How RP1 Plus Nivolumab Overcame Two CRLs to Win Approval in Melanoma

In August 2026, the FDA granted accelerated approval to vusolimogene oderparepvec-wtpg (Tudriqev; RP1) in combination with nivolumab (Opdivo) for the treatment of adult patients with unresectable advanced cutaneous melanoma that progressed on a PD-1–blocking antibody–based regimen, capping a regulatory review that spanned more than 19 months and 2 complete response letters (CRLs).¹ The clearance rests on data from the single-arm phase 1/2 IGNYTE trial (NCT03767348), an oncolytic immunotherapy program whose path to a label required a public advisory committee hearing to discuss exactly how much evidentiary weight a single-arm study of the intratumorally delivered therapy can carry.^1-3

RP1 is a herpes simplex virus type 1–based oncolytic immunotherapy engineered to express granulocyte-macrophage colony-stimulating factor and a fusogenic glycoprotein, administered by direct intratumoral injection.⁴ Michael K. Wong, MD, PhD, FRCPC, IGNYTE's lead study author and former physician in chief and professor of oncology at Roswell Park Comprehensive Cancer Center in Buffalo, New York, noted that the trial design was developed in collaboration with the FDA, with the goal of delivering a new treatment option for patients whose melanoma had progressed on anti–PD-1 therapy, including those previously treated with ipilimumab (Yervoy) plus nivolumab.⁵

"The trial design was done in collaboration and with advice from the agency, and it happened in a time when there really was no real option in the patient population under study," Wong said in an interview with OncLive. "I think there's been changes at the agency in how to interpret data."

What was the regulatory history before approval?

Replimune first submitted a biologics license application (BLA) for RP1 plus nivolumab in November 2024, and the FDA accepted it under priority review in January 2025 with a Prescription Drug User Fee Act target action date of July 22, 2025.⁵^,⁶ The first CRL, issued that month, stated that the single-arm IGNYTE trial was not an adequate and well-controlled investigation capable of providing substantial evidence of effectiveness, largely because the heterogeneous trial population made it difficult to isolate RP1's contribution from that of nivolumab.⁵^,⁷

The FDA accepted a second BLA in October 2025 with a target action date of April 10, 2026.⁵^,⁸ Another CRL followed in April 2026, this time citing deficiencies related to both IGNYTE and the confirmatory phase 3 IGNYTE-3 trial (NCT06264180).⁵^,⁹ A third BLA, accepted in June 2026 as a class 1 response, set a goal date of August 2, 2026, and triggered a public meeting of the FDA's Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC).⁵^,¹⁰

How was the IGNYTE designed?

IGNYTE was a single-arm, multicohort, dose-escalation and -expansion study initiated in 2018, with an anti–PD-1–refractory cutaneous melanoma cohort added in 2019.² The registrational cohort enrolled 140 patients with unresectable stage IIIB to IV disease that had progressed after at least 8 weeks of treatment with nivolumab or pembrolizumab (Keytruda), given alone or with anti–CTLA-4 therapy, as the most recent line of treatment. Patients were required to have at least 1 measurable lesion per RECIST 1.1 criteria and injectable lesions of at least 1 cm in longest diameter.²^,⁴

Patients received an initial intratumoral RP1 dose at 1×10⁶ plaque-forming units (PFU)/mL, followed by up to 7 additional doses every 2 weeks at 1×10⁷ PFU/mL. Nivolumab at 240 mg was initiated with the second RP1 dose and given every 2 weeks for up to 8 cycles, then continued at 480 mg every 4 weeks for up to 21 additional cycles. The primary end point was objective response rate (ORR) by blinded independent central review (BICR) per (modified) RECIST 1.1 criteria.²^,⁴

"The definition of PD-1–refractory disease in this trial exceeds those that are used, for instance, by the Society for Immunotherapy of Cancer,” Wong said, citing the requirement of at least 8 weeks of anti–PD-1 therapy as the most recent line, radiographically confirmed progression separated by at least a month, and blinded independent review of both progression and response. "One-third of patients had elevated lactate dehydrogenase, over 55% were PD-L1 negative by immunohistochemistry, 44% had [progressed on] prior ipilimumab plus nivolumab, and 66% had primary resistance, so this was not a favorable-risk population."

