Replimune Group Inc. has announced that the FDA is reviewing its biologics license application for the combination of RP1 (vusolimogene oderparepvec) and nivolumab (Opdivo) for the treatment of adult patients with advanced melanoma who have previously progressed on a PD-1 inhibitor. This regulatory milestone follows the FDA's granting of breakthrough therapy designation to the combination, signaling its potential to address a critical unmet need in patients with limited treatment options. The application is based on data from the phase 1/2 IGNYTE trial (NCT03767348), which demonstrated promising efficacy and a manageable safety profile in this challenging patient population.
IGNYTE Trial Results
The phase 1/2 IGNYTE trial enrolled 156 patients with cutaneous melanoma who had progressed on prior PD-1 inhibitors. The study's anti-PD-1–failed melanoma cohort showed an overall response rate (ORR) of 32.7% (95% CI not provided) at a median follow-up of 15.4 months (range, 0.5-55.5). This included a complete response (CR) rate of 14.7% and a partial response (PR) 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 PR rates of 22.0% and 15.9%, respectively. Among those with prior exposure to both PD-1 and CTLA-4 inhibitors (n = 74), the ORR was 27.0%, with CR and PR rates of 6.8% and 20.3%, respectively.
Sushil Patel, PhD, CEO of Replimune, stated, "Today is an important milestone for Replimune and for the melanoma community as we are 1 step closer to having another potential treatment available for patients who have limited options after progressing on anti-PD-1–containing regimens."
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 the data analysis. Notably, 70.4% of responding patients had lesions beyond their target lesions that were not injected with RP1, suggesting a systemic effect of the combination therapy.
Safety Profile
The combination of RP1 and nivolumab demonstrated a manageable safety profile, with most adverse events (AEs) being grade 1 or 2. The most common treatment-related AEs included chills (34.0%; grade 3, 0.7%), fatigue (33.3%; grade 3, 1.3%), and pyrexia (31.4%; no grade 3/4). Grade 4 AEs were rare, with one case each of increased alanine aminotransferase levels, increased blood bilirubin levels, cytokine release syndrome, hepatic cytolysis, splenic rupture, and myocarditis. No grade 5 AEs were observed.
Ongoing Phase 3 Trial
The confirmatory phase 3 IGNYTE-3 trial (NCT06264180) is currently enrolling patients with advanced melanoma who have progressed on anti-PD-1 and anti-CTLA-4 therapy or who are not candidates for anti-CTLA-4 treatment. The primary endpoint of the study is overall survival (OS), and secondary endpoints include progression-free survival (PFS) and ORR. This trial aims to confirm the findings of the phase 1/2 study and potentially establish RP1 plus nivolumab as a new standard of care for this patient population.
Study Design and Dosing
In the IGNYTE trial, patients received RP1 at 1 x 106 pfu/mL during cycle 1, followed by RP1 at 1 x 107 pfu/mL plus nivolumab at 240 mg during cycles 2 through 8; nivolumab at 240 mg during cycle 9; and nivolumab at 480 mg every 4 weeks during cycles 10 through 30. Each cycle was 2 weeks long. Patients needed to have at least 1 measurable and injectable lesion, adequate organ function, no prior treatment with oncolytic therapy, and an ECOG performance status of 0 or 1.
