RP1's Long Road: A Timeline of RP1's Regulatory Journey in Advanced Melanoma

Few investigational therapies in melanoma have had a regulatory path as winding as vusolimogene oderparepvec (RP1), the oncolytic herpes-virus-based immunotherapy. Paired with nivolumab (Opdivo), RP1 has produced durable responses in patients with advanced melanoma who progressed on anti–PD-1 therapy, and up to this point, the combination has now received 2 complete response letters (CRLs) on its way toward a third FDA decision. With an advisory committee meeting expected in late July 2026 and a Prescription Drug User Fee Act (PDUFA) date of August 2, 2026, on the calendar, here is a step-by-step look back from 2022 to present day and the journey RP1 has taken.

1. Early signal in non-melanoma skin cancer (2022)

Before melanoma became the headline indication, RP1 combined with nivolumab was already producing responses in non-melanoma skin cancers.¹ Data from the phase 1/2 IGNYTE trial (NCT03767348), presented at the Multidisciplinary Head and Neck Cancers Symposium, showed encouraging activity across cutaneous squamous cell carcinoma, basal cell carcinoma, Merkel cell carcinoma, and angiosarcoma, including a complete response rate approaching 50% in cutaneous squamous cell carcinoma. The safety profile was manageable, with most treatment-related adverse effects limited to grade 1 or 2.

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2. The melanoma cohort delivers (June 2024)

Topline data from IGNYTE's melanoma cohort showed that RP1 plus nivolumab produced an objective response rate (ORR) of 32.9% for the standard RECIST v1.1 criteria and 33.6% for the modified RECIST v1.1 guidelines in patients with melanoma who had progressed on prior anti–PD-1 therapy, with responses lasting more than 6 months and a median duration of response exceeding 35 months.² The results built on data first presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, and the drug's developer signaled plans to submit a biologics license application (BLA) to the FDA in the second half of 2024.

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3. A successful pre-BLA meeting (September 2024)

Ahead of any formal submission, the drug's developer met with the FDA in a pre-BLA meeting and came away with confirmation that the accelerated approval pathway remained available for RP1 in anti–PD-1–failed melanoma.³ That meeting, grounded in the 32.9% response rate and 55% clinical benefit rate observed in IGNYTE, set the stage for a formal filing.

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4. Breakthrough Therapy Designation and the first BLA (November 2024)

The FDA granted RP1 plus nivolumab breakthrough therapy designation for advanced melanoma, and a submission of the first BLA for the combination under the accelerated approval pathway occurred.⁴ The designation leaned on the anti–PD-1–failed melanoma cohort of IGNYTE, where grade 3 or higher treatment-related adverse effects occurred in just 12.8% of patients and no RP1-related deaths were reported. The confirmatory phase 3 IGNYTE-3 trial (NCT06264180) continued enrolling in parallel.

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5. Priority Review granted (January 2025)

The FDA accepted the BLA and granted priority review, setting a PDUFA date of July 22, 2025.⁵ The application was supported by IGNYTE data showing a 38.7% ORR in patients with advanced melanoma who had progressed on anti–PD-1 therapy, with the confirmatory IGNYTE-3 trial continuing to enroll patients against a comparator arm of physician's choice therapy.

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6. Fresh data at ASCO 2025 (June 2025)

While the BLA was under review, updated IGNYTE analyses presented at the 2025 ASCO Annual Meeting showed that deep or visceral tumor injections of RP1, including into lung and liver lesions, were feasible and produced numerically higher response rates than superficial injection alone.⁶ Pneumothorax occurred in a small share of lung injections but was largely self-resolving.

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7. The first complete response letter (July 2025)

Over a month later, the FDA issued a CRL for the RP1 BLA. The agency said IGNYTE was not an adequate and well-controlled trial to establish substantial evidence of effectiveness, citing heterogeneity in the patient population and questions about the trial's design, including the contribution of each component of the regimen.⁷ Notably, the FDA did not raise any safety concerns.

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8. A Type A meeting gets scheduled (September 2025)

In the wake of the CRL, Replimune and the FDA scheduled a Type A meeting to work through the agency's concerns.⁸ A briefing book was submitted by the developer addressing the patient population, criteria for anti–PD-1 resistance, and the “contribution of components” question, alongside additional analyses of the existing BLA data and the design of the confirmatory IGNYTE-3 trial.

