A Randomized, Phase 2/3, Open-Label Study to Investigate the Efficacy and Safety of RP2 in Combination With Nivolumab Versus Ipilimumab in Combination With Nivolumab in Immune Checkpoint Inhibitor-Naïve Adult Patients With Metastatic Uveal Melanoma

Overview

RP2 is an investigational, intratumoral oncolytic immunotherapy based on herpes simplex virus type 1 (HSV‑1). It is engineered to enhance direct tumor killing and stimulate systemic anti‑tumor immunity and is being evaluated primarily in a phase 1, open‑label trial (NCT04336241), including monotherapy and combinations with PD‑1/PD‑L1 inhibitors. As of the latest meeting reports, development has expanded to tumor‑specific cohorts (e.g., metastatic uveal melanoma) and to combinations in hepatocellular carcinoma with atezolizumab plus bevacizumab. (ascopubs.org)

Mechanism of action

• Backbone/route: Replication‑competent HSV‑1 administered by image‑guided intratumoral injection. (ascopubs.org)
• Transgenes: Encodes a fusogenic glycoprotein (GALV‑GP‑R−), GM‑CSF, and an anti‑CTLA‑4 antibody‑like molecule to promote tumor cell lysis, local antigen presentation, and checkpoint blockade within the tumor microenvironment and draining lymph nodes. (ascopubs.org)
• Immune biomarkers (clinical): Treatment has been associated with increased CD8+ T‑cell infiltration, increased PD‑L1 expression in tumors, and expansion/emergence of peripheral T‑cell clones, supporting systemic immune activation. (ascopubs.org, aacrjournals.org)

Dosing used in phase 1: RP2 recommended phase 2 dose is 1×10^6 PFU/mL once, then up to seven additional doses at 1×10^7 PFU/mL every 2 weeks (≤10 mL per treatment day). (ascopubs.org)

Efficacy

• Uveal melanoma (metastatic), phase 1 cohort (ASCO 2024): Among 17 patients (most pretreated with both PD‑1 and CTLA‑4 inhibitors), overall response rate (ORR) was 29.4% (5/17; all partial responses). Disease control rate (DCR) was 58.8%. Median duration of response at data cutoff was 11.5 months (range 2.8–21.2), with some responses ongoing. Responses were seen with RP2 monotherapy (1/3) and RP2+nivolumab (4/14). (ascopubs.org)

• Multi‑tumor, early phase 1 experience (ESMO 2022 poster):

• RP2 monotherapy: Objective responses in 3/9 patients, including a complete response lasting ≥15 months (mucoepidermoid carcinoma) and durable partial responses in esophageal cancer and uveal melanoma.
• RP2 + nivolumab: ORR 44.4% in cutaneous melanoma (4/9), 25% in uveal melanoma (2/8), and 33% in head and neck squamous cell carcinoma (1/3). Several responses were durable (>425 days), including in anti‑PD‑1–refractory disease. (oncologypro.esmo.org)

These data are from nonrandomized, early‑phase cohorts; randomized studies are being planned or initiated based on these findings. (ascopubs.org)

Safety

Across phase 1 reports, RP2 alone and with nivolumab showed a generally manageable safety profile: the most common treatment‑related adverse events were grade 1–2 pyrexia, chills, fatigue, hypotension, pruritus, and influenza‑like illness. In the uveal melanoma cohort, grade 3 treatment‑related hypotension occurred in 2 patients on RP2+nivolumab; no grade 4/5 treatment‑related events were reported. ESMO 2022 reported no grade 4/5 events in the multi‑tumor experience. (ascopubs.org, oncologypro.esmo.org)

Ongoing/Planned studies

• Phase 1 (NCT04336241): RP2 monotherapy and RP2+nivolumab; recruitment and expansion cohorts ongoing, with estimated primary completion in 2026. (ichgcp.net, cdek.pharmacy.purdue.edu)
• HCC combination (trial-in-progress): RP2 with atezolizumab plus bevacizumab in advanced/unresectable HCC; rationale includes potential synergy with PD‑L1 blockade and bevacizumab‑facilitated intratumoral distribution. (ascopubs.org)

Further reading

• ASCO 2024: Safety, efficacy, and biomarker results in metastatic uveal melanoma (phase 1 cohort). (ascopubs.org)
• ESMO 2022: Phase 1 RP2 monotherapy and RP2+nivolumab across tumor types (poster 827P). (oncologypro.esmo.org)
• AACR 2022: Clinical biomarker studies with RP2 indicate potent immune activation. (aacrjournals.org)
• Trial-in-progress (ASCO 2024/2025): RP2 with atezolizumab plus bevacizumab in HCC. (ascopubs.org)
• Phase 1 study record and design details (NCT04336241). (ichgcp.net, cdek.pharmacy.purdue.edu)

Notes: Data summarized here come from conference abstracts/posters and trial registry entries; peer‑reviewed, full‑length clinical publications may not yet be available. (ascopubs.org, oncologypro.esmo.org)

Last updated: Sep 2025

Key Inclusion Criteria:

* Patients who are 18 years of age or older at the time of signed informed consent.

* Patients with confirmed diagnosis of metastatic Uveal melanoma not amenable to surgical resection.

* Has at least 1 measurable and injectable tumor of ≥ 1 cm in longest diameter (≥ 1.5 cm in the shortest axis for a lymph node \[LN\]) that is amenable to serial RP2 injections.

* Must be willing to provide tumor biopsy samples.

* LDH ≤ 2 × upper limit of normal (ULN).

* Has adequate hematologic, hepatic and renal function

* Prothrombin time (PT) ≤ 1.5 × ULN (or international normalization ratio \[INR\] ≤ 1.3) and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN.

* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.

* Life expectancy of \> 6 months as estimated by the Investigator.

Key Exclusion Criteria:

* Any exposure to immune checkpoint inhibitor (ICIs) since the time of first being diagnosed with uveal melanoma.

* Known acute or chronic Hepatitis B or C infection or human immunodeficiency virus (HIV) infection or any other uncontrolled infection.

* Current active significant herpetic infections or prior complications of HSV-1 infection.

* Any central nervous system (CNS) involvement of melanoma, including carcinomatous meningitis.

* Major surgery ≤ 2 weeks prior to the first dose of study intervention.

* Any bleeding, thrombotic and/or other event that places the patient at an unacceptable risk of complications of intratumoral therapy.

* Active, known, or suspected autoimmune disease requiring systemic treatment.

* Prior treatment with an oncolytic virus.

* Requires intermittent or chronic use of systemic (oral or IV) antivirals with known antiherpetic activity (eg, acyclovir).

* Systemic anticancer therapy or prior radiotherapy within 2 weeks of the first dose.

* Has received Investigation agent within 4 weeks or 5 half-lives (whichever longer) prior to the first dose.

* Conditions requiring treatment with immunosuppressive doses (\> 10 mg per day of prednisone or equivalent) of systemic corticosteroids other than for corticosteroid replacement therapy within 14 days after enrollment.

Additional inclusion/ exclusion criteria are outlined in the study protocol