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.