RP1, a new drug for patients whose skin cancer does not respond to conventional treatments, has offered hope—at least for those participating in clinical trials. The drug demonstrated significant promise in these trials, leading to its fast-track development by the end of 2024, with expectations of quick approval from the Food and Drug Administration. However, as of last month, the FDA has declined to approve RP1 twice, leaving researchers puzzled and drug developers concerned.
Each year, the U.S. sees approximately 110,000 new cases of melanoma, with 2.2 percent of the population likely to be affected during their lifetime. In its initial stages, melanoma skin cancer is highly treatable, boasting a survival rate exceeding 99 percent. However, once the disease metastasizes, treatment becomes more challenging, and the five-year survival rate drops to around 16 percent. Introducing a new treatment option like RP1 for patients unresponsive to first-line treatments could significantly impact patient outcomes.
“There’s really no second-line treatments” for some patients, says Yana Najjar, director of the Clinical and Translational Research Center at the University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center. “This is a population that has been left behind. This is where I had hoped RP1 would come in.”
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RP1 is an oncolytic immunotherapy drug composed of an engineered virus, specifically a modified herpesvirus, that is injected directly into melanoma tumors. Once inside, the virus causes cancer cells to burst, prompting the immune system to attack similar cancer cells while sparing healthy tissue.
Early trials of RP1 were highly effective, earning the drug the FDA’s “breakthrough therapy” designation, which aims to expedite the development of drugs for serious conditions. Despite this status, RP1 has faced unexpected challenges with the FDA, surprising the Replimune Group, the company behind the drug.
“I’ve just never seen the agency behave like this,” says Replimune CEO Sushil Patel. “It’s actually putting us in a very, very difficult position.”
The Department of Health and Human Services did not respond to a request for comment regarding the FDA’s rejection of RP1 and the apparent changes in drug approval processes.
The previous year, the IGNYTE phase 1/2 clinical trial demonstrated that nearly 33 percent of patients with treatment-resistant advanced melanoma experienced improvement with the combination of RP1 and the immunotherapy drug nivolumab, significantly higher than the 6 to 7 percent response rate for nivolumab alone. Although the initial FDA review panel recommended approval, Replimune received a “complete response letter” (CRL) rejecting the drug just before the deadline on July 21, 2025.
The letter highlighted two main issues: the trial population was too heterogeneous, given differences in prior therapies and disease extent, and the reviewers were uncertain whether the positive outcomes were due to RP1 or nivolumab. The trial lacked a control group receiving a placebo, a decision made to avoid keeping patients on ineffective medications. Researchers, clinicians, and patient advocates quickly defended RP1, arguing the FDA’s rejection was a mistake.
In an open letter to the FDA, the lead physician of the IGNYTE trial and 22 other oncology researchers emphasized the requirement for trial admission: participants must have previously tried drugs like nivolumab without improvement, resulting in a necessarily heterogeneous real-world patient population.
“There are a lot of strong feelings on this, understandably,” says Michael Postow, a medical oncologist and chief of the melanoma service at Memorial Sloan Kettering Cancer Center. “This is a space where patients need new advances the most…. It’s always nice to have another option for them.”
The FDA allowed Replimune to resubmit the application with additional data and analyses from the ongoing IGNYTE phase 3 trial. Replimune resubmitted in October 2025, confident about the drug’s imminent release, Patel says. Yet, the company faced another rejection.
The second CRL, issued on April 10, repeated many of the previous trial-design concerns, which Replimune believed were addressed through ongoing communication. However, upon reviewing the letter, Replimune discovered that the FDA review team overseeing the application had been replaced before the resubmission evaluation “to maintain objectivity and account for potential bias,” which is atypical for resubmissions.
“This is all unexpected,” Patel says, highlighting that the second CRL was published online before Replimune could review and discuss the FDA’s concerns with employees. “It’s been a very disturbing situation…, just the shifting goalposts of FDA regulations and requirements.”
The second rejection has sparked fresh backlash from clinicians and patients, leading Secretary of Health and Human Services Robert F. Kennedy, Jr., to distance himself from the contentious decision. The rejection is particularly perplexing for the research community, given the trial’s apparent success in treating patients with limited options.
“I and many others have seen patients benefit from treatment,” says Najjar, who oversees UPMC patients enrolled in the IGNYTE trial as the site’s principal investigator. “It’s well tolerated, so the way I looked at it was: Why not approve it? Let us give it to patients because we all want to.”
Despite the support from oncologists, Replimune is in a “very difficult position,” according to Patel. Following the CRLs, the company’s stock plummeted, prompting layoffs of employees involved in the marketing and manufacturing of the new drug. Replimune officials must now determine whether a viable path exists for RP1. Meanwhile, others in the industry worry that RP1’s rejection may signal a broader shift at the FDA, complicating the approval process for new melanoma drugs.
“I think the lack of clarity and [the] inconsistency with the FDA … is just actually creating a lot of anxiety for those drug developers wondering, ‘Do we have a path forward now?’” Patel says.
Under the Trump administration, the FDA has seen numerous changes in staffing and leadership, possibly affecting the drug approval landscape. In February, FDA commissioner Marty Makary and director of the agency’s Center for Biologics Evaluation and Research (CBER) Vinay Prasad announced a departure from the long-standing approval process: instead of requiring two phase 3 trials, one “pivotal” trial, typically randomized and controlled, would suffice. The goal was to streamline and expedite drug development.
Adapting trials for advanced cancer drugs to meet these new specifications could prove challenging. For drugs like RP1, intended for patients unresponsive to other therapies, a randomized controlled trial would be impractical, as control group participants would need to continue ineffective treatments. Many researchers and clinicians in oncology are now waiting for further clarification from the FDA.
“I understand the challenges of regulatory environment,” Postow says. “I really just want to make sure we all know what to do next here because we need some guidance.
