992O - Pembrolizumab for HPV-associated recurrent respiratory papillomatosis

Background

Recurrent respiratory papillomatosis (RRP) is an orphan disease caused by infection with human papillomavirus (HPV) types 6 and 11. RRP is a disabling condition with no cure and adversely affects breathing in children and adults. Up to 8.9% of patients with RRP have pulmonary involvement, which carries a 32-fold increased lifetime risk of malignant transformation. Repeat surgical or procedural interventions to debulk the papillomas within the respiratory tract are the standard of care treatment. Due to multifocal involvement and tolerogenic host immune responses to chronic HPV infection, systemic pembrolizumab was evaluated as an alternative treatment option for patients with RRP.

Methods

In this single-arm phase II clinical trial, RRP patients with laryngeal, tracheal, or pulmonary disease were treated with pembrolizumab monotherapy for up to 24 months. A Simon two-stage design was used to assess the best objective response rate (ORR) based on endoscopic lesional (EL) burden and Response Evaluation Criteria in Solid Tumors (RECIST). Safety was a co-primary endpoint. Additional endpoints included duration of response and patient-reported outcomes.

Results

Between May 27, 2016, and January 17, 2019, 21 patients were registered for the trial. EL-ORR was 52.4% (11/21) (two-stage 95% CI: 0.29 to 0.74). The median time to response (range) was 7.7 months (2.3-24.5 months), and the duration of response (range) was 14.1 months (0.7-19.5 months). Treatment was well tolerated with > 61% (13/21) of participants completing two years of treatment. The median number of surgical interventions was reduced by 4 per year (p<0.01). Increases in IFN-g secreting HPV-specific CD8+ T cells correlated with disease regression. At the end of treatment, 90% (19/21) reported intravenous infusion of pembrolizumab was preferred over current standard of care surgery or in-office procedures.

Conclusions

Pembrolizumab treatment was well-tolerated in a patient population with chronic HPV infection. Furthermore, patients with HPV-associated RRP achieved a durable clinical benefit, which resulted in an improved quality of life. Patient-reported outcomes show a preference for treatment with systemic pembrolizumab over a surgery-based standard of care.

Clinical trial identification

DFHCC #15-469; NCT02632344.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Merck Sharp & Dohme Llc, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Food and Drug Administration Orphan Products Grants Program.

Disclosure

S. Pai: Financial Interests, Personal, Advisory Board: Sensei, Scopus, Cue Biopharma, Merck, MSD, Lyell, Recurrent Respiratory Papillomatosis; Financial Interests, Institutional, Research Funding: Merck, AstraZeneca; Financial Interests, Institutional, Research Grant: National Cancer Institute, National Institute of Dental and Craniofacial; Financial Interests, Personal, Other: Cancer Research. J.C. Park: Financial Interests, Institutional, Local PI: Inhibrx, Ankyra, ALX, A2 Bio, CUE Bio, Alentis. All other authors have declared no conflicts of interest.