FDA Issues Second CRL for RP1/Nivolumab in Advanced Melanoma

The FDA has given a second complete response letter (CRL) to vusolimogene oderparepvec (RP1) in combination with nivolumab (Opdivo) for the treatment of adult patients with unresectable or metastatic melanoma who have progressed on or after prior anti–PD-1 therapy.¹

In a letter from the FDA, “data presented are insufficient to conclude substantial evidence of effectiveness of [RP1] for treatment of unresectable advanced cutaneous melanoma.”

Furthermore, the FDA provided guidance on the deficiencies of the trial. The letter which highlights RPL-001-16, also known as the phase 1/2 IGNYTE trial (NCT03767348), is not considered to be well-thought controlled clinical trial. The full data of which were previously presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.² These data found that those with deep/visceral injections vs superficial injections had numerically higher response rates.

Clinical Efficacy: Data from the IGNYTE Trial

Overall, 140 patients within the IGNYTE trial were assessed and had confirmed disease progression while on prior anti–PD-1 therapy. Seven patients with lung injections had pneumothorax events in 5.8% of injections at grade 1 and grade 2, which were self-resolved. One lung injection led to pneumothorax and required chest tube insertion, which occurred within 7 days following RP1 injection.

Topline data included an objective response rate (ORR) by blinded independent central review per RECIST v1.1 of 32.9%, with a complete response (CR) observed in 15.0%, and a partial response (PR) in 17.9%. For patients who were treated with deep/visceral plus superficial injections (n = 14), the ORR was 42.9%, all of which were PRs. For those with superficial injections only (n = 104), the ORR was 29.8%, the CR rate was 17.3%, and the PR rate was 12.5%. Those with deep/visceral injections only had an ORR of 40.9%, a CR rate of 13.6%, and a PR rate of 27.3%.

For those with injected lesions (n = 73), there was at least a 30% reduction in 93.6% of patients, and in 79.0% (n = 94) for those with non-injected lesions.

The primary end points were safety and efficacy by the modified RECIST 1.1 criteria. Secondary end points included investigator-assessed ORR, duration of response, CR rate, central and investigator-assessed progression-free survival, and 1- and 2-year overall survival.

RP1 Safety Profile

All-grade treatment-related adverse effects for the superficial only, deep/visceral plus superficial, and deep/visceral only included fatigue (89.4%; 85.7%; 95.5%), pyrexia (29.8%; 21.4%; 40.9%), chills (28.8%; 35.7%; 45.5%), nausea (21.2%; 21.4%; 27.3%).

Previous Regulatory Actions

The approval follows a complex regulatory journey; the FDA previously issued a complete response letter (CRL) in August 2025, regarding the initial biologics license application accepted (BLA) in January 2025.^3,4 The FDA noted that data from the IGNYTE trial were not adequate to provide evidence of effectiveness. There was also heterogeneity of the patient population, which the FDA could not adequately interpret. There were no safety issues.

In October 2025, the FDA accepted the resubmitted BLA and set the April 10, 2026, Prescription Drug User Fee Act Date based on the Class 2 resubmission timeline.⁵

References

1. Complete response. April 10, 2026. FDA. Accessed April 10, 2026. https://tinyurl.com/ys3etmrj
2. In GK, Wong MKK, Sacco JJ, et al. Response analysis for injected and non-injected lesions and of the safety and efficacy of superficial and deep/visceral RP1 injection in the registrational cohort of anti–PD-1–failed melanoma patients of the IGNYTE trial. J Clin Oncol. 2025;43(suppl 16):9537. doi: 10.1200/JCO.2025.43.16_suppl.9537
3. Replimune receives complete response letter from FDA for RP1 biologics license application for the treatment of advanced melanoma. News release. Replimune. July 22, 2025. Accessed April 2, 2026. https://tinyurl.com/2335n7sk
4. Replimune announces biologics license application acceptance and priority review for RP1 for the treatment of advanced melanoma. News release. Replimune. January 21, 2025. Accessed April 2, 2026. https://tinyurl.com/94jc39by
5. Replimune announces FDA acceptance of BLA resubmission of RP1 for the treatment of advanced melanoma. News release. Replimune. October 20, 2025. Accessed April 2, 2026. https://tinyurl.com/5yad7vza