A phase II study of pembrolizumab for HPV-associated papilloma patients with laryngeal, tracheal, and/or pulmonary involvement.

2502 Background: Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus (HPV) types 6 & 11. RRP proliferates in the respiratory tract impacting breathing, swallowing, and voice and carries a 1-4% risk of malignant transformation. There is no curative therapy for RRP. Given the tolerized host immune response against HPV, in part through upregulation of the PD1:PDL1 axis, the safety and efficacy of pembrolizumab (pembro) as a novel treatment for this benign tumor patient (pt) population was evaluated in a phase II clinical trial. Methods: RRP pts > 12 years of age were treated with pembro 200mg every 3 weeks. Adjuvant surgical debridement of RRP was permitted for airway obstruction but not dysphonia. Primary endpoints were best overall response (ORR) (measured by endoscopic lesional burden) and safety. Greater than 5 pts with disease in response out of 21 (assuming > 1 of first n = 11 with disease in response) provided 86% power to distinguish between a 15% and a 38% ORR (one-sided 8% binomial test). Serial biopsies (up to 8 biopsies/patient over the 24 months of treatment) to identify biomarkers of response and mechanisms of immune resistance (PD-L1 expression, mutations in HLA class I antigen presentation machinery, and tumor mutational burden) are underway. Results: Accrual is complete (n = 21 pts accrued between May 2016 and Jan 2019). Median age (range) was 45 (19-68), 57% (12/21) were male and 67% (14/21) were white. As of February 1, 2019, ORR is 43% (9/21) (.95 two-stage CI: 22%-66%) (4 of 11 with juvenile-onset RRP and 5 of 10 with adult-onset RRP disease responded). No complete responses have been observed. Fatigue was the most frequent treatment related adverse event (TRAEs); Grade 3 TRAEs included uveitis and hypophysitis, both were reversible upon pembro discontinuation. The frequency of surgical interventions was reduced in all pts undergoing surgery for airway palliation prior to study entry. Conclusions: Pembro reduces the need for routine surgical interventions based on the response rates being achieved. Further study of pembro +/- other agents is warranted to achieve and sustain complete responses in this population. Clinical trial information: NCT02632344.