed OSCC during the study, with a 2-year CFS of 73% (95% CI 53%-86%).

Two patients (6%) discontinued because of side effects and 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 pre-treatment biopsy, while only 4 of the 14 patients (29%) who did not develop OSCC had 9p21.3 loss.

The authors underlined that other studies using immunotherapy to treat patients with high-risk oral premalignant lesions are ongoing. In an invited commentary, Drs. Bishal Gyawali and Garth W. Strohbehn wrote that these are interesting early data, but the study is only hypothesis generating in the absence of randomisation.

A major concern with treatment of premalignant conditions is overtreatment. With preventive therapy, the potential for overtreatment and harm is even higher than for adjuvant treatment and may involve a larger population; thus, evidence-based standards for adoption should be more stringent.

The commentators emphasized that we should not forget the end goal of prevention, which is not to treat the conditions per se, but to help populations that have a high risk of developing cancer live longer and better. Second, context matters. Cancers with efficacious, tolerable, cost-effective treatments may be more efficiently and cost-effectively managed by screening-based early detection than expensive, toxic, therapy-based prevention.

An intervention’s efficacy must be tested in well-designed, well-conducted randomised studies that minimise bias and assess outcomes that matter to public health, including mortality, number needed to treat to prevent a cancer death, and number needed to harm by causing a chronic, serious, or fatal adverse event. Once efficacy is established, trade-offs (including cost-effectiveness) must be quantified, and decisions made via a predictable and agreed-upon framework. According to the commentators, the use of immunotherapy has a long way to go to satisfy these principles for secondary prevention of cancer.