Oral proliferative leukoplakia (PL) is an aggressive precancerous disease characterized by multifocal lesions and a high-risk of transformation to oral squamous cell carcinoma (OSCC). There are no effective therapies that prevent progression to oral cancer. PL demonstrates a rich immune microenvironment, providing strong rationale to evaluate PD-1 blockade as preventative immunotherapy.
This single-arm, phase 2 trial investigated nivolumab (N) among patients (pts) with PL (multifocal, contiguous, or a single lesion ≥4 cm with any degree of epithelial dysplasia); a history of previously treated early-stage OSCC was permitted. Pts underwent pre-treatment biopsy of 1-3 sites then received 4 doses of N (480 mg IV) every 28-days, followed by re-biopsy. Intraoral photographs and bidirectional measurements occurred at each visit. Primary endpoint: change in composite score (size and degree of dysplasia) pre- to post-treatment (CR: >80% decrease in score; PR: 40-80% decrease; PD: ≥10% increase in composite score or new OSCC). Secondary endpoints: safety, cancer-free survival (CFS). Exploratory aims: PD-L1 status, genomic and immune profiling parameters.
Between 1/2019 and 12/2021, 33 pts enrolled; 30 evaluable to date. Median age: 64 (range: 32-80), mostly women (18, 60%), 16 (53%) former/current smokers; oral tongue (13, 43%) was the main disease subsite; 8 (27%) had prior OSCC. A decrease of ≥40% in composite score was observed in 37% of pts (3 CRs and 8 PRs); 14 (47%) had stable disease, 4 experienced PD. 26 (86%) completed all 4 doses of N; 2 (7%) discontinued for toxicity, 2 (7%) for PD. Grade 3-4 irAEs were noted among 7 (23%) pts (hyperglycemia, colitis, hepatitis). At median follow-up of 16.3 mos (4.1-34.3+), median CFS was not reached, with 7 (23%) cancer events observed (3 among prior responders); 1-year CFS: 76.5% (95%CI 54.5-88.8). All pts are alive at last follow-up. Baseline median PD-L1 CPS trended higher among responders (15 vs. 5, p=0.10).
Nivolumab yielded a best response of PL regression among 37% of pts with a favorable overall CFS. This is the first study to demonstrate evidence of efficacy using preventative immunotherapy for high-risk oral precancerous disease.
Clinical trial identification
Legal entity responsible for the study
G.J. Hanna, MD and BMS.
G.J. Hanna: Financial Interests, Institutional, Sponsor/Funding: BMS; Financial Interests, Institutional, Research Grant: Bicara, Exicure, Gateway for Cancer Research, GSK, Kite, NantKwest, Regeneron, Sanofi Genzyme; Financial Interests, Personal, Advisory Board: Coherus, Maverick, Merck. A. Villa: Financial Interests, Institutional, Research Grant: PCCA, Merck. N.S. Treister: Financial Interests, Personal, Advisory Role: MuReva Phototherapy; Financial Interests, Institutional, Research Grant: THOR Photomedicine Ltd; Financial Interests, Personal, Advisory Board: Alosa Health. R. Uppaluri: Financial Interests, Personal and Institutional, Research Grant, Advisory Board: Merck. R. Haddad: Non-Financial Interests, Personal, Member: NCCN; Financial Interests, Personal and Institutional, Advisory Role: Celgene, Merck, BMS, AstraZeneca, Pfizer, Genentech, Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Eisai, Loxo, Immunomic Therapeutics, GSK, Gilead, Vaccinex, EMD Serono, BioNTech AG, Achilles Therapeutics, Bayer, Coherus, MIRATI; Financial Interests, Institutional, Research Grant: Kura. All other authors have declared no conflicts of interest.