RP2 oncolytic immunotherapy alone and in combination with nivolumab (nivo) in patients with advanced solid tumors: Final safety, efficacy, and biomarker results from the phase 1 first-in-human (FIH) study.

2504 Background: RP2 is an HSV-1-based oncolytic immunotherapy expressing a fusogenic glycoprotein (GALV-GP-R – ), human GM-CSF, and a human anti–CTLA-4 antibody. We present final safety, efficacy, and biomarker data from the FIH study of RP2 in patients (pts) with advanced solid tumors (NCT04336241). Methods: Enrolled pts had advanced/metastatic solid tumors with ≥1 measurable, injectable lesion (≥1 cm) and had progressed following, or could not tolerate, available standard therapy. Pts received RP2 monotherapy via intratumoral injection in dose escalation (Part 1; 5 doses Q2W). Pts in Parts 2 (RP2 + nivo) and 3 (RP2 monotherapy) received up to 8 doses of RP2 (Q2W × 8 or Q2W × 4 followed by Q4W × 4 doses) at the RP2D. In Part 2, nivo was administered starting at Cycle 2 or 4 for ~20 to 22 months. Pts could receive an additional course of RP2 per protocol. Results: As of 01DEC2025, 85 pts (median age 59 y) were enrolled and treated in RP2 (n = 25) or RP2 + nivo (n = 60) cohorts. Tumor types included uveal or cutaneous melanoma (UM, n = 17; CM, n = 11); colorectal (n = 14), head and neck (n = 13), and pancreatic (n = 12) cancers; and sarcoma (n = 7); 42% of pts received prior immune checkpoint inhibitor treatment. All pts have completed treatment. Treatment-related adverse events (TRAEs) in > 10% of pts included pyrexia, chills, fatigue, influenza-like illness, hypotension, pruritus, and nausea. Grade ≥3 TRAEs occurred in 20% of pts (no single event occurred in > 2 pts). A majority of pts (58/85) received injections into deep/visceral lesions, mainly in liver and lung, which were well tolerated. Among pts with ≥1 post-baseline scan (75/85), the ORR was 17.3% (13/75; 1 unconfirmed) with a median DOR of 22.1 months and DCR (CR+PR+SD) of 44.0% (33/75). Responses occurred in 5/15 (33.3%) pts with UM. RP2 monotherapy resulted in confirmed responses in 4/21 (19%) pts (1 esophagogastric adenocarcinoma, 1 UM, 1 chordoma, 1 mucoepidermoid), with best overall response of CR and median DOR not reached. Tumor regression occurred in both injected and non-injected lesions, including all 3 pts with monotherapy responses with non-injected lesions. A robust intratumoral immune response with increased CD8+ T-cell infiltrates, PD-L1 upregulation, and inflammatory immune pathway activation were observed, as well as epitope spreading with novel virus- and cancer-associated T-cell clones. Conclusions: RP2 ± nivo treatment was well tolerated in pts with both superficial and deep visceral metastases. Durable responses were observed with RP2 monotherapy and RP2 + nivo in heavily pretreated pts with diverse tumors with evidence of systemic anti-tumor immune activity, including tumor reduction in distant non-injected lesions. This study supports the ongoing evaluation of RP2 in pts with UM (NCT06581406) and the planned evaluation in other solid tumors. Clinical trial information: NCT04336241 .