The U.S. Food and Drug Administration (FDA) has granted accelerated approval to vusolimogene oderparepvec-wtpg (TUDRIQEV®; Replimune), a genetically modified oncolytic viral therapy, in combination with nivolumab (Opdivo®; Bristol Myers Squibb), for adult patients with unresectable advanced cutaneous melanoma that has progressed following a PD-1-blocking antibody-based regimen.[1][2][3][5]
The approval applies to a patient population in which treatment options become limited after progression on PD-1-directed therapy. Melanoma is the fifth most common cancer in the United States, with an estimated 105,000 new diagnoses in 2025 and nearly 8,500 deaths annually. More than half of patients treated with checkpoint inhibitors either do not respond or eventually progress after an initial response.
Vusolimogene oderparepvec is the first oncolytic virus therapy approved specifically for melanoma after progression on a PD-1-blocking regimen and only the second oncolytic virus therapy approved by the FDA for a cancer indication.[1]
The approval followed a public FDA Advisory Committee meeting. On July 30, 2026, the Cellular, Tissue, and Gene Therapies Advisory Committee reviewed the application and heard testimony from patients, advocates, clinicians, and independent experts before deliberating. The combination had previously received Breakthrough Therapy designation, an FDA expedited-development designation for therapies addressing serious conditions in which preliminary clinical evidence suggests substantial improvement over available therapy.
An Engineered Virus With a Different Mechanism
Vusolimogene oderparepvec is an engineered herpes simplex virus type 1 (HSV-1) designed to infect and destroy tumor cells while stimulating an immune response against the tumor.[3]
The viral backbone has two genes deleted. ICP34.5 normally helps HSV-1 overcome cellular antiviral defenses and contributes to neurovirulence. ICP47 normally interferes with antigen presentation. Removing these genes is intended to reduce the virus’s ability to cause serious infection while retaining selective replication in tumor cells.
The engineered virus also contains two additional genes. One encodes a fusogenic protein derived from gibbon ape leukemia virus, which is intended to enhance direct tumor-cell killing. The second encodes human granulocyte-macrophage colony-stimulating factor (GM-CSF), which is intended to recruit and activate dendritic cells and monocytes at the injection site.
Vusolimogene oderparepvec is administered by direct injection into accessible tumors. Superficial lesions can be injected directly, while deeper visceral lesions can be treated with image guidance. As the virus replicates within tumor cells, infected cells undergo lysis and release tumor antigens, viral antigens, and inflammatory signals. The treatment is designed to promote immune-cell recruitment and an antitumor immune response that can extend beyond the injected lesion.
Nivolumab provides a complementary mechanism. Blocking PD-1 is intended to maintain T-cell activity after immune cells have been recruited to the tumor.[3][4]
Biodistribution and Viral Shedding
Biodistribution data from the IGNYTE program (ClinicalTrials.gov identifier NCT03767348) included quantitative PCR testing of blood, urine, and swab samples from 278 patients. Viral DNA was detected in blood within 6 hours of injection in a minority of patients and then declined. No viral DNA was detected in blood, urine, or swab samples from any patient 30 days after the final dose.
Viral DNA was detected more frequently on the surface of injected lesions than in systemic samples. In a small subset of positive surface samples, viral culture confirmed the presence of live, potentially infectious virus.No transmission of vusolimogene oderparepvec to a close contact was reported during the trial.
The IGNYTE Trial
The approval is based on data from IGNYTE, an open-label, multiregional, single-arm Phase 1/2 study. The registrational cohort included 140 adults with stage IIIB, IIIC, or IV unresectable melanoma who had experienced disease progression, documented by imaging, biopsy, or clinical observation, after at least eight consecutive weeks of prior anti-PD-1-based therapy.
Patients who had previously received an oncolytic virus were excluded. Other exclusion criteria included uncontrolled or untreated central nervous system metastases, active or prior hepatitis B, hepatitis C, or HIV infection, a history of severe complications from HSV-1 infection, and the need for chronic systemic corticosteroids.
Patients received intratumoral vusolimogene oderparepvec every two weeks for eight consecutive doses. Treatment began at 10⁶ plaque-forming units (PFU)/mL during week 1 and increased to 10⁷ PFU/mL for subsequent doses.
Nivolumab was started with the second TUDRIQEV dose at 240 mg intravenously every two weeks for 16 weeks, followed by nivolumab 480 mg every four weeks for a total treatment period of up to 24 months.
Investigators could administer up to 16 additional doses of TUDRIQEV at 10⁷ PFU/mL every two weeks. These additional doses could be given with nivolumab or as vusolimogene oderparepvec monotherapy if nivolumab had been discontinued because of toxicity.
