RP1 plus nivolumab produced a 44% objective response rate (8/18) in an ad hoc analysis of acral melanoma patients from the IGNYTE Phase 2 cohort, with a median duration of response of 11.9 months (3.9, not reached). Safety was limited mainly to transient grade 1–2 treatment-related adverse events.
Replimune disclosed the subgroup readout at ESMO 2025 alongside confirmation that IGNYTE-3, a randomized Phase 3 trial of RP1 plus nivolumab versus physician’s choice in melanoma progressed on anti–PD-1 and anti–CTLA-4 therapy, is recruiting. The Phase 2 IGNYTE cohort enrolled 140 patients with post–PD-1 progression and dosed RP1 intratumorally every two weeks for up to eight administrations, combined with nivolumab, then continued nivolumab maintenance for up to two years with additional RP1 allowed as indicated. A separate ESMO poster covers non-melanoma skin cancers, underscoring the company’s broader skin oncology ambitions.
Strategically, elevating an acral melanoma signal is a calculated move. Acral disease is uncommon, responds poorly to checkpoint monotherapy, and often presents with in-transit lesions that are technically amenable to intratumoral delivery. A 44% response rate, even in a small, uncontrolled subset, contrasts with the historically low activity seen after PD-1 failure and creates a narrative for differentiation against both systemic rechallenge and available intralesional options. The flip side is the inherent fragility of an ad hoc, n=18 analysis with potential selection bias and heterogeneous lesion accessibility. Replimune’s real test is not whether RP1 can generate responses in injectable acral metastases, but whether the effect generalizes and sustains in a controlled setting with complex endpoints.
For sites and CROs, the operational footprint matters. RP1 requires intratumoral administration into superficial and, at times, deep or visceral targets, introducing imaging support, interventional radiology time, and biosafety oversight typical of oncolytic viruses. Dosing every two weeks for multiple cycles and coordinating with nivolumab infusions adds logistics and chair-time pressure at already capacity-constrained centers. Sites will need consistent procedures for lesion selection, image-guided access, and response adjudication in the presence of treated and untreated lesions. At the same time, CROs should expect higher monitoring complexity around injection technique, dose volumes, and lesion-level outcomes. Sponsors considering combination strategies will watch whether the regimen’s procedural demands deter community sites or limit accrual speed in Phase 3.
Regulators will focus on durability and the breadth of benefits beyond easily accessible lesions, as well as on activity post-PD-1/PD-1/CTLA-4 exposure, where physicians’ choice controls often underperform. A favorable safety profile supports use in fragile, heavily pretreated melanoma, but the dependence on intratumoral access could constrain the label or require clear guidance on deep lesion administration. The inclusion of nivolumab in patients previously progressed on PD-1 also invites scrutiny about the contribution of components, making randomized evidence pivotal for any approval path.
What to watch next: interim analyses from IGNYTE-3, particularly overall response and durability stratified by lesion accessibility and acral versus non-acral subtypes; operational feasibility signals such as proportion of patients requiring image-guided injections and treatment discontinuations due to procedural limitations; and manufacturing and supply reliability for a live viral therapy as trial scale expands. If the randomized data replicate the magnitude and durability indicated by the acral subset, RP1 could shift practice for post–ICI melanoma with injectable disease. If not, the field may continue to favor systemic or simpler intralesional approaches, and RP1’s value proposition will hinge on targeted niches like acral and in-transit metastases where site capability aligns with the product’s delivery model.
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.
