FDA Issues CRL for Vusolimogene Oderparepvec in Advanced Melanoma

Replimune Group, Inc., announced that the FDA has issued a complete response letter (CRL) for its biologics license application seeking accelerated approval of vusolimogene oderparepvec (RP1) in combination with nivolumab for patients with advanced melanoma, citing concerns with the IGNYTE (NCT03767348) trial’s design and interpretability but raising no safety issues.

FDA cites trial design concerns and lack of substantial evidence in denying approval for Replimune’s biologics application in advanced melanoma. | Image credit: Postmodern Studio - stock.adobe.com

“We are surprised by this FDA decision and disappointed for advanced melanoma patients who have limited treatment options, as highlighted by the granting of breakthrough status at the time we provided the IGNYTE primary data,” said Sushil Patel, PhD, CEO of Replimune, in a statement.¹ “The issues highlighted in the CRL were not raised by the agency during the mid- and late-cycle reviews. Additionally, we had also aligned on the design of the confirmatory study. We strongly believe that RP1 in combination with nivolumab can bring substantial benefit to advanced melanoma patients.”

Replimune will request a Type A meeting with the FDA, which it expects to be scheduled within 30 days. The company plans to engage with the agency as quickly as possible to identify a viable path toward accelerated approval of RP1—without which it says further development of the therapy for patients with advanced cancer with limited treatment options may not be feasible.

RP1 in combination with nivolumab was evaluated in patients with advanced melanoma who had previously failed anti–PD-1 therapy.² The trial enrolled 156 patients, including a registration-directed cohort of 140 individuals. The overall objective response rate (ORR) was 31.4%, with a complete response rate of 12.2%. Notably, responses were seen across disease stages and prior treatment settings, including in visceral and uninjected lesions.

Among patients with primary resistance to anti–PD-1 therapy, the ORR was 34.1%, and responses in this difficult-to-treat population were often durable, lasting over 24 months in some cases. The combination regimen was generally well tolerated, with mostly grade 1 to 2 adverse events and a single grade 5 event attributed to nivolumab.

The CRL for Replimune’s RP1 comes just days after the FDA issued a separate CRL to Genentech for the combination of glofitamab-gxbm (Columvi) with gemcitabine and oxaliplatin (GemOx) for relapsed or refractory diffuse large B-cell lymphoma (DLBCL).³ In that case, the agency determined that data from the phase 3 STARGLO (NCT04408638) study were not sufficient to support approval in the second-line setting for patients ineligible for stem cell transplant.

The FDA’s Oncologic Drugs Advisory Committee voted 8 to 1 against the relevance of the STARGLO trial results to support the use of glofitamab combined with chemotherapy in US patients with relapsed or refractory DLBCL.

The STARGLO trial also served as a confirmatory study for glofitamab’s existing third-line accelerated approval, raising broader questions about the FDA’s evolving expectations around clinical trial design and evidentiary standards for combination regimens seeking approval through the accelerated pathway.

References

1. Replimune receives complete response letter from FDA for RP1 biologics license application for the treatment of advanced melanoma. News release. Replimune. July 22, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-receives-complete-response-letter-fda-rp1-biologics

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(16_suppl):9517-9517. doi:10.1200/jco.2024.42.16_suppl.9517

3. Shaw M. FDA delivers a CRL to glofitamab for relapsed/refractory DLBCL. AJMC®. July 18, 2025. Accessed July 22, 2025. https://www.ajmc.com/view/fda-delivers-a-crl-to-glofitamab-for-relapsed-refractory-dlbcl