Efficacy Population
Of the 140 enrolled patients, 91 had at least one noninjected lesion and constituted the efficacy-evaluable population. Responses in noninjected lesions provide evidence of antitumor activity beyond the tumors directly exposed to the virus. The median patient age was 62 years, 68% were male, and 80% had stage IV disease. PD-L1 expression was negative in 54% of patients. Lung, liver, and brain metastases were present in 45%, 24%, and 7% of patients, respectively. Thirteen percent had previously received anti-PD-1 therapy in the adjuvant setting.
The principal efficacy endpoints were objective response rate and duration of response. Tumor assessments were performed every eight weeks using radiographic imaging and, when applicable, caliper measurements with photography. The objective response rate was 24.2% (95% CI, 15.8%-34.3%). Median duration of response was 14.1 months (95% CI, 10.7 months to not reached), with observed responses ranging from 3.9 months to more than 34.6 months. Among respondents, 86.1% maintained their response for at least 6 months, and 54.6% for at least 12 months.
Michael K. Wong, MD, PhD, the primary investigator of IGNYTE and former Physician-in-Chief at Roswell Park Comprehensive Cancer Center, described the approval as providing a treatment option for a broad population of patients, including those with BRAF-naïve or previously treated disease and those whose melanoma relapsed after adjuvant therapy.
Accelerated Approval Requires Confirmatory Evidence
Vusolimogene oderparepvec received accelerated approval based on objective response rate and duration of response rather than demonstrated improvement in overall survival. Under the accelerated approval pathway, the FDA has required Replimune to conduct postapproval confirmatory studies to verify and further characterize clinical benefit. Continued approval of vusolimogene oderparepvec for this indication may depend on the results of those studies.
A Phase 3 confirmatory trial, IGNYTE-3 (NCT06264180), is underway and is evaluating vusolimogene oderparepvec in combination with nivolumab.
Safety Profile
In the IGNYTE population, TUDRIQEV plus nivolumab was generally described as well tolerated. Most treatment-related adverse events were grade 1 or 2, and no grade 4 or 5 events were reported. Serious adverse reactions occurred in 35% of the 140 patients who received the combination. Arthralgia, hypophysitis, immune-mediated enterocolitis, and pyrexia were each reported in two patients.
Adverse reactions resulted in permanent discontinuation of vusolimogene oderparepvec in 2.9% of patients. Individual cases included elevated amylase and lipase levels, myocarditis, and pneumonitis.
What Remains Unknown
The accelerated approval does not establish an overall-survival benefit for vusolimogene oderparepvec plus nivolumab. The registrational IGNYTE cohort was designed and analyzed primarily around objective response rate and response duration. Whether the combination improves overall survival, and the magnitude of any such benefit, is being addressed through confirmatory clinical development. The efficacy-evaluable population consisted of 91 patients. Although the population included patients with a range of disease characteristics, the sample size limits the ability to fully characterize responses across all clinical and biological subgroups of anti-PD-1-resistant melanoma.
The durability of responses beyond the follow-up available at the time of approval also remains to be established. The pricing of vusolimogene oderparepvec and detailed information regarding patient access, including the scope of Replimune’s ReplimuneConnect Plus support program, were not included in the material reviewed for this article.
A New Treatment Option After PD-1 Failure
Vusolimogene oderparepvec adds a treatment approach with a mechanism distinct from conventional systemic checkpoint inhibition for patients with unresectable advanced cutaneous melanoma whose disease has progressed after PD-1-directed therapy. The treatment combines direct tumor injection with an engineered oncolytic virus and continued PD-1 blockade. In the IGNYTE registrational population, the combination achieved an objective response rate of 24.2%, with a median response duration of 14.1 months. Those results form the basis of the FDA’s accelerated approval. They do not establish overall survival benefit, and the approval remains subject to confirmatory evidence.
The Phase 3 IGNYTE-3 study will provide the next level of evidence needed to determine the clinical benefit of TUDRIQEV plus nivolumab in this treatment setting.
