It’s been a whirlwind few weeks. I’ve been on a long-overdue family vacation—celebrating a wedding in New York and taking some quiet time in Switzerland. It’s been good to reset. But now, back stateside and catching up on oncology news, I came across a headline I didn’t want to believe: the FDA has denied approval for Replimune’s RP1 in advanced melanoma.
This decision hits hard. I’m a long-standing supporter of intratumoral therapies, especially in PD-1–refractory melanoma where options remain frustratingly limited. In my experience, these therapies can truly shift the immune landscape within tumors. RP1—vusolimogene oderparepvec—is a genetically engineered herpes simplex virus designed to directly kill cancer cells while also jumpstarting a broader systemic immune response. When combined with nivolumab, an anti–PD-1 therapy, RP1 showed real promise.
So what happened?
The Rejection
On July 22, 2025, the FDA issued a Complete Response Letter (CRL) to Replimune, effectively rejecting RP1’s biologics license application for advanced melanoma. While the agency didn’t cite any safety concerns, it raised serious issues with the IGNYTE trial design:
- The study wasn’t considered adequately controlled.
- The patient population was too heterogeneous to confidently interpret results.
- The FDA couldn’t determine which component—RP1 or nivolumab—was driving efficacy.
This last point feels particularly frustrating. Every patient in the trial had already failed anti–PD-1 therapy. These were refractory cases—nivolumab alone had already stopped working. So to question the contribution of RP1 when patients were clearly not responding to PD-1 blockade alone seems disconnected from the clinical reality. Add to the list the many frustrating steps this health administration has done!
The IGNYTE Trial: Promising Signals
In the anti–PD-1-failed melanoma cohort of the IGNYTE study, RP1 plus nivolumab produced an overall response rate of 32.7%—a strong signal in this tough-to-treat population. Responses were not limited to injected lesions; visceral sites like liver and lung also responded, suggesting systemic immune activation.
Even more compelling, responses were deep, durable, and consistent over extended follow-up. The therapy was generally well tolerated, even with deep or visceral injections.
A Tale of Two Standards?
It’s hard not to compare this outcome to the FDA’s approval of Iovance’s lifileucel (TIL therapy) not too long ago. Lifileucel was approved under accelerated review based on a 31.5% ORR in a similarly refractory population. That trial, too, was single-arm and open-label, yet the agency accepted it as sufficient.
Why the discrepancy? It may come down to:
- Trial design complexity and patient heterogeneity in IGNYTE
- FDA concerns about isolating RP1’s efficacy in a combination setting
- A broader trend of increased regulatory scrutiny—even for therapies with breakthrough designation
The Human Impact
This isn’t just about regulatory nuance. For patients with PD-1 refractory melanoma, especially those who can’t tolerate or access TIL therapy, RP1 could have been a lifeline. It’s relatively easy to administer, well tolerated, and shows the kind of efficacy we dream about in this space.
I’ve personally seen how oncolytic virus therapy can work, and I’ve shown pictures of dramatic responses in my talks. RP1 is the next evolution of that potential. It’s disappointing—deeply disappointing—not to have it in our arsenal.
Looking Ahead
Replimune plans to meet with the FDA to discuss next steps. I hope the door isn’t closed. The data are compelling, the need is urgent, and the therapy is innovative. I remain optimistic that with further dialogue and refined study design, RP1 will find its way back.
And on a personal note—I’ll soon be starting my next chapter soon. Beginning December 1st, I’ll be returning to clinic full time in a permanent role, continuing to focus on melanoma and sarcoma. I’ll share more about that soon in a separate post, but I’m energized and excited to get back to doing what I love: caring for patients and pushing the field forward, in collaboration with industry partners, colleagues, and the broader oncology community.
For now, here’s hoping RP1 gets another shot. We’re down… but we’re not out.
About the author
Dr. Sajeve Thomas is a distinguished medical professional and a compassionate guide in the field of oncology. With over a decade of dedicated experience as a board-certified medical oncologist/internal medicine specialist, Dr. Thomas has become a trusted expert in the treatment of melanoma, sarcoma, and gastrointestinal conditions. He brings a wealth of expertise to the complex and challenging world of oncology.
Disclosures:
Dr. Thomas serves as a speaker for Bristol Myers Squibb (BMS), Merck, Ipsen, Natera, Immunocore, Pfizer, and SpringWorks. He also receives industry grants in support of numerous clinical trials.