FDA Grants Breakthrough Therapy Designation to RP1 Plus Nivolumab for Advanced Melanoma
核心洞察
The FDA granted Breakthrough Therapy Designation to vusolimogene oderparepvec (RP1) combined with nivolumab for advanced melanoma (搜索) after anti-PD-1 therapy failure.
A Biologics License Application (BLA) has been submitted for RP1 with nivolumab under the Accelerated Approval pathway for previously treated advanced melanoma (搜索).
Phase 1/2 IGNYTE trial data showed a 33.6% objective response rate with RP1/nivolumab in anti-PD-1 failed melanoma (搜索), supporting the BTD decision.
Replimune's vusolimogene oderparepvec (RP1), in combination with nivolumab, has received Breakthrough Therapy Designation (BTD) from the FDA for the treatment of advanced melanoma (搜索) following prior anti-PD-1 therapy. A Biologics License Application (BLA) has also been submitted to the FDA under the Accelerated Approval pathway for this combination in patients with advanced melanoma who have progressed on anti-PD-1 regimens.
The BTD was supported by data from the anti-PD-1 failed melanoma (搜索) cohort of the phase 1/2 IGNYTE trial (NCT03767348). This open-label, dose-escalation, and dose-expansion trial demonstrated a confirmed objective response rate (ORR) of 33.6% (by independent review using modified RECIST v1.1 criteria) with the RP1/nivolumab combination. Notably, complete responses were observed in 15.0% of patients. Subgroup analysis revealed an ORR of 34.4% in patients with primary anti-PD-1 resistance and 26.2% in those previously treated with anti-PD-1 plus anti-CTLA-4 therapy.
Survival Outcomes in IGNYTE Trial
The IGNYTE trial also reported encouraging overall survival (OS) rates. At one year, the OS rate was 75.3% (95% CI, 66.9%-81.9%), and at two years, it was 63.3% (95% CI, 53.6%-71.5%). The median OS had not been reached at the time of analysis.
Safety Profile
The combination therapy demonstrated a manageable safety profile. Grade 3 or higher treatment-related adverse events occurred in 12.8% of patients, with most toxicities being grades 1 or 2. No RP1-related deaths were reported.
Ongoing Phase 3 IGNYTE-3 Trial
The efficacy and safety of RP1 in combination with nivolumab are being further evaluated in the phase 3 IGNYTE-3 trial (NCT06264180). This randomized, multicenter, open-label trial is enrolling patients with advanced melanoma (搜索) who have progressed on both anti-PD-1 and anti-CTLA-4 therapies. Patients are randomized to receive either RP1 plus nivolumab or investigator's choice of treatment, which may include nivolumab and relatlimab (Opdualag), anti-PD-1 monotherapy (nivolumab or pembrolizumab), or single-agent chemotherapy (dacarbazine, temozolomide, or paclitaxel).
The primary endpoint of the IGNYTE-3 trial is overall survival (OS), assessed up to approximately 55 months. Secondary endpoints include progression-free survival (PFS) and objective response rate (ORR) per RECIST v1.1 criteria.
Eligibility and Exclusion Criteria
Key inclusion criteria for the IGNYTE-3 trial include histologically or cytologically confirmed unresectable or metastatic stage IIIb to IV/M1a through M1d cutaneous melanoma (搜索), confirmed disease progression on anti-PD-1 and anti-CTLA-4 treatment, documented BRAF V600 mutation status, and an ECOG performance score of 0 or 1. Exclusion criteria include primary mucosal or uveal melanoma, more than two prior lines of systemic therapy for advanced melanoma, known acute or chronic hepatitis, known HIV infection, history of significant cardiac disease, and known active central nervous system metastases.
Dosing and Treatment Schedule
The IGNYTE-3 trial consists of a 28-day screening period, a treatment period of up to approximately 2 years, and a follow-up period of up to 3 years after treatment completion. RP1 is administered intratumorally every 2 weeks for up to 8 cycles, starting on day 1. Nivolumab infusion is administered concurrently with RP1 every 2 weeks for the first dose, followed by dosing every 4 weeks for up to 20 months.