Riebel, N.

6041 Background: Human papillomavirus (HPV) E6/E7 oncoproteins mediate immune evasion by down-regulating Type 1 interferons, TLR9, MHC Class I/II as well as other mechanisms, resulting in persistent infection and initiation of ̃5% of all cancers globally. Similarly, established cancers evade immune surveillance utilizing parallel mechanisms including the expression of checkpoint proteins. PDS0101 is a molecularly targeted immunotherapeutic based on an enantiospecific cationic lipid nanoparticle platform containing HPV16 neoantigens that exhibits anti-tumor activity with checkpoint inhibitors (CPIs) by upregulating Type I interferons and promoting antigen processing and cross presentation. This allows generation of high levels of polyfunctional HPV16-specific CD8 and CD4 T cells in vivo as well as immune memory. VERSATILE-002 (NCT04260126) is a phase 2 study of the combination of PDS0101 and pembrolizumab in treatment of CPI naïve and refractory patients with recurrent or metastatic HPV16-related HNSCC. Herein, we report preliminary safety and efficacy data for CPI naïve patients at a prespecified interim analysis. Methods: Subjects are treated with pembrolizumab 200mg IV every three weeks plus SC PDS0101 following pembrolizumab on days one of Cycles1-4 and Cycle12; pembrolizumab continues up until 35 cycles, disease progression or intolerance to therapy. Results: Eighteen CPI naïve subjects with confirmed HPV16 tumors and a CPS score > = 1, median age 62 yrs (range 46-71), all male, 17 (94%) of whom were White and 16 (88.9%) not Hispanic or Latino, received at least one cycle of combination therapy. At the time of analysis, 17 (94%) subjects had received > = 4 doses of PDS0101 (median 4, range 1-5) and pembrolizumab (median 7, range 1-14). There were no Grade 3 or greater treatment-related toxicities and no drug discontinuation related to toxicity or immune-related AEs. Clinical activity (CR+PR+SD) was seen in 13 (72.2%) of 18 subjects, with best overall reponse per RECIST1.1 documenting: OR in 7 (38.9%; 2 CR, 5PR); stable disease (SD) in 6 (33.3%) and progressive disease in 3 (16.7%); 2 subjects had missing data. Tumor reduction was seen in 4 of 6 (67%) subjects with SD. Nine-month PFS and OS rates (95% CI) were 52% (22.5, 74.7) and 81% (37.8, 95.5) respectively; median PFS and OS have not been reached. Conclusions: The combination of PDS0101 and pembrolizumab demonstrates an excellent safety profile with preliminary evidence of clinical activity in the majority of CPI naïve patients with HPV-related HNSCC. Clinical trial information: NCT04260126.

6012 Background: Up to 70% of oropharyngeal cancers in the US are reported to be HPV-mediated with most caused by HPV16 infection. First line treatment for patients with unresectable, recurrent or metastatic (R/M) disease is pembrolizumab with or without chemotherapy, but most patients eventually experience disease progression. PDS0101 is a novel, investigational HPV16-targeted immunotherapy that stimulates a potent, targeted T cell attack against HPV16-positive cancers. Methods: VERSATILE-002 (NCT04260126) is an open-label, non-randomized, Simon 2-stage study evaluating the combination of PDS0101 and pembrolizumab in subjects with HPV16-positive R/M HNSCC in 2 cohorts: ICI-naïve and ICI-refractory. All subjects receive pembrolizumab IV Q3W with PDS0101 SC administered concurrently during Cycles 1, 2, 3, 4, and 12 (max 5 doses). The primary endpoint of the study is confirmed Best Overall Response per RECIST 1.1. Herein we update the safety, PFS, and OS data for the ICI-naïve subjects. Results: Forty-eight subjects who received at least one cycle of combination therapy (safety population) had a median age of 62.5 (range 45 – 83), were 93.8% male, 93.8% White, and 62.5% ECOG 0. Among this population, the median overall treatment duration in months was 3.5 (range 0.0 – 19.5). The median number of PDS0101 doses was 4 (range 1 – 5); 56.3% received 4 doses and 22.9% received 5 doses. The median number of pembrolizumab doses was 5 (range 1 – 29); 27.1% received ≥10 doses. Efficacy was evaluated in 34 subjects (47.1% with CPS ≥20) who had assessment of tumor response following treatment (efficacy population). Tumor reduction (maximum percent change from baseline) was seen in 23 (67.6%) subjects. Nine subjects (26.5%) had confirmed response including 1 CR and 8 PR, 15 subjects had SD (44.1%), and 9 subjects had PD (26.5%). One subject was not evaluable (2.9%). The median PFS was 10.4 months (95% CI 4.2, 15.3). Among the safety population, median overall survival was non-estimable due to the ongoing survival status of study subjects. The estimated 12-month OS rate was 87.1%. Thirty-three (68.5%) subjects had mild or moderate (Grade 1 or 2) PDS0101-related TEAE (TRAE); the most common were fatigue and injection site reactions (ISRs). Only 3 subjects (6.3%) had Grade 3 TRAEs: fatigue, ISR, blood alkaline phosphatase increased, and hyperglycemia. No subjects had Grade 4 or 5 TRAE. No subject came off study due to toxicity. Conclusions: PDS0101 with pembrolizumab is well tolerated in this ICI naïve R/M HPV-associated HNSCC population. Median PFS was 10.4 months which compares favorably to published median PFS of 2-3 months for approved ICIs when used as monotherapy in patients with similar PD-L1 levels. The estimated 12-month OS of 87.1% is promising compared to published results of about 36-50%. These results justify a confirmatory randomized, controlled study. Clinical trial information: NCT04260126 .