Clinical Trials
- Intratumoral Vusolimogene Oderparepvec (VO) in Combination With Pembrolizumab for Angiosarcoma – ClinicalTrials.gov ID NCT06898970
- An Expanded Access Program for VO (RP1) in Combination With Nivolumab in Patients With Advanced Melanoma (RPL-EAP-001)ClinicalTrials.gov ID NCT06590480
- Study of RP1 Monotherapy and RP1 in Combination With Nivolumab (IGNYTE) (IGNYTE) – ClinicalTrials.gov ID NCT03767348
- VO and Nivolumab vs Physician’s Choice in Advanced Melanoma That Progressed on Anti-PD-1 & Anti-CTLA-4 Drugs [IGNYTE-3] – ClinicalTrials.gov ID NCT06264180
Highlights of Prescribing Information
Nivolumab (Opdivo®; Bristol Myers Squibb)[Prescribing Information]
Vusolimogene oderparepvec-wtpg (TUDRIQEV®; Replimune)[Prescribing Information]
- Indication: vusolimogene oderparepvec, in combination with nivolumab, is indicated for adults with unresectable advanced cutaneous melanoma whose disease has progressed on a PD-1-blocking antibody-based regimen. The approval was granted under the FDA accelerated approval pathway based on objective response rate and duration of response.
- Dosage and administration: vusolimogene oderparepvec is administered at 1 mL per cm of the largest tumor dimension, with a maximum total volume of 10 mL across all treated lesions during a treatment session. Lesion size is reassessed at each treatment visit. When multiple tumors are present, the largest and most rapidly growing accessible lesions are prioritized for injection. Vusolimogene oderparepvec is administered every two weeks for eight consecutive doses. The initial concentration is 10⁶ PFU/mL at week 1, followed by 10⁷ PFU/mL for subsequent doses. Nivolumab is initiated intravenously beginning at week 3 according to its prescribing information. Because of a potential drug interaction, antiviral medications require a 72-hour delay relative to vusolimogene oderparepvec administration.
References
[1] U.S. Food and Drug Administration. FDA grants accelerated approval to vusolimogene oderparepvec-wtpg in combination with nivolumab for melanoma. August 6, 2026.
[2] Replimune Group, Inc. Replimune Announces FDA Accelerated Approval of TUDRIQEV™ in Combination with Nivolumab for Unresectable Advanced Cutaneous Melanoma After Progression on an anti-PD-1 Based Regimen. Press release. August 6, 2026.
[3] Wong MK, Milhem MM, Sacco JJ, Michels J, In GK, Muñoz Couselo E, Schadendorf D, Beasley GM, Niu J, Chmielowski B, Wise-Draper TM, Bowles TL, Tsai KK, Lebbé C, Gaudy-Marqueste C, Middleton MR, Skolariki A, Samson A, Chesney JA, VanderWalde AM, Zakharia Y, Harrington KJ, Appleton E, Bommareddy PK, Zhu J, Viana M, Hou JW, Coffin RS, Robert C. RP1 Combined With Nivolumab in Advanced Anti-PD-1-Failed Melanoma (IGNYTE). J Clin Oncol. 2025 Nov 20;43(33):3589-3599. doi: 10.1200/JCO-25-01346. Epub 2025 Jul 8. PMID: 40627813; PMCID: PMC12622257.
[4] Roulstone V, Kyula J, Appleton E, Bommareddy PK, Patrikeev A, Jones S, Kuncheria L, Chan Wah Hak CM, Foo S, Baldock H, Wongariyapak A, Leslie I, Pickering R, Zierhut C, Smith HG, Mohan N, Murano C, Hubbard LC, Dean I, Patin EC, Gkantalis J, Mansfield D, Pedersen M, McLaughlin M, Goicoechea M, Layzell S, Mannion J, Fernando W, Meier P, Vile R, Melcher A, Coffin RS, Harrington KJ. Effects of oncolytic immunotherapy with RP1 (vusolimogene oderparepvec) on immune cells mediate responsiveness to anti-PD-1 via STING-mediated interferon signaling. J Immunother Cancer. 2026 Mar 3;14(3):e013692. doi: 10.1136/jitc-2025-013692. PMID: 41775431; PMCID: PMC12959060.[5] JNCCN 360 Staff. FDA Approves Vusolimogene Oderparepvec and Nivolumab for Advanced Melanoma. August 7, 2026.
[6] U.S. Food and Drug Administration. Cellular, Tissue, and Gene Therapies Advisory Committee Meeting. July 30, 2026. Meeting announcement.
[7] U.S. Food and Drug Administration. TUDRIQEV (vusolimogene oderparepvec-wtpg) Prescribing Information. 2026.
[8] U.S. Food and Drug Administration. Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics.
This article is intended for informational purposes for healthcare professionals and does not constitute medical advice. The prescribing information referenced here is not a complete summary of safety data. Clinicians should consult the full FDA-approved labeling before making treatment decisions. TUDRIQEV was approved under the FDA accelerated approval pathway; continued approval for this indication may depend on verification of clinical benefit in confirmatory trial(s).
Featured image © 2026 CH/JCO Used with permission.
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