RP1 and the FDA: A Missed Opportunity in Advanced Melanoma? With Matthew Hadfield, DO, and Justin Moser, MD

The recent decision by the FDA to withhold approval of RP1 (vusolimogene oderparepvec), an oncolytic virus therapy for metastatic melanoma, has come as a surprise to the oncology community. In this candid discussion, Dr. Matthew Hadfield of Brown University and Dr. Justin Moser of Honor Health—both experts in early drug development for cutaneous malignancies—share their perspectives on the regulatory setback, its implications for clinical practice, and the broader impact on patients with limited treatment options. Their insights shed light on the complexities of the FDA approval process and underscore the urgent need for transparent, patient-centered decision-making in oncology drug development.

Initial Reactions to the FDA’s Unexpected Rejection of RP1

Dr. Moser described the decision as “very unexpected,” emphasizing that the regulatory process is typically collaborative and iterative, with the FDA providing guidance at each step. “For the FDA to come back at the last minute and say they’re going to withhold approval because of study design concerns is really concerning,” he said. Both clinicians agreed that the abrupt reversal undermines trust in the process and ultimately harms patients who participated in the study and those who could have benefited from the therapy.

Trial Design Controversy: What Went Wrong?

The FDA’s main objection centered on the IGNYTE study’s single-arm design, which combined RP1 with nivolumab in patients with refractory melanoma. The agency argued that the lack of a control arm made it difficult to isolate the contribution of each drug. Dr. Moser pointed out the inconsistency, noting, “Tumor-infiltrating lymphocyte (TIL) therapy got a conditional accelerated approval based on the same design just about a year and a half ago.” He stressed that such design elements are typically agreed upon with the FDA before patient enrollment, making the last-minute concerns particularly frustrating. “These are things that should have been addressed on the front end, not the backend, before we started enrolling patients,” he added.

Lost Opportunity for Patients

For patients with metastatic melanoma who are refractory to programmed cell death protein (PD-1) inhibitors and lack a BRAF mutation, treatment options are extremely limited. Dr. Hadfield highlighted the gap: “If you’re BRAF wild-type, there’s really not much; TIL, which is not accessible to everyone, is really the only other option.” Dr. Moser agreed, explaining that most patients in this setting could have been candidates for RP1, especially since TIL therapy is only available at select centers and is not suitable for many due to its intensity. “When you look at the data of RP1 and compare that to the data of TIL, we see similar response rates, but RP1 could have benefited more patients, especially those who aren’t candidates for TIL or don’t have access,” he said.

Mechanistic Rationale and Real-World Impact

RP1’s mechanism as an oncolytic virus offers a unique approach by potentially resensitizing tumors to PD-1 inhibitors. Dr. Hadfield noted, “The toxicity profile is very favorable. It’s an injection, it can be given at more centers, and the response rates are similar to TIL.” Dr. Moser added that RP1’s ability to treat deeper lesions and larger tumor volumes distinguishes it from earlier viral therapies like T-VEC. “RP1 was designed to go around all those things, so there’s a really good rationale that this was going to benefit patients,” he said.

What’s Next for RP1 and Patient Access?

Looking ahead, Dr. Moser explained that the trial sponsor plans to meet with the FDA to seek a path forward, whether through modifying the ongoing confirmatory study or appealing the decision. “Hopefully they can find a way forward for this treatment, because again, it works and patients have benefited,” he said. Both clinicians stressed the urgency of maintaining access to promising therapies and the need for regulatory consistency. “It’s a huge opportunity loss if they don’t reverse this decision for a lot of patients, unfortunately,” Dr. Hadfield concluded. “I think we should be vocal about this oncologists, and hopefully patient advocacy groups are also speaking out and trying to support getting this overturned so that we can increase access for patients.”

Key Takeaways

The FDA’s last-minute rejection of RP1 for metastatic melanoma was unexpected and has significant implications for patients and clinical research.
The main issue cited was the single-arm trial design, despite prior FDA agreement and precedent with similar therapies.
RP1 could have filled a critical gap for patients who are ineligible for or unable to access TIL therapy.
The decision highlights the need for transparent, consistent regulatory processes to avoid undermining patient trust and access to innovative treatments.

About the Speakers

Matthew Hadfield, DO, is a Medical Oncologist at Brown University/Legorreta Cancer Center, with a pending faculty appointment at the Warren Alpert School of Medicine of Brown University. He recently completed his Hematology/Oncology Fellowship at Brown University. Dr. Hadfield’s clinical and research interests are in phase 1 clinical trials and developmental therapeutics, as well as cutaneous malignancies and immunotherapy-related adverse events.

Justin Moser, MD, is a Medical Oncologist at Honor Health in Scottsdale, Arizona. He specializes in the development of novel therapies for melanoma, squamous cell carcinoma of the skin, Merkel cell carcinoma, basal cell carcinoma, and uveal melanoma. Dr. Moser runs a translational research program focused on better understanding uveal melanoma an investigating novel treatment options for this rare disease.