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

Abstract

2590 Background: Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus (HPV) types 6 & 11. RRP proliferates in the squamous epithelium lining the respiratory tract impacting breathing, swallowing, and voice and carries a 3-5% risk of malignant transformation. Given the multi-focality of the disease and tolerized host immune response against HPV, in part through upregulation of the PD1:PDL1 axis, the safety and efficacy of systemic 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. Primary endpoints were best overall response (ORR) (measured by endoscopic lesional burden) and safety. Greater than 5 pts with disease 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). HPV-specific CD8+ T cell frequency and functional states and biomarkers of response and immune resistance are being evaluated in serial tissue and liquid biopsies (up to 8 biopsies/patient over the 24 months of treatment). Results: The Simon two-stage, stage 1 criteria was met. A total of 21 patients were enrolled and all are now off treatment. Median age (range) was 45 (19-68), 57% (12/21) were male and 67% (14/21) were white. 48% (10/21) had Juvenile-onset (Jo)-RRP, 57% (12/21) had pulmonary RRP involvement, and 19% (4/21) had SCC derived from their RRP. 62% (13/21) completed 24 months of treatment. Reasons for discontinuation included disease progression (14%, 3/21), treatment related adverse event (TRAEs) (14%, 3/21), and study withdrawal (10%, 2/21). A partial response (≥25% reduction in endoscopic tumor burden score) was observed in 57% (12/21) (95% CI: 34%-78.2%) of pts (7 of 10 with Jo-RRP and 5 of 11 with Adult-onset (Ao)-RRP disease responded). Stable disease was observed in 33% (7/21). No complete responses were observed. Fatigue was the most frequent TRAEs; Grade 3 TRAEs included uveitis and hypophysitis, both of which were reversible upon pembro discontinuation and steroid use. At a median follow-up: 25.6 (6.2-38.1 months), the mean number of surgical interventions was reduced by 7 surgeries/year (p = 0.004) in pts treated on the trial for > 12 months, and, upon treatment completion, durable clinical benefit was observed with no additional treatment needed for the duration of the clinical trial follow-up for some pts. Conclusions: Pembro reduces the need for routine surgical interventions based on the durable 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.

Interim Results of a Phase 1/2 Open‐Label Study of INO‐3107 for HPV‐6 and/or HPV‐11‐Associated Recurrent Respiratory Papillomatosis

“…However, disease recurrence can occur when bevacizumab is discontinued, 21,22 suggesting long‐term immunologic control of the disease is needed to provide long‐lasting protection. Two separate studies investigating the use of avelumab or pembrolizumab for the treatment of adult patients with RRP have shown significant reductions in RRP disease burden without surgery, with evaluable HPV‐specific T‐cell responses in several patients; treatment was well tolerated 11,12,14 . Studies on the use of locally injected cidofovir as an adjuvant treatment with surgical debulking of papillomatous disease have shown equivocal results, with clinical benefit not always demonstrated 12 ; moreover, a Cochrane review of the sole prospective clinical study in this regard found no significant difference between cidofovir treatment and placebo at 12 months 23 …”

“…The safety profile and efficacy of INO-3107 plus EP in the present study are in line with other nonsurgical/ adjuvant therapies for RRP, such as bevacizumab and ICIs, and appear to be better than those of the antiviral medication, cidofovir. [11][12][13][14][15] Two recent systematic reviews of bevacizumab for the treatment of severe RRP have shown marked improvements in symptoms with a reduced need for surgical intervention during long-term follow-up (range, 2 months to 5 years), with many patients not requiring any surgery while on treatment. Bevacizumab treatment was safe and well tolerated, with side effects considered as mild or moderate.…”

“…Studies have also demonstrated benefits for the treatment of RRP with other systemic therapies, including bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor, and immune checkpoint inhibitors (ICIs), such as avelumab and pembrolizumab. [11][12][13][14][15] INO-3107 is an investigational DNA immunotherapy designed to elicit targeted T-cell responses against HPV-6 and HPV-11. It comprises a single plasmid encoding both HPV-6 and HPV-11 E6 and E7 proteins, plus a single plasmid that encodes interleukin-12.…”

“…Specific to RRP, a pilot clinical study of an investigational HPV‐6‐specific DNA immunotherapy, INO‐3106, administered IM/EP in 2 patients with HPV‐6‐associated papillomatosis resulted in surgery‐free intervals of >500 and >900 days, 10 providing additional proof‐of‐concept of the tolerability, immunogenicity, and efficacy of this technology. Studies have also demonstrated benefits for the treatment of RRP with other systemic therapies, including bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor, and immune checkpoint inhibitors (ICIs), such as avelumab and pembrolizumab 11–15 …”

Recurrent Respiratory Papillomatosis: An Update

“…45,46 Multiple PD-1 inhibitors such as pembrolizumab and avelumab are involved in clinical trials for treatment of adult RRP. 47,48…”