The FDA did not raise any safety issues in the complete response letter.
The FDA has issued a complete response letter (CRL) to vusolimogene oderparepvec (RP1) in combination with nivolumab (Opdivo) for the treatment of patients with advanced melanoma who were previously administered an anti–PD-1 regimen, according to a news release from the drug’s developer, Replimune.1
The FDA indicated that data from the phase 1/2 IGNYTE trial (NCT03767348) were not adequate to provide evidence of effectiveness. Additionally, the agency cited that the trial could not be adequately interpreted due to the heterogeneity of the patient population, as well as due to items related to the trial design, such as contribution of components. The agency did not raise any safety issues.
In the phase 1/2 IGNYTE trial, investigators evaluated the immunotherapy in combination with nivolumab for patients with advanced melanoma who progressed following an anti–PD-1 therapy. Investigators previously presented findings from the trial at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.2
The findings showed that among all patients treated with RP1 injections (n = 140), the objective response rate (ORR) was 32.9% (n = 46), with 15.0% (n = 21) of patients achieving a complete response (CR) and 17.9% (n = 25) of patients achieving a partial response (PR). Additionally, among 78 injected lesions in responders, any reduction was seen in 98.7%, including 53.8% experiencing a best reduction of 100%. Among 119 non-injected lesions, the respective rates were 96.6% and 39.5%.
The ORR among patients with superficial tumors (n = 104), defined as those that could be visualized or palpated and accessed with standard-sized needles and syringes, was 29.8% (n = 31), with 17.3% (n = 18) experiencing a CR and 12.5% (n = 13) experiencing a PR as best response. Among those with superficial plus deep or visceral tumors (n = 14), defined as those that could not directly be observed or palpated and required imaging guidance to inject, the ORR was 42.9% (n = 6), all of which were PRs. Among those with deep or visceral tumors only (n = 22), the ORR was 40.9% (n = 9), with 13.6% (n = 3) of patients achieving a CR and 27.3% (n = 6) of patients achieving a PR.
“We are surprised by this FDA decision and disappointed for patients with advanced melanoma who have limited treatment options as highlighted by the granting of breakthrough status at the time we provided the IGNYTE primary data,” Sushil Patel, PhD, chief executive officer of Replimune, said in the news release.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 [patients with] advanced melanoma.”
The primary objective for the phase 1/2 trial was safety and efficacy of RP1 by BICR using modified RECIST v1.1 criteria.4 Secondary end points included progression-free survival (PFS) and ORR, as well as duration of response and 1- and 2-year overall survival outcomes. At a data cut-off date of March 8, 2024, the median follow-up of the primary analysis was 15.5 months (range, 0.5-47.6).
Patients received an initial dose of RP1 at 106 PFU/mL during the first treatment cycle. From cycles 2 to 8, patients received 107 PFU/mL of RP1 and 240 mg of nivolumab every 2 weeks; during cycle 9, patients received 240 mg of nivolumab every 2 weeks; and during cycles 10 to 30, patients were treated with 480 mg of nivolumab every 4 weeks. Two-week drug holidays occurred between cycles 1 and 2, 8 and 9, and 9 and 10. Following cycle 30, a 100-day safety follow-up was initiated.
Eligibility criteria included advanced melanoma following progression on prior anti–PD-1 therapy, measurable disease per RECIST v1.1 guidelines, and adequate organ therapy.3 Patients were also included if they had a life expectancy of at least 3 months, at least 1 injectable lesion, and an ECOG performance score of 0 to 1.
The treatment is currently undergoing confirmatory analysis in the randomized, multicenter, open-label phase 3 IGNYTE-3 trial (NCT06264180), which is monitoring RP1 plus nivolumab in patients with advanced melanoma who progressed on anti–PD-1 and anti–CTLA-4 therapy.
Patients were excluded from trial participation if they received prior treatment with oncolytic therapy, had a history of viral infections, prior complications with herpes infections, or a chronic use of anti-viral agents. Additional exclusion criteria included uncontrolled or untreated brain metastases and a history of either interstitial lung disease, non-infectious pneumonitis, or clinically significant cardiovascular disease.
The incidence of treatment-related AEs (TRAEs) in patients with only superficial tumors, only deep or visceral tumors, or both types of tumors was 89.4%, 95.5%, and 85.7%, respectively. The respective grade 3 or 4 TRAE rates were 14.4%, 4.5%, and 14.3%. The most common TRAEs across the 3 groups included fatigue (31.7%, 31.8%, and 42.9%), pyrexia (29.8%, 40.9%, and 21.4%), chills (28.8%, 45.5%, 35.7%), nausea (21.2%, 27.3%, and 21.4%), influenza-like illness (12.5%, 45.5%, and 14.3%), and injection-site pain (12.5%, 22.7%, and 21.4%).
Among 7 patients with lung injections, pneumothorax events were reported in 5.8% (n = 3/52) of injections and included 1 grade 1 event and 2 grade 2 events. Both events were self-resolved, and further doses were given without additional events. A single lung injection led to pneumothorax requiring invasive intervention, and all events occurred within 7 days of RP1 injection.
Additionally, among 48 liver injections that were administered in 8 patients, no elevated liver function tests were observed. Furthermore, no liver or abdominal cavity bleeding events were reported in the study.
The FDA received a biologics license application for the RP1 combination in November 2024.4 Additionally, RP1/nivolumab earned priority review from the agency in January 2025.5
Developers plan to interact with the FDA to find a path forward for the accelerated approval of the combination in this patient group.
References
- 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 22, 2025. https://tinyurl.com/2335n7sk
- In GK, Wong MK, 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
- Study of RP1 monotherapy and RP1 in combination with nivolumab (IGNYTE). ClinicalTrials.gov. Updated January 24, 2025. Accessed July 10, 2025. https://tinyurl.com/3czdx3zs
- 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 10, 2025. https://tinyurl.com/2p8ym2tj
- 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 10, 2025. https://tinyurl.com/94jc39by