Replimune Group Inc. has submitted a biologics license application to the FDA seeking accelerated approval for RP1 (vusolimogene oderparepvec) in combination with nivolumab (Opdivo) for treating adult patients with advanced melanoma who have previously progressed on PD-1 inhibitor therapy. The FDA has granted breakthrough therapy designation to the combination, potentially expediting its path to approval.
The application is based on data from the anti-PD-1-failed melanoma cohort of the phase 1/2 IGNYTE trial (NCT03767348). The study enrolled patients with cutaneous melanoma who had progressed on prior PD-1 inhibitors and had at least one measurable and injectable lesion. Patients received RP1 at 1 x 106 pfu/mL in the first cycle, followed by RP1 at 1 x 107 pfu/mL plus nivolumab at 240 mg in subsequent cycles. The primary objective was to evaluate the safety and efficacy of the combination.
IGNYTE Trial Results
The IGNYTE trial included 156 patients, with a median follow-up of 15.4 months (range, 0.5-55.5). The overall response rate (ORR) was 32.7%, comprising a complete response (CR) rate of 14.7% and a partial response rate of 17.9%. In the subgroup of patients who had received prior anti–PD-1 monotherapy (n = 82), the ORR was 37.8%, with CR and partial response rates of 22.0% and 15.9%, respectively. Among patients with prior exposure to both PD-1 and CTLA-4 inhibitors (n = 74), the ORR was 27.0%, with CR and partial response rates of 6.8% and 20.3%, respectively.
According to Sushil Patel, PhD, CEO of Replimune, this submission marks a significant step toward providing a new treatment option for melanoma patients who have progressed on anti-PD-1-containing regimens.
Duration and Depth of Response
At a median follow-up of 27.9 months (range, 10.5-55.5) in responders, the median duration of response (DOR) was 36.57 months (95% CI, 23.89-not reached). The disease control rate (DCR) was 55%, and 65% of responses were ongoing at the time of data analysis. Notably, 70.4% of responding patients experienced responses in lesions beyond those injected with RP1, with similar durations and kinetics observed in both injected and non-injected lesions.
Safety Profile
The combination's safety profile was characterized by predominantly grades 1 and 2 adverse events (AEs), with a low incidence of grades 3 and 4 AEs. The most common treatment-related AEs included chills (34.0%), fatigue (33.3%), and pyrexia (31.4%). Grade 4 AEs were rare, with single occurrences of increased alanine aminotransferase levels, increased blood bilirubin levels, cytokine release syndrome, hepatic cytosis, splenic rupture, and myocarditis. No grade 5 AEs were reported.
Ongoing Phase 3 Trial
The confirmatory phase 3 IGNYTE-3 trial (NCT06264180) is currently enrolling patients with advanced melanoma who have progressed on PD-1- and CTLA-4–directed therapy or are ineligible for CTLA-4–directed therapy. The primary endpoint is overall survival (OS), with secondary endpoints including progression-free survival (PFS) and ORR.
