A Randomized, Phase 2/3 Clinical Trial Investigating RP2 Plus Nivolumab Vs Ipilimumab Plus Nivolumab in Immune Checkpoint Inhibitor–naïve Patients with Metastatic Uveal Melanoma

TPS9598 Background: Uveal melanoma (UM) is the most common primary intraocular malignancy, accounting for ~90% of ocular melanomas and 5% of all melanomas. Half of patients with UM develop metastases, most commonly in the liver (~90%). The prognosis for patients with metastatic UM (mUM) is poor, with a median overall survival (OS) of ~1 year. Effective treatment options for mUM are limited, as it responds poorly to single-agent immune checkpoint inhibitors (ICIs; <10% response rate). Response rates are slightly higher with combination therapies (12%–18%), but these often have increased toxicity. Tebentafusp is FDA-approved for mUM based on survival benefit but is restricted to patients who are HLA-A*02:01 positive, and only ~10% of patients achieve an objective response. RP2 is a selectively replication-competent herpes simplex virus type 1–based oncolytic immunotherapy expressing GM-CSF, a fusogenic glycoprotein (GALV-GP-R − ), and an anti–CTLA-4 antibody-like molecule. Prior preliminary clinical data of intratumoral RP2 as monotherapy or in combination with nivolumab demonstrated a promising safety profile and anti-tumor activity with an overall response rate (ORR) of 29.4% and disease control rate of 58.8% in 17 patients with mUM, most of whom had received prior ICIs. This study will assess the efficacy and safety of RP2 + nivolumab vs ipilimumab + nivolumab in patients with ICI-naïve mUM. Methods: This is a multicenter, randomized, controlled, phase 2/3 study (NCT06581406; RP2-202). Key eligibility criteria include age ≥18 years and confirmed unresectable mUM with at least 1 lesion amenable to injection; up to 1 prior line of therapy in the metastatic setting is allowed. Patients with prior exposure to ICIs since the time of mUM diagnosis, >50% liver involvement, or previous selected liver-directed therapies are not eligible. Enrolled patients (N = ~280) will be randomized 1:1 to receive either RP2 + nivolumab or ipilimumab + nivolumab. In the RP2 + nivolumab arm, RP2 will be given intratumorally initially at 1 × 10 6 plaque-forming units (PFU)/mL, then every 2 weeks (Q2W) at 1 × 10 7 PFU/mL for 7 doses in combination with intravenous (IV) nivolumab (240 mg). In the ipilimumab + nivolumab arm, patients will receive IV ipilimumab (3 mg/kg) and IV nivolumab (1 mg/kg) Q3W for 4 doses. Patients in both arms may then receive IV nivolumab at 240 mg Q2W or 480 mg Q4W for up to 2 years. The co-primary endpoints are OS and progression-free survival by independent central review using RECIST 1.1. Secondary endpoints are ORR, duration of response, disease control rate, clinical benefit rate, duration of clinical benefit, and safety, including incidence of treatment-emergent adverse events (AEs), serious AEs, and immune-mediated AEs. Clinical trial information: NCT06581406 .