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9. The first resubmission is accepted (October 2025)

Following the Type A meeting, Replimune resubmitted its BLA with additional information, data, and analyses.⁹ The FDA accepted the resubmission as a complete response to the CRL and set a new PDUFA date of April 10, 2026, under a Class 2 resubmission timeline.

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10. A second complete response letter (April 2026)

On the newly set PDUFA date, the FDA issued a second CRL, again stating that the data presented were insufficient to establish substantial evidence of effectiveness for RP1 in unresectable advanced cutaneous melanoma.¹⁰ The agency reiterated that IGNYTE was not considered a well-controlled trial and again flagged the design of the confirmatory IGNYTE-3 study, particularly around isolating RP1's individual contribution to the combination's effect.

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11. Experts revisit the data (April 2026)

In the aftermath of the second CRL, clinicians took a closer look at what IGNYTE had shown. Sarah Weiss, MD, director of the Melanoma/Cutaneous Oncology Program, medical oncologist, and associate professor of medicine in the Division of Medical Oncology at Rutgers Cancer Institute, highlighted that 15% of patients achieved a complete response, many of whom had primary resistance to prior anti–PD-1 therapy, and that the combination's 2-year overall survival (OS) rate topped 60%, underscoring the disconnect between the clinical data and the regulatory outcome.

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12. Three-year survival data emerge (June 2026)

At the 2026 ASCO Annual Meeting, a 3-year landmark survival analysis of IGNYTE reported a median OS of 32.9 months for RP1 plus nivolumab in anti–PD-1–progressed melanoma, with 1-, 2-, and 3-year OS rates of 75.3%, 61.5%, and 47.8%, respectively.¹¹ Among the 140 patients enrolled, those who responded to treatment had not reached a median OS, compared with 18.5 months among non-responders.

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13. A second resubmission — and a path to a decision (June 26, 2026)

Weeks after the survival data were presented, the FDA accepted a second BLA resubmission, this time classifying it as a complete, Class 1 response.¹² The agency set a PDUFA date of August 2, 2026, and told the company to expect an advisory committee meeting in late July.

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What's next

All eyes now turn to the FDA's Oncologic Drugs Advisory Committee (ODAC), expected to convene on July 30, 2026, ahead of the August 2, 2026, PDUFA date. After 2 complete response letters, this next review will determine whether RP1 plus nivolumab — a combination that has consistently shown durable, deep responses in a population with few remaining options — finally clears the regulatory bar the FDA has twice found it hasn't met.

References

1. Niu J, Milhem MM, Vanderwalde AM, et al. Safety and efficacy of RP1 + nivolumab in patients with non-melanoma skin cancer of the head and neck: results from IGNYTE phase 1/2 multi-cohort clinical trial. Presented at: 2022 Multidisciplinary Head and Neck Cancers Symposium; February 24-26, 2022; Phoenix, Arizona. Accessed July 16, 2026. https://bit.ly/3shikch
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(suppl 16):9517. doi:10.1200/JCO.2024.42.16_suppl.9517
3. Replimune announces positive pre-BLA meeting with FDA and confirms BLA submission on track for 2H 2024. News release. Replimune Group, Inc. September 9, 2024. Accessed July 16, 2026. https://tinyurl.com/yrjffwxa
4. Replimune receives breakthrough therapy designation for RP1 and submits RP1 biologics license application to the FDA under the accelerated approval pathway. News Release. Replimune. November 21, 2024. Accessed July 16, 2026. https://tinyurl.com/2p8ym2tj
5. Replimune announces biologics license application acceptance and priority review for RP1 for the treatment of advanced melanoma. News release. Replimune. January 21, 2025. Accessed July 16, 2026. https://tinyurl.com/94jc39by
6. 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
7. 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 July 16, 2026. https://tinyurl.com/2335n7sk
8. Replimune announces Type A meeting scheduled with FDA. News release. Replimune. September 2, 2025. Accessed July 16, 2026. https://tinyurl.com/y95a24u6
9. Replimune announces FDA acceptance of BLA resubmission of RP1 for the treatment of advanced melanoma. News release. Replimune. October 20, 2025. Accessed July 16, 2026. https://tinyurl.com/5yad7vza
10. Complete response. April 10, 2026. FDA. Accessed July 16, 2026. https://tinyurl.com/ys3etmrj
11. 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
12. Replimune announces FDA acceptance of RP1 biologics license application resubmission for advanced melanoma. News release. June 26, 2026. Accessed July 16, 2026. https://tinyurl.com/4sdytzn4