Replimune goes pivotal in uveal melanoma

Replimune has already started pivotal development of its first-generation oncolytic virus, and now clinicaltrials.gov has revealed a planned phase 2/3 study for its next-generation project.The company’s lead asset, RP1 (vusolimogene oderparepvec) is being developed for post-checkpoint inhibitor melanoma; meanwhile its follow-on, RP2, is targeted at the smaller niche of uveal melanoma. Here, Immunocore’s Kimmtrak has been approved – but, unlike Immunocore, Replimune won’t be restricted to the most common HLA type, because of the projects’ different modalities.Replimune’s phase 2/3 trial, which is due to start in January 2025, will test RP2 plus Opdivo, versus Opdivo plus Yervoy, in checkpoint inhibitor-naive metastatic uveal melanoma patients.Uveal melanoma is thought to affect around 1,000 patients in the US each year. PD-(L)1 inhibitors aren’t approved for uveal melanoma, and these drugs have shown limited activity here, according to Replimune. An uncontrolled investigator-sponsored study of Opdivo plus Yervoy found, among 33 patients, an ORR of 18%, median PFS of 5.5 months, and median OS of 19.1 months.Meanwhile, a phase 1 trial of RP2 has reported an ORR of 29% among 17 uveal melanoma patients. Responses were seen in one of three patients receiving RP2 monotherapy, and four of 14 subjects getting RP2 plus Opdivo.Notably, 70% of patients had received both prior anti-PD-1 and anti-CTLA-4 therapy, so it’s possible that the numbers could improve in the upcoming checkpoint inhibitor-naive trial.Not HLA restrictedAlso encouragingly for Replimune, responses to RP2 were seen in patients positive and negative for HLA-A2*02:01. As RP2 is an oncolytic virus it’s designed to spur a broad immune response, while Immunocore’s Kimmrak, because it’s based on a T-cell receptor, is restricted to HLA-A2*02:01-positive patients, the most common subtype among the Caucasian population.However, Replimune isn’t alone here, with Ideaya Biosciences also claiming broad utility of its PKC inhibitor darovasertib. That project is in a phase 2/3 trial in HLA-A2-negative metastatic uveal melanoma (where it’s being given alongside Pfizer’s Xalkori), and a phase 2 study in (neo)adjuvant uveal melanoma.Other contenders include Aura Biosciences, which has the phase 3 Compass trial under way, testing its virus-like drug conjugate belzupacap sarotalocan (bel-sar) in choroidal melanoma, a subtype of uveal melanoma.Immatics has also said it might include uveal melanoma patients in a phase 2/3 study of its anti-PRAME T-cell receptor project IMA20, although presumably like Kimmtrak that will also be limited to patients with a specific HLA subtype.RP1 vs RP2Replimune’s RP1 and RP2 are both based on a herpes simplex virus engineered to express GM-CSF and a fusogenic protein, GALV-GP R-. RP2 additionally expresses an anti-CTLA4 antibody-like molecule, and is designed to target less immunologically responsive tumour types.Last month Replimune dosed the first patient in the confirmatory Ingyte-3 trial of RP1; the company is planning an accelerated approval filing based on the Ignyte study, data from which were reported in June.Since then the group’s market cap has climbed to $700m. But, with big tests remaining, it might be premature to declare victory for oncolytic viruses. Replimune’s oncolytic virus candidatesProjectDescriptionStatusRP1 (vusolimogene oderparepvec)HSV expressing GALV-GP R- & GM-CSFFiling planned H2 2024 in post-PD-1 melanoma, based on Ignyte; 1st pt enrolled in confirmatory Ignyte-3 Aug 2024RP2HSV expressing GALV-GP R-, GM-CSF & anti-CTLA-4Ph1 uveal melanoma data at ASCO 2024; ph2/3 begins Jan 2025Note: GM-CSF=granulocyte-macrophage colony-stimulating factor; HSV=herpes simplex virus. Source: OncologyPipeline & clinicaltrials.gov.