What efficacy data did the CTGTAC review, and how did the FDA and sponsor disagree?

At the July 30, 2026, meeting, the CTGTAC voted 10 to 3 that IGNYTE's efficacy results were evaluable and clinically meaningful for RP1 plus nivolumab in this setting.^1,3 As reported by Replimune, the confirmed ORR across the 140-patient cohort was 33.6% (95% CI, 25.8%-42.0%), including a 16.4% complete response (CR) rate and a 17.1% partial response rate; median duration of response (DOR) was 24.8 months (95% CI, 14.1-not estimable), and median time to response was 3.9 months.³ At a March 8, 2026, data cutoff, median overall survival (OS) was 32.9 months (95% CI, 25.8-46.0), with a 3-year OS rate of 47.8% (95% CI, 38.6-56.5); median progression-free survival was 3.6 months (95% CI, 2.0-5.0).

The FDA argued that IGNYTE did not meet the "adequate and well-controlled" bar required for accelerated approval, contending that RECIST 1.1 criteria, designed for systemic therapies, could not reliably characterize responses at intratumorally injected lesions, and citing reinjection beyond progression, confounding from biopsies and surgical procedures, and retrospective histology reclassification as factors that may have inflated results.² In an analysis excluding patients with all target lesions injected or no target lesions at baseline, ORR fell to 15.7% (95% CI, 10.1%-22.8%) with a median DOR of 14.1 months (95% CI, 10.7-not reached); a further sensitivity analysis of the remaining evaluable population (n = 89) showed an ORR of 24.7% (95% CI, 16.2%-35.0%).²

Replimune countered that the intervention was prespecified in the protocol and that RP1's dual mechanism drives a systemic T-cell response against both injected and noninjected lesions, pointing to an ORR of 28.7% (95% CI, 20.4%-38.2%) among noninjected measured lesions alone.³ The company also argued that the 33.6% ORR observed was roughly 5 times the 5% to 7% response rate expected with further anti–PD-1 monotherapy after progression, and cited the 2024 accelerated approval of lifileucel (Amtagvi), which was based on the single-arm phase 2 C-144-01 trial (NCT02360579), which showed a 31.5% ORR in a similar post–anti–PD-1 melanoma population (n = 73), as regulatory precedent.^2,3

"Once you are in a situation where you have PD-1–refractory disease, rechallenging with PD-1 again really isn't a treatment which has any great efficacy," Wong said, adding that in the ongoing, randomized IGNYTE-3 trial, investigators given a free choice of comparator have almost never selected anti–PD-1 rechallenge. "It almost universally never happens, because many of us in the field realize that's a futile response."

What efficacy data ultimately supported the approved label?

In the population the agency used to support the label (n = 91), RP1 plus nivolumab produced an ORR of 24.2% (95% CI, 15.8%-34.3%) with a median DOR of 14.1 months (95% CI, 10.7-not reached), figures that track closely with the FDA's own sensitivity analysis presented at the advisory committee meeting rather than Replimune's initial 33.6% BICR-assessed ORR across the full 140-patient cohort.^1-3 The confirmatory IGNYTE-3 trial is ongoing, with OS data expected in 2030.^2,3

What was the safety profile of RP1 plus nivolumab?

