FDA Issues Second CRL for RP1/Nivolumab in Advanced Melanoma

A complete response letter (CRL) was sent concerning the resubmitted biologics license application (BLA) for RP1 (vusolimogene oderparepvec), an oncolytic virus therapy, in combination with nivolumab (Opdivo) as treatment for advanced melanoma following progression on an anti–PD-1 containing regimen.¹

The BLA was initially based on results from the pivotal phase 2 IGNYTE trial (NCT03767348) that showed efficacy of the combination with a confirmed overall response rate (ORR) by independent central review of 33.6% including 15.0% complete response (CR) rate.² The approval of RP1 was previously met with a complete response letter (CRL) citing issues with the design of the study and interpretation of the results.³

Despite updated findings including exploratory analyses and an unplanned analysis from the phase 3 IGNYTE-3 trial (NCT06264180), the FDA found deficiencies in the trials related to the patient population and trial designs.

“We acknowledge inherent confounding factors related to drug development in this disease setting,” the CRL stated. “Nevertheless, these factors carry the potential to confound the assessments for establishing the treatment effect of your product.”

Supporting Study Data

RP1 is an oncolytic immunotherapy based on a clinical strain of herpes simplex virus type 1 engineered to express granulocyte-macrophage colony-stimulating factor and GALV-GP-R–, building on talimogene laherparepvec (T-VEC), the first FDA-approved oncolytic immunotherapy.²

The phase 1/2 IGNYTE trial investigated RP1 as a monotherapy or in combination with nivolumab. The registrational phase 2 cohort enrolled 140 patients with unresectable stage IIIB to IV cutaneous melanoma to receive RP1 plus nivolumab after receiving prior anti–PD-1 therapy.²

Patients received an initial intratumoral injection of RP1 with up to 7 additional doses every 2 weeks, plus 240 mg nivolumab every 2 weeks for up to 2 years. The primary end point was ORR and secondary end points included duration of response, CR rate, progression-free survival (PFS), and overall survival (OS).

The responses were durable with 69.5% ongoing at 1 year, and responses were seen in noninjected lesions, demonstrating a systemic effect.

The median PFS for all patients was 3.6 months (95% CI, 2.0-5.0), with 35.5 months (95% CI, 21.3 to not reached) for responders and 1.9 months (95% CI, 1.8-1.9) for nonresponders. The 1- and 2-year OS rates were 75.3% and 63.3%, respectively, with the median OS not reached.

The combination had a manageable safety profile with a low rate of grade 3 and 4 adverse events. The safety profile overlapped with that of nivolumab alone with no additive toxicity due to the combination.

“The IGNYTE clinical trial was a single-arm study, and the results should therefore be contextualized with historical data for patients with melanoma that progressed while being treated with anti–PD-1 therapy. Previous studies have shown that only 6% to 7% of patients are expected to respond to continued anti–PD-1 monotherapy after confirmed progression on an anti–PD-1–containing regimen,” wrote the IGNYTE study authors.

Prior Deferral of Approval

On July 22, 2025, a CRL was issued to indicate that the approval could not be granted based on the initial BLA based on data from IGNYTE, suggesting that the trial was not adequate and well controlled, and also raising issues about the heterogeneity of the patient population.³ It did not identify safety concerns. The CRL also raised issues with the design of the confirmatory phase 3 trial, IGNYTE-3, concerning the contribution of the component therapies.

IGNYTE-3 is ongoing and has a targeted enrollment of 400 patients.⁴ The combination of RP1 and nivolumab is being compared 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 as well as BRAF-targeted therapy in eligible patients.

Conclusions from FDA Review

The FDA’s Center for Biologics Evaluation and Research identified the issues with the IGNYTE study, chiefly the inability to isolate the contribution of RP1 vs nivolumab, the heterogeneity of the study population, and the “uncertainty of response assessments including surgical interventions” that could confound results.

The FDA stated that the trial’s inclusion of patients who had received prior PD-1 therapy in either the adjuvant or advanced setting with varying durations of prior therapy made cross-trial comparison with historical controls challenging. Without adequate comparison with a similarly heterogenous population, the single-arm trial was not sufficient to show how RP1 plus nivolumab would compare with nivolumab monotherapy or other immunotherapy rechallenge.

The FDA also highlighted that 49% of patients with objective responses had all target lesions injected with RP1, and 2 additional patients with a response did not have target lesions per independent review, leading to the conclusion that 53% of those with response did not have measurable noninjected target lesions that could indicate systemic antitumor activity.

They also identified retreatment of new or growing lesions with RP1 took place before independent review confirmed progressive disease, which could confound the rate and duration of response. Surgical procedures including biopsies on target lesions were also identified as a factor that could affect measurement of response in these lesions.

Another factor identified was the use of histopathologic assessments that were not centrally reviewed, which also made it difficult to distinguish between local and systemic effects of therapy.

Early Phase 3 Outcomes

The resubmitted BLA included ORR results for 22 patients who received RP1 plus nivolumab and 18 who received physician’s choice in the phase 3 trial, which comprised 10% of the planned enrollment. The FDA considered this to not meet the evidentiary standards because of the limited number of patients, investigator assessment, and lack of duration of response data. As the analysis was not prespecified, progression-free survival could not be interpreted easily.

The FDA was also provided with exploratory analyses from IGNYTE showing patients with disease response immediately after receiving anti–PD-1 therapy, responses in both injected and noninjected lesions, and progression-free survival.

These amended submissions were not considered sufficient to show the trial is adequate and well controlled to demonstrate efficacy.

Company Response

In a news release, Replimune Group expressed disappointment at the FDA decision given the favorable ORR, and cited “inconsistent agency process and communication” that led to a rejection despite the previous acceptance of the BLA based on the IGNYTE study data for accelerated approval. They disputed the FDA’s conclusions regarding tumor assessment methodology and stated that detailed analyses supporting their position had been submitted with the second BLA.⁵

Sushil Patel, PhD, CEO of Replimune, suggested that without a timely accelerated approval, “the development of RP1 will not be viable.”

“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,” Patel stated in the news release.

Next Steps

The trial sponsor is required to resubmit or withdraw the application within 1 year and address all deficiencies with the resubmission. A Type A post-action meeting with the FDA to clarify the needs of the resubmission can be requested within 3 months.

REFERENCES

1. Complete response letter. FDA. April 10, 2026. Accessed April 10, 2026. https://tinyurl.com/4nrh4fdj

2. 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

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 March 2, 2026. https://tinyurl.com/2x2zvr58

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. NCT06264180. Updated February 9, 2026. Accessed March 2, 2026. https://clinicaltrials.gov/study/NCT06264180

5. Replimune receives complete response letter from the FDA for RP1 biologics license application for the treatment of advanced melanoma. News release. Replimune. April 10, 2026. Accessed April 13, 2026. https://tinyurl.com/4tj7wpav