Replimune Receives Second CRL for RP1 With Nivolumab for Treatment of Advanced Melanoma

Replimune received a complete response letter (CRL) from the FDA for RP1 (vusolimogene oderparepvec) in combination with nivolumab (Opdivo; Bristol Myers Squibb) for the treatment of advanced melanoma, according to a news release.¹ Although it received FDA priority review in January 2025, the treatment received a CRL from the FDA in July 2025.^2,3

RP1 is based on a proprietary strain of herpes simplex virus engineered and genetically armed with a fusogenic protein (GALV-GP R-) and granulocyte-macrophage colony-stimulating factor intended to maximize tumor-killing potency, the immunogenicity of tumor cell death, and the activation of a systemic antitumor immune response. Its biologics license application indication is for melanoma, the fifth most common cancer that is estimated to affect about 112,000 new US patients.

Standard-of-care therapy includes immune checkpoint blockade; however, approximately half of patients do not respond or experience disease progression, underscoring the critical need for newer therapeutic options.¹

“It is deeply disappointing that the FDA has not exercised regulatory flexibility to meet patients’ needs, given the data supporting strong efficacy and the favorable safety profile. Approximately 8500 Americans with advanced melanoma die every year. The country’s foremost melanoma specialists stood behind the RP1 data.…” Sushil Patel, PhD, CEO of Replimune, said in the news release announcing the CRL.¹

Per the FDA’s feedback, IGNYTE-3(NCT06264180),⁴ a randomized, controlled, multicenter, open-label phase 3 clinical study, was initiated. The trial is assessing RP1 in combination with nivolumab compared with physician’s choice of treatment in patients with unresectable stage IIIb through IV cutaneous melanoma. Enrolled patients had progressed on regimens containing anti–PD-1 and anti–CTLA-4 therapy (administered either in combination or sequentially), or were not candidates for anti–CTLA-4 treatment.⁴

Further, early results from the phase 2 IGNYTE trial (NCT03767348)⁵ confirmed that the overall response rate was approximately 32.9% ([95% CI, 25.2%-41.3%]; 15.0% complete response) in patients receiving the RP1 regimen. Responses occurred with similar frequency, depth, duration, and kinetics in injected and noninjected patients, including in visceral lesions, the study authors wrote. Additionally, the median duration of response was 33.7 months (95% CI, 14.1-not reached), and overall survival rates at 1 and 2 years were 75.3% (95% CI, 66.9%-81.9%) and 63.3% (95% CI, 53.6%-71.5%), respectively.⁶

Treatment-related adverse event (AE) rates were mostly grades 1 and 2 (77.1%), with only 9.3% of patients reporting grade 3 AEs and 3.6% reporting grade 4. There were no grade 5 AEs.⁶

Following the first CRL, Replimune requested a Type A meeting with the FDA, which was held in September 2025. During this meeting, the FDA reportedly did not raise further concerns regarding heterogeneity of the patient population in the IGNYTE trials and acknowledged that randomly assigning patients to an anti–PD1-only arm in the confirmatory study was not feasible.¹

“As we previously communicated, without timely accelerated approval, the development of RP1 will not be viable. We are devastated for our committed employees who have worked tirelessly for patients, but at this point we have no choice but to eliminate jobs, including substantially scaling back our US-based manufacturing operations,” Patel explained. “A treatment desperately needed by patients will not be available. Not because the medicine failed. Because the system did.”¹

REFERENCES

1. Replimune receives complete response letter from the FDA for RP1 biologics license application for the treatment of advanced melanoma. Replimune. News release. April 10, 2026. Accessed April 13, 2026. https://ir.replimune.com/news-releases/news-release-details/replimune-receives-complete-response-letter-fda-rp1-biologics-0

2. Ferruggia K. FDA gives priority review to vusolimogene oderparepvec for melanoma. Pharmacy Times. January 22, 2025. Accessed April 13, 2026. https://www.pharmacytimes.com/view/fda-gives-priority-review-to-vusolimogene-oderparepvec-for-melanoma

3. McGovern G. FDA issues CRL to Replimune for vusolimogene oderparepvec with nivolumab for advanced melanoma. Pharmacy Times. July 22, 2025. Accessed April 13, 2026. https://www.pharmacytimes.com/view/fda-issues-crl-to-replimune-for-vusolimogene-oderparepvec-with-nivolumab-for-advnaced-melanoma

4. 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 March 13, 2026. Accessed April 13, 2026. https://www.clinicaltrials.gov/study/NCT06264180

5. Study of RP1 monotherapy and RP1 in combination with nivolumab (IGNYTE). ClinicalTrials.gov. Updated February 13, 2026. Accessed April 13, 2026. https://clinicaltrials.gov/study/NCT03767348

6. Wong MK, Milhem MM, Sacco JJ, et al. RP1 combined with nivolumab in advanced anti–PD-1–failed melanoma (IGNYTE). J Clin Oncol. 2025;43(33):3589-3599. doi:10.1200/JCO-25-01346