Background: T-VEC, a genetically modified herpes simplex virus-1, is the first FDA- and EMA-approved oncolytic viral immunotherapy designed to enhance systemic antitumor immune responses. R/M HNSCC is a disease with considerable clinical complexity and poor prognosis. Pembro is a PD-1-specific humanized monoclonal antibody currently approved as first-line Tx for this disease, but there is an unmet need among many patients (pts). To meet this gap, the safety and preliminary efficacy of T-VEC plus pembro in pts with R/M HNSCC was evaluated in a phase 1b study (Harrington et al. Clin Cancer Res. 2020). Here, we present results of the final analysis of this study (NCT02626000). Methods: Eligible pts (≥18 yrs) had ECOG-PS of 0 or 1; histologically confirmed R/M HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx unsuitable for curative surgical resection or radiotherapy; platinum-refractory and with injectable tumors. Pts with known active CNS metastases and any systemic or local therapy 28 days before enrollment were excluded. T-VEC was injected intralesionally up to 8.0 mL of 10⁶ PFU/mL according to lesion sizes on day 1; after 3 weeks, subsequent doses of ≤8.0 mL of 10⁸ PFU/mL were given Q3W. Pembro was given intravenously at 200 mg Q3W. Pts were followed-up for 36 mos after the last patient was enrolled in the study. Key endpoints (irRECIST per investigator assessment) were objective response rate (ORR), best overall response (BOR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 36 pts (80.6% male) were enrolled and treated: 28 (77.8%) had confirmed PD-L1-positive tumor (CPS ≥1), 5 (13.9%) were HPV-positive, 13 (36.1%) had metastatic disease, and 19 (52.8%) had prior lines of therapy in the R/M setting. At the final analysis, 7 pts (19.4%) completed the study, and 29 (80.6%) discontinued the study due to death. Safety profile was consistent with that at 1-yr analysis (Harrington et al. Clin Cancer Res. 2020). Confirmed ORR was seen in 16.7% (95% CI, 6.4–32.8). No patient had a complete response as their BOR, 6 (16.7%) had a partial response, 8 (22.2%) had stable disease, 6 (16.7%) had progressive disease, 6 (16.7%) were unevaluable, and 10 (27.8%) died before the first response assessment. The DCR was 38.9% (95% CI, 23.1–56.5). The median DOR was 45.9 mos (95% CI, 8.5–NE). The median PFS was 3.0 mos (95% CI, 2.0–5.8), and the median OS was 5.8 mos (95% CI, 2.9–11.4). Conclusions: The safety results at 3 yrs for T-VEC plus pembro in pts with R/M HNSCC were consistent with those of the 1-yr analysis. Although the response rate was consistent with that observed with pembro alone in historical HNSCC studies, the extended DOR in responding patients warrants further investigation. Clinical trial information: NCT02626000