The objective response rate was 33.6%, with a median duration of response of 24.8 months, in anti–PD-1–refractory advanced melanoma treated with RP1 plus nivolumab, based on updated IGNYTE cohort data. Duration was consistent across PD-L1–positive and negative tumors and in both primary and secondary resistance settings, with a median of 24.8 months in PD-L1–negative patients and 22.6 months in those with primary resistance. Biomarker analyses presented in a late-breaking session at SITC 2025 indicated the combination of upregulated gene signatures associated with PD-1 responsiveness. They reversed multiple resistance mechanisms, including low intratumoral T cell levels, impaired antigen presentation, and weak IFN-γ signaling.
The core update centers on new pharmacodynamic evidence paired with extended clinical follow-up in the 140-patient phase 2 IGNYTE cohort of stage IIIB–IV melanoma with confirmed progression on prior anti–PD-1 therapy. RP1 was given intratumorally every 2 weeks for up to 8 doses, followed by nivolumab maintenance; RP1 retreatment was allowed if indicated. Two SITC posters added operationally relevant signals: comparable efficacy across BRAF-mutant and wild-type subgroups, with greater activity in BRAF-naïve patients, and tolerability, with apparent clinical benefit when extending RP1 beyond eight doses. Together, the data reinforce a salvage strategy predicated on reconditioning the tumor microenvironment to re-enable PD-1 activity rather than layering additional toxicity.
Strategically, Replimune is pushing differentiation on the mechanism. Oncolytic HSV-1 therapy has a mixed legacy in melanoma. Still, the biomarker readout is designed to answer the field’s skepticism: namely, whether intratumoral viruses can generate systemic, durable benefit in patients who have already failed PD-1. The consistency of duration across PD-L1 strata and resistance phenotypes is notable, underscoring the need for biomarker gating and simplifying site screening and enrollment. Still, this remains a single-arm dataset in a setting where salvage ipilimumab-based regimens and TIL therapy have established benchmarks. Without a randomized comparator, regulators and payers are likely to scrutinize contextualized efficacy and durability, the magnitude of benefit in visceral disease, and the real-world deliverability of a procedure-heavy regimen.
For sites and CROs, the operational footprint is nontrivial. Intratumoral administration into superficial and deep/visceral lesions requires imaging support, interventional expertise, biosafety protocols for handling an oncolytic HSV-1, and coordination with PD-1 infusion schedules. The allowance for RP1 retreatment and signals of benefit beyond eight doses adds scheduling complexity and could extend resource needs per patient. On the upside, the absence of mandatory biomarker selection broadens the pool, potentially easing accrual in a population that can be recruitment-challenged post–PD-1. Subgroup parity across BRAF status reduces stratification friction, but the greater activity in BRAF-naïve patients will invite prospective stratification and sensitivity analyses in any registrational plan.
Next, watch for clarity on the regulatory path and study design choices that bridge this signal to approval-grade evidence. A randomized comparison against current salvage options, prespecified analyses in visceral and liver metastases, and independent confirmation of the biomarker mechanism would strengthen the case. Manufacturing scale and consistent lot release for a live viral product, plus site onboarding for intratumoral administration at community centers, remain tangible execution risks. If the durability holds in a controlled setting and logistics can be standardized, RP1 plus nivolumab could compete on operational simplicity relative to TILs while avoiding the toxicity and complexity of doublet checkpoint intensification. The field will examine whether these mechanistic reversals of resistance translate into a survival benefit and are reproducible across diverse practice environments.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
