FDA Accepts RP1 BLA Resubmission for Advanced Melanoma

The FDA has accepted for review the resubmission of a biologics license application (BLA) for vusolimogene oderparepvec (RP1) in combination with nivolumab (Opdivo) for the treatment of advanced melanoma, according to a news release from Replimune. The FDA classified the submission as a complete, class 1 response with a goal date of August 2, 2026, and has notified the company to expect an advisory committee meeting in late July 2026.¹

The resubmission seeks accelerated approval of the oncolytic virus therapy based on data from the phase 2 IGNYTE trial (NCT03767348), which evaluated RP1 combined with nivolumab in patients with confirmed progression on an anti-PD-1–containing regimen. The acceptance marks the latest development in a prolonged regulatory process that has twice ended in rejection.²

Challenges in the Approval Process

RP1 is an HSV-1–based oncolytic immunotherapy engineered to express granulocyte-macrophage colony-stimulating factor (GM-CSF) and GALV-GP R⁻, building on the mechanism of talimogene laherparepvec (T-VEC; Imlygic), the first FDA-approved oncolytic immunotherapy.

The initial BLA was based on IGNYTE results showing a confirmed overall response rate (ORR) by independent central review of 33.6%, including a 15.0% complete response (CR) rate, in 140 patients with unresectable stage IIIB to IV cutaneous melanoma after prior anti–PD-1 therapy.

A first complete response letter (CRL) was issued July 22, 2025, which identified inadequacy of the trial design as the primary concern, raised issues regarding heterogeneity of the patient population, and also with the design of the confirmatory IGNYTE-3 trial (NCT06264180) concerning the contribution of the component therapies. The CRL did not identify safety concerns.²

Following resubmission with additional exploratory analyses and early data from the confirmatory phase 3 IGNYTE-3 trial (NCT06264180), the FDA issued a second CRL on April 10, 2026.³ The agency cited the inability to isolate the contribution of RP1 vs nivolumab in a single-arm trial lacking an adequate contemporaneous control, compounded by heterogeneity in the study population's prior therapy history, including patients who had received anti–PD-1 therapy in either the adjuvant or advanced setting with varying treatment durations, that made cross-trial comparison with historical controls unreliable. The FDA also flagged that 49% of patients with objective responses had all target lesions injected with RP1, and that 53% of responders did not have measurable noninjected target lesions that could confirm systemic antitumor activity. Early IGNYTE-3 data covering 22 patients on the RP1 arm and 18 on the physician's choice arm, approximately 10% of planned enrollment, were included in the resubmission, but were deemed insufficient to meet evidentiary standards.

Supporting Efficacy Data

The 3-year overall survival (OS) analysis from IGNYTE, reported in an oral presentation at the 2026 ASCO Annual Meeting, provided updated evidence for the combination's durability.⁴ The median OS was 32.9 months (95% CI, 25.8-46.0), with 1-, 2-, and 3-year OS rates of 75.3%, 61.5%, and 47.8%, respectively. Among responders, the 3-year OS rate was 83.5% (95% CI, 68.5%-91.8%) vs 26.4% (95% CI, 16.9%-36.9%) among nonresponders, with median OS not reached in the responder group vs 18.5 months among nonresponders. The median duration of response was 24.8 months, with 44.8% of responses ongoing at 3 years. The safety profile remained manageable, with grade 3/4 treatment-related adverse events in 12.8% of patients and no grade 5 events.

Ongoing Confirmatory Trial and Near-Term Outlook

IGNYTE-3 is actively enrolling toward a target of 400 patients and compares RP1 plus nivolumab with physician's choice of nivolumab/relatlimab (Opdualag), single-agent anti-PD-1, or single-agent chemotherapy in patients with confirmed disease progression after anti–PD-1 and, in eligible patients, BRAF-targeted therapy. The primary end point is OS with key secondary end points of progression-free survival and ORR.

The FDA's class 1 designation for the resubmission typically indicates that all deficiencies were addressed with existing data rather than requiring new clinical studies. An advisory committee meeting in late July will provide a public forum for discussion of the risk-benefit profile before the action date.¹

REFERENCES

1. Replimune announces FDA acceptance of RP1 biologics license application resubmission for advanced melanoma. News release. Replimune Group, Inc. June 26, 2026. Accessed June 29, 2026. https://tinyurl.com/3ka5xryw

2. Replimune receives complete response letter from FDA for RP1 biologics license application. News release. Replimune Group, Inc. July 22, 2025. Accessed June 29, 2026. https://tinyurl.com/2x2zvr58

3. Complete response. April 10, 2026. FDA. Accessed June 29, 2026. https://tinyurl.com/ys3etmrj

4. Wong MKK, Sacco JJ, In GK, et al. A 3-year landmark overall survival analysis of RP1 plus nivolumab in patients with anti–PD-1–failed melanoma from the IGNYTE clinical trial. J Clin Oncol. 2026;44(suppl 16):9518. doi:10.1200/JCO.2026.44.16_suppl.9518