Among safety-evaluable patients (n = 140), the most common nonlaboratory adverse effects (AEs) reported in more than 10% of patients included fatigue, pyrexia, infections, chills, musculoskeletal pain, nausea, diarrhea, injection site reaction, headache, cough, influenza-like illness, rash, vomiting, pruritus, arthralgia, constipation, decreased appetite, dizziness, dyspnea, hemorrhage, edema, and abdominal pain.¹ Any-grade treatment-emergent AEs occurred in 97.9% of patients, with grade 3 or higher events in 31.4% and serious adverse effects in 35.7%; treatment-emergent AEs led to death in 8.6% of patients.² AEs of special interest flagged by the FDA during review included tumor hemorrhage, sepsis, and capillary leak syndrome.²

RP1 is dosed at 1 mL/cm of the largest tumor dimension, up to a maximum of 10 mL across all treated lesions per session, with lesion size reassessed before each dose. Treatment is given every 2 weeks for 8 consecutive doses, starting at 10⁶ PFU/mL and stepping up to 10⁷ PFU/mL for subsequent doses; for patients with multiple tumors, the label recommends prioritizing the fastest-growing and largest new or existing lesions suitable for injection. Nivolumab initiation is recommended at week 3.¹

What are the next steps for RP1 plus nivolumab in melanoma?

With accelerated approval secured, confirmatory data from IGNYTE-3 will determine whether the combination converts to traditional approval; OS results are not expected until 2030.²^,³ In the interim, Wong noted that RP1 plus nivolumab addresses a population where the only other FDA-approved option is tumor-infiltrating lymphocyte (TIL) therapy, a modality he called logistically demanding for many patients relative to an intratumoral–systemic combination.⁵ The advisory committee's discussion, and the gap between the sponsor's initial ORR and the figure that ultimately supported the label, is likely to inform how future single-arm, intratumorally delivered therapies are evaluated for accelerated approval in solid tumors.

"With the approval of RP1 plus nivolumab, it now will fit into the post–PD-1 immunotherapy-refractory space. The only other FDA-approved therapy in that space presently is the use of tumor-infiltrating lymphocyte therapies," Wong said "No matter how you look at it, it's a little harder to get patients into TIL therapies" given the need for lesion harvesting, manufacturing, lymphodepleting chemotherapy, infusion, and interleukin-2 support, As RP1 plus nivolumab takes its place in the treatment landscape, it has more of a universal appeal in this patient population."

References

1. FDA grants accelerated approval to vusolimogene oderparepvec-wtpg in combination with nivolumab for melanoma. News release. FDA. August 6, 2026. Accessed August 26, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-vusolimogene-oderparepvec-wtpg-combination-nivolumab-melanoma
2. BLA 125827 vusolimogene oderparepvec (RP1): FDA briefing document. FDA. July 30, 2026. Accessed August 26, 2026. https://www.fda.gov/media/193879/download
3. BLA 125827 vusolimogene oderparepvec (RP1): sponsor presentation. Replimune. July 30, 2026.
4. 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
5. Ryan C. FDA advisory committee to weigh RP1 plus nivolumab in anti–PD-1–pretreated advanced melanoma. OncLive. Published July 29, 2026. Accessed August 26, 2026. https://www.onclive.com/view/fda-advisory-committee-to-weigh-rp1-plus-nivolumab-in-anti-pd-1-pretreated-advanced-melanoma
6. Replimune announces biologics license application acceptance and priority review for RP1 for the treatment of advanced melanoma. News release. Replimune. January 21, 2025. Accessed August 26, 2026. https://ir.replimune.com/news-releases/news-release-details/replimune-announces-biologics-license-application-acceptance-and
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 August 26, 2026. https://ir.replimune.com/news-releases/news-release-details/replimune-receives-complete-response-letter-fda-rp1-biologics
8. Replimune announces FDA acceptance of BLA resubmission of RP1 for the treatment of advanced melanoma. News release. Replimune. October 20, 2025. Accessed August 26, 2026. https://ir.replimune.com/news-releases/news-release-details/replimune-announces-fda-acceptance-bla-resubmission-rp1-0
9. Complete response letter for BLA 125827. FDA. April 10, 2026. https://download.open.fda.gov/crl/CRL_BLA125827_20260410.pdf
10. Replimune announces FDA acceptance of RP1 biologics license application resubmission for advanced melanoma. News release. Replimune. June 26, 2026. Accessed August 26, 2026. https://ir.replimune.com/news-releases/news-release-details/replimune-announces-fda-acceptance-rp1-biologics-license