Background: Uveal melanoma, although rare, represents the most common primary intraocular tumor in adults and is associated with high risk of liver metastases. Effective treatments are limited as uveal melanoma is an immunologically cold tumor that does not respond well to immunotherapy. RP2 is an enhanced-potency oncolytic herpes simplex virus type 1 expressing human granulocyte-macrophage colony-stimulating factor, fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R−), and an anti–CTLA-4 antibody-like molecule. Here, we present updated safety and efficacy data of RP2 monotherapy and RP2 + nivolumab (nivo; anti–PD-1) in patients (pts) with uveal melanoma. Methods: Pts ≥18 years old with histologically or cytologically confirmed advanced or metastatic non-neurological solid tumors (including uveal melanoma) who progressed on or could not tolerate standard therapy were included; pts had ≥1 measurable and injectable tumor (≥1 cm). After determination of the recommended phase 2 dose of RP2 (concentration of 10⁶ plaque-forming units [PFU]/mL intratumorally [IT] once followed by up to 7 additional IT doses at 10⁷ PFU/mL; [≤10 mL total/treatment day with amount per lesion determined by tumor diameter]), pts received RP2 monotherapy every two weeks (Q2W) or RP2 Q2W + nivo (NCT04336241). Responses were assessed using modified Response Evaluation Criteria in Solid Tumors version 1.1. Results: As of December 30, 2022, 17 pts with uveal melanoma were enrolled (RP2 monotherapy, n = 3; RP2 + nivo, n = 14). The majority of pts received both anti–PD-1 and anti–CTLA-4 therapy (12/17, 70.6%) and 17.6% received ≥3 prior lines of therapy. The overall objective response rate for the 14 pts with sufficient follow up for analysis was 28.6% [4/14] (all partial responses [PRs]; RP2 monotherapy, 1/3; RP2 + nivo, 3/11). The disease control rate (complete response + PR + stable disease [SD]) was 57.1% (8/14; 4 pts with SD in RP2 + nivo cohort). The median (range) duration of response at the data cut-off was 5.8 (1.7–14.7) months. The most common overall Grade 1–2 treatment-related adverse events (TRAEs; ≥20%) were pyrexia, chills, fatigue, and hypotension. The only Grade 3 TRAE occurring in > 1 pt was hypotension (2 pts receiving RP2 + nivo); no Grade 4–5 TRAEs were observed. Conclusions: Preliminary RP2 monotherapy and RP2 + nivo data demonstrated a favorable safety profile and meaningful antitumor activity in pts with metastatic uveal melanoma, an immunologically cold tumor with few effective treatment options. These data continue to support the hypothesis that IT oncolytic immunotherapy expressing anti–CTLA-4 in combination with anti–PD-1 may provide clinically meaningful benefit in pts with hard-to-treat/unresponsive tumors. Clinical trial information: NCT04336241.