The immune checkpoint inhibitor nivolumab (Opdivo) appears to prevent the transformation of oral proliferative leukoplakia (PL), a high-risk precancerous disease, into oral cancer, suggest the results from a phase 2 study.
“We think that immunotherapy as a preventative strategy, either as first-line or even secondary prevention, should be further explored,” said lead researcher Glenn J. Hanna, MD, director, Center for Salivary and Rare Head and Neck Cancers, Dana-Farber Cancer Institute, Boston, Massachusetts.
The research was presented at the European Society for Medical Oncology 2022 Congress in Paris, France.
Oral leukoplakia refers to a white plaque of “questionable cancer risk” that affects about 4% of the global population, Hanna explained. However, about 5% of leukoplakia cases develop into oral proliferative leukoplakia, an aggressive form of the disease characterized by multifocal lesions. It has a high risk of transformation to oral squamous cell carcinoma (OSCC), at approaching 10% per year, and the 5-year cancer-free survival rate is estimated to be 47%.
While there are no effective therapies to prevent progression to oral cancer, the condition does have a “rich immune microenvironment,” potentially making it amenable to programmed death (PD)-1 blockade, Hanna said.
His team conducted a single-arm, phase 2 trial involving 33 patients with proliferative leukoplakia with ≥ 2 multifocal lesions, or contiguous lesions of ≥ 3 cm, or a single lesion ≥ 4 cm with any degree of epithelial dysplasia. The median age was 63.2 years, and 55% were women. Just over half (52%) were never smokers.
The main disease subsite was the oral tongue in 39% of participants, followed by the buccal gingiva in 30%, and 24% of patients had a prior diagnosis of OSCC.
Following a pretreatment biopsy at one to three sites, the patients received four doses of nivolumab every 28 days, followed by rebiopsy. At each visit, the patients had intraoral photographs taken of the lesions and measurements taken.
The median time from study registration to the first dose of nivolumab was 9 days. The majority (88%) of patients completed all four doses of nivolumab.
The median time from the first dose of nivolumab to the posttreatment biopsy was 115 days, and ranged from 29 to 171 days.
The overall response rate, defined as a ≥ 40% decrease in a composite score combining the size and degree of dysplasia between the pre- and posttreatment assessments, was observed in 36.4% of patients.
After a median follow-up of 14.7 months, the median cancer-free survival was not reached, with cancer events recorded in 21.2% of patients. The median time from the last dose of nivolumab to the first OSCC event was 3.7 months.
Cancer-free survival at 1 year was calculated to be 77.7%, which was unchanged at 2 years. At the final follow-up, all patients were still alive.
Additional analysis of the biopsies revealed that the lesions had programmed death ligand 1 (PD-L1) combined positive scores that ranged from 0 to 80, with 66.7% of patients having a score of ≥ 1. A cutoff score of ≥ 20 did not reveal any significant differences in cancer-free survival rates.
Turning to safety, Hanna said that nivolumab was associated with “acceptable toxicity” in this “non-cancer population,” with 21.2% of patients experiencing a grade 3-4 adverse event.
The most common adverse events of any grade were fatigue (55%), diarrhea (27%), elevated alanine transaminase levels (18%), elevated aspartate transaminase levels (18%), and other skin disorders (18%).
With a relatively low rate of adverse events and a “clinical benefit” in up to a third of patients, Hanna said that this was the “first study to our knowledge to demonstrate the potential efficacy of anti-PD-L1 blockade among patients with a high-risk oral precancerous disease.”
Discussing this study at the meeting, Amanda Psyrri, MD, PhD, professor of medical oncology, Attikon University Hospital, Athens, Greece, who was not involved in the research, said these data were “very interesting” but she expressed some reservations over the way the study was conducted.
She said that the composite score to measure response rates was “defined arbitrarily” and its prognostic value “has not been demonstrated,” and also pointed out that mixed responses by lesions within the same patient led to changes in scores.
In addition, the time interval between the end of treatment and lesion rebiopsy was “highly variable,” and the follow-up period was short.
Consequently, Psyrri believes the importance of the findings is “unclear,” especially as several patients who responded to nivolumab went on to develop cancer anyway, a finding that needs further investigation.
The study was funded by Bristol Myers Squibb.
Hanna declared relationships with BMS, Bicara, Exicure, Gateway for Cancer Research, GSK, Kite, NantKwest, Regeneron, Sanofi Genzyme, Maverick, and Merck.
ESMO Congress 2022. Presented Sept. 12, 2022. Abstract 650O.
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