One of the most frustrating moments in oncology is seeing a promising therapy repeatedly delayed while patients continue to run out of treatment options.
That is why I continue to follow the story of RP1 (vusolimogene oderparepvec), an investigational oncolytic immunotherapy being developed for patients with advanced melanoma whose disease has progressed despite prior anti–PD-1 immunotherapy.
For many patients, progression after PD-1 therapy marks a difficult crossroads. Some patients with BRAF-mutated disease may still have targeted therapy options available. Others may be candidates for tumor-infiltrating lymphocyte (TIL) therapy, dual checkpoint blockade, or clinical trials, although response rates with dual checkpoint therapy after prior PD-1 monotherapy remain relatively modest. But for older patients or those with BRAF wild-type disease and no actionable mutations, the list of available treatments becomes much shorter.
RP1 is designed to be injected directly into tumors. It is a genetically modified herpes simplex virus engineered not only to destroy cancer cells locally, but also to stimulate a broader immune response against cancer throughout the body. This is one of the most intriguing aspects of oncolytic viral therapy: the possibility that treating one tumor can help the immune system recognize and attack tumors elsewhere.
That phenomenon has been observed repeatedly with intratumoral therapies over the years, and it is one reason many melanoma specialists remain enthusiastic about this approach.
What Did the IGNYTE Trial Show?
In the phase 1/2 IGNYTE study, patients with advanced melanoma who had progressed on prior anti–PD-1 therapy received RP1 in combination with nivolumab.
The results were encouraging:
- Objective response rate of approximately 33–34%
- Complete response rate of approximately 15%
- Median duration of response exceeding two years
- Durable survival outcomes in a population with otherwise limited options
Importantly, responses were not limited to tumors that were directly injected. Investigators observed shrinkage in uninjected lesions as well, supporting the concept that RP1 may generate a systemic immune response rather than merely a local effect.
The safety profile was generally consistent with what oncologists expect from oncolytic viral therapy. Most side effects were manageable and included flu-like symptoms, fevers, chills, and injection-site reactions. Serious adverse events occurred but were relatively uncommon.
Why Has Approval Been Delayed?
Despite these results, RP1 has now faced multiple regulatory setbacks.
The FDA’s concerns have focused largely on the design of the supporting clinical trial, particularly the absence of a randomized control arm and questions regarding how much benefit can be attributed specifically to RP1 when administered alongside nivolumab.
Reasonable people can disagree on this issue.
From a clinical perspective, many physicians struggle with the argument that the observed responses are simply due to nivolumab alone. These patients had already demonstrated progression on prior PD-1-based therapy before entering the study. While retreatment with PD-1 blockade may contribute in some cases, many clinicians believe the magnitude and durability of responses suggest that RP1 is providing meaningful additional benefit.
That debate has become one of the more closely watched regulatory discussions in melanoma.
What Happens Next?
There is finally some encouraging news.
In May 2026, Replimune announced that it had reached agreement with the FDA regarding a path forward for resubmission of its application. The agency indicated that it would treat the resubmission as a priority because of the significant unmet need facing patients with advanced melanoma after PD-1 failure.
Whether this third attempt ultimately leads to approval remains to be seen.
But for patients who have exhausted standard immunotherapy options, every additional treatment matters. Having another mechanism of action available—particularly one capable of producing durable complete responses—would represent a meaningful advance.
As someone who has participated in multiple intratumoral therapy trials over the years, I have personally seen patients experience impressive and sometimes unexpected responses. The field continues to evolve, and RP1 may ultimately become an important part of that story.
For now, we wait for the next chapter. Hopefully, this time, patients will finally have access to another treatment option they have been waiting for.
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 BMS, Merck, Ipsen, Natera, Immunocore, Pfizer, Sun Pharma, SpringWorks. He also receives industry grants in support of numerous clinical trials.
Disclosure: Any patient stories, scenarios, or clinical examples presented in this article are fictionalized, composite illustrations created for educational purposes. They do not describe any specific individual and are not intended to represent any actual patient treated by the author or institution.
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