After 2 CRLs, FDA Approves Vusolimogene Oderparepvec With Nivolumab for Advanced Melanoma

The FDA has granted accelerated approval to vusolimogene oderparepvec-wtpg (Tudriqev; Replimune Group, Inc), a genetically engineered oncolytic viral immunotherapy, in combination with nivolumab (Opdivo; Bristol Myers Squibb) for adult patients with unresectable advanced cutaneous melanoma who have experienced disease progression on a PD-1–blocking antibody-based regimen.¹ The approval, announced August 6, 2026, caps a multiyear regulatory path for the therapy that included 2 prior complete response letters (CRLs).^2,3

Anti–PD-1 refractory melanoma is a type of advanced skin cancer that no longer responds to immune checkpoint blockade, which is a common component of standard-of-care treatment. Despite ongoing therapy, tumors in this population can continue to grow through mechanisms that help them evade immune detection, leaving clinicians with few effective options.¹

“For patients with advanced melanoma that has stopped responding to PD-1 blocking therapy, the prognosis is often devastating, and options have been far too limited. Clinicians managing these patients know this urgency firsthand,” Karim Mikhail, B Pharm, MS, acting director of the FDA’s Center for Biologics Evaluation and Research (CBER), said in the agency’s announcement. “Today’s important milestone gives oncologists a meaningful new tool—and more patients a fighting chance.”¹

Tudriqev’s Mechanism and Administration

Tudriqev is built on a modified herpes simplex virus type 1 (HSV-1) backbone engineered to selectively infect, replicate within, and destroy tumor cells while stimulating a broader systemic immune response against the cancer. When used alongside nivolumab, an anti–PD-1 immunotherapy, Tudriqev is intended to help restore antitumor immune activity in patients whose disease previously stopped responding to checkpoint inhibition.¹

The therapy is administered via an intratumoral injection every 2 weeks for 8 consecutive doses. Treatment begins with a lower-concentration dose, followed by a higher concentration for all subsequent injections, with volume determined by the size of the tumor. Nivolumab is introduced intravenously (IV) starting at week 3 of treatment.¹

Clinical Evidence Supporting Approval

The accelerated approval is supported by clinical data from an open-label, multiregional, single-arm phase 2 trial, IGNYTE (NCT03767348)⁴, which enrolled 140 adults with stage IIIB, IIIC, or IV unresectable advanced melanoma who had progressed after at least 8 consecutive weeks of prior anti–PD-1–based therapy. Among 91 evaluable patients, approximately 24% achieved an objective response, with a median response duration of 14.1 months.¹

The most common adverse events (AEs), each occurring in more than 10% of patients, included fatigue, pyrexia, infections, chills, musculoskeletal pain, nausea, diarrhea, injection site reaction, and headache, among others. The FDA flagged important safety considerations specific to the therapy’s viral platform, including the risk of inadvertently transmitting herpes infection to close contacts, the potential for herpes infection or reactivation in the patient, and complications related to the injection procedure itself.¹

On July 30, 2026, the FDA convened its Cellular, Tissue, and Gene Therapies Advisory Committee to review the application, hearing from patients, patient advocates, clinicians, and independent experts before committee deliberation. The application had previously received both breakthrough therapy and priority review designations.^1,5

A Winding Path to Approval

The approval follows 2 setbacks for the regimen. In July 2025, the FDA issued a CRL stating that the IGNYTE trial was not an adequate and well-controlled study providing substantial evidence of effectiveness, citing heterogeneity within the enrolled patient population. The agency did not raise safety concerns at that time.² Replimune pursued a Type A meeting with the FDA and initiated the confirmatory IGNYTE-3 trial (NCT06264180)⁶, a randomized, controlled, phase 3 study comparing Tudriqev plus nivolumab with physician’s choice of therapy in patients who had progressed on both anti–PD-1 and anti–CTLA-4–containing regimens.²

A second CRL followed in April 2026, despite the FDA reportedly not raising further concerns about population heterogeneity during the intervening Type A meeting.³ In the CRL announcement, Sushil Patel, PhD, CEO of Replimune, stated the decision would result in the company scaling back its US manufacturing operations and eliminate jobs, calling the setback a failure “because the system did,” not necessarily because “the medicine failed.”³

Earlier data from the phase 2 IGNYTE trial had shown an overall response rate of approximately 32.9% with the Tudriqev combination regimen, including a 15.0% complete response rate, a median duration of response of about 33.7 months, and 1- and 2-year overall survival rates of 75.3% and 63.3%, respectively.³

What It Means for Pharmacists

As a condition of accelerated approval, Replimune is required to conduct postapproval trials to verify and describe Tudriqev's clinical benefit, and continued approval may depend on confirmation of that benefit in a confirmatory trial, which is expected to draw on the ongoing IGNYTE-3 study.^1,2 For oncology and specialty pharmacists, the approval introduces a new intratumoral, virus-based immunotherapy with a distinct handling and counseling profile—including precautions around accidental herpes transmission to caregivers and household contacts—and a titrated 2-dose-concentration schedule that pharmacists will need to help teams track across the 8-dose regimen.

REFERENCES

1. FDA approves new engineered viral immunotherapy for patients with treatment-resistant advanced melanoma. News release. FDA. August 6, 2026. Accessed August 6, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-new-engineered-viral-immunotherapy-patients-treatment-resistant-advanced-melanoma

2. McGovern G. FDA issues CRL to Replimune for vusolimogene oderparepvec with nivolumab for advanced melanoma. Pharmacy Times. July 22, 2025. Accessed August 6, 2026. https://www.pharmacytimes.com/view/fda-issues-crl-to-replimune-for-vusolimogene-oderparepvec-with-nivolumab-for-advnaced-melanoma

3. McGovern G. Replimune receives second CRL for RP1 with nivolumab for treatment of advanced melanoma. Pharmacy Times. April 13, 2026. Accessed August 6, 2026. https://www.pharmacytimes.com/view/replimune-receives-second-crl-for-rp1-with-nivolumab-for-treatment-of-advanced-melanoma

4. Study of RP1 Monotherapy and RP1 in Combination With Nivolumab (IGNYTE) (IGNYTE). ClinicalTrials.gov identifier: NCT03767348. Updated February 13, 2026. Accessed August 6, 2026. https://clinicaltrials.gov/study/NCT03767348

5. Ferruggia K. FDA gives priority review to vusolimogene oderparepvec for melanoma. Pharmacy Times. January 22, 2025. Accessed August 6, 2026. https://www.pharmacytimes.com/view/fda-gives-priority-review-to-vusolimogene-oderparepvec-for-melanoma

6. VO and Nivolumab vs Physician's Choice in Advanced Melanoma That Progressed on Anti-PD-1 & Anti-CTLA-4 Drugs [IGNYTE-3]. ClinicalTrials.gov identifier: NCT06264180. Updated July 15, 2026. Accessed August 6, 2026. https://clinicaltrials.gov/study/NCT06264180