FDA Receives BLA for RP1 and Nivolumab Combo in Advanced Melanoma

• A biologics license application (BLA) seeking the accelerated approval of RP1 (vusolimogene oderparepvec) plus nivolumab (Opdivo) in adult patients with advanced melanoma who have received previous treatment with a regimen containing a PD-1 inhibitor has been submitted to the FDA.
• Findings from the phase 1/2 IGNYTE trial (NCT03767348) support this submission.
• Breakthrough therapy designation from the FDA has also been granted for the combination in the same setting.

The FDA has received a BLA submission seeking the accelerated approval of RP1 plus nivolumab for the potential treatment of adult patients with advanced melanoma who have received prior treatment with a regimen that contains a PD-1 inhibitor.¹

Safety and efficacy data from the anti-PD-1–failed melanoma cohort of the phase 1/2 IGNYTE trial support this BLA submission. Of the patients included in this cohort and at a median follow-up of 15.4 months (range, 0.5-55.5), the overall response rate (ORR) was 32.7%. This included complete response (CR) and partial response (PR) rates of 14.7% and 17.9%, respectively.2

For the 82 patients who had received prior anti–PD-1 monotherapy, the ORR, CR, and PR rates were 37.8% 22.0%, and 15.9%. Further, the respective rates for patients with prior exposure to both PD-1 and CTLA-4 inhibitors (n = 74) were 27.0%, 6.8%, and 20.3%.

“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,” Sushil Patel, PhD, chief executive officer of Replimune, in a press release.¹

The safety profile of the combination was generally categorized by low-grade adverse events (AEs), with most being grade 1 or 2. A low incidence of grade 3 or 4 AEs were observed, and no grade 5 AEs were seen.

Common treatment-related AEs included chills (34.0%, with 0.7% experiencing grade 3), fatigue (33.3%, with 1.3% experiencing grade 3), pyrexia (31.4%, no grade 3/4), nausea (22.4%, no grade 3/4), and influenza-like illness (19.2%, no grade 3/4). Other frequently reported AEs were injection site pain (14.7%, no grade 3/4), diarrhea (13.5%, with 0.6% experiencing grade 3), vomiting (13.5%, no grade 3/4), and headache (12.8%, no grade 3/4). Grade 4 AEs were rare but included increased alanine aminotransferase, increased blood bilirubin, cytokine release syndrome, hepatic cytolysis, splenic rupture, and myocarditis.

Concept illustration of skin cancer

About the IGNYTE Trial of RP1 and Nivolumab

The phase 1/2, open-label, dose-escalation and -expansion IGNYTE trial enrolled 156 patients with cutaneous melanoma who had progressed on prior PD-1 inhibitors, 16 of whom had been treated in prior cohorts of IGNYTE.² Enrollment was open to patients with confirmed progression while receiving treatment with anti–PD-1 alone or in combination with anti–CTLA-4 for 8 weeks or more as the last prior treatment, including as adjuvant treatment, with anti–PD-1 failed advanced melanoma, measurable disease, an ECOG performance status of 0 to 1, and adequate organ function. Additionally, patients were required to have not been previously treated with oncolytic therapy.

Patients received RP1 at 1 x 10⁶ pfu/mL during cycle 1, which began 28 days after screening. Subsequently, patients received 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.

The primary end points were to evaluate safety and efficacy. Secondary end points included ORR by independent central review (ICR) using mRECIST 1.1, with assessment also by standard RECIST 1.1, CR rate, duration of response, duration of clinical benefit, disease control rate, progression-free survival (PFS), 1- and 2-year overall survival (OS).

Future Directions

The confirmatory phase 3 IGNYTE-3 trial (NCT06264180) is currently enrolling patients with advanced melanoma who have progressed on anti-PD1 and anti-CTLA-4 therapy, or who are not candidates for anti-CTLA-4 treatment. Here, patients will receive RP1 in combination with nivolumab.

The primary end point of the study is OS, and secondary end points include PFS and ORR.³

REFERENCES

1. Replimune receives breakthrough therapy designation for RP1 and submits RO1 biologics license application to the FDA under the accelerated approval pathway. News release. Replimune Group, Inc. November 21, 2024. Accessed November 25, 2024. https://tinyurl.com/3uh38cxu

2. Wong MKK, Sacco JJ, Robert C, et al. Efficacy and safety of RP1 combined with nivolumab in patients with anti–PD-1–failed melanoma from the IGNYTE clinical trial. J Clin Oncol. 2024;42(suppl 16):9517. doi:10.1200/JCO.2024.42.16_suppl.9517

3. VO and nivolumab vs physician’s choice in advanced melanoma that progressed on anti-PD-1 & anti-ctla-4 drugs (IGNYTE-3). ClinicalTrials.gov. Updated November 20, 2024. Accessed November 25, 2024. https://clinicaltrials.gov/study/NCT06264180