For patients whose skin cancer doesn’t respond to traditional treatments, a new drug called RP1 has been a lifeline—at least for those who can get into a clinical trial. The drug has shown so much promise in such trials that, at the end of 2024, its development was placed on a fast track, with all signs pointing to a speedy approval by the Food and Drug Administration. But as of last month, the FDA has twice opted not to approve RP1, puzzling researchers and worrying drug developers.

Approximately 110,000 new cases of melanoma are diagnosed each year in the U.S., and 2.2 percent of people will be diagnosed with it at some point during their life. In its early stages, melanoma skin cancer is highly treatable, with a greater than 99 percent survival rate. Once the disease spreads to other areas of the body, however, treatment becomes much more difficult, and the five-year survival rate dips to roughly 16 percent. Adding even one new option—such as RP1—for people whose melanoma has not responded to first-line treatments could make a big difference for patients’ prognoses.

“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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Called an oncolytic immunotherapy drug, RP1 is made of an engineered virus—in this case, a modified version of a herpesvirus—that gets injected directly into melanoma tumors. Once inside, the virus causes the cancer cells to burst, and in doing so, they trigger the body’s immune system to kill all similar cancer cells without damaging healthy tissue.

Early trials of the drug were so effective that the FDA gave RP1 “breakthrough therapy” designation, which the agency uses to make sure effective therapies for serious conditions can reach patients as quickly as possible. Despite that fast-track status, RP1 has encountered more hurdles from the agency than was expected by Replimune Group, the company producing 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 as of publication to a request for comment about the FDA’s rejection of RP1 and apparent shifts in drug approval processes.

Last year the drug’s phase 1/2 clinical trial, IGNYTE, showed that nearly 33 percent of patients with treatment-resistant advanced melanoma saw their condition improve with a combination of RP1 and a widely used immunotherapy drug called nivolumab. This is a much higher success rate than the 6 to 7 percent of similar patients who responded to nivolumab alone. The initial FDA review panel recommended that the drug be approved, but just days before the deadline, on July 21, 2025, Replimune received a “complete response letter” (CRL) from the FDA: a rejection.

This letter outlined two main problems with the trial: the study population was too heterogeneous—defined as participants’ differing prior therapies, extent of disease and other factors—and the reviewers were not confident that the positive results were linked to RP1 rather than nivolumab. That second issue stemmed from the trial setup, which didn’t have a control group receiving a placebo instead of RP1. That decision was made because all the participants had not previously responded to drugs like nivolumab on their own, and it would be unethical to keep patients on a drug that hadn’t previously worked for them. Many researchers, clinicians and patient advocates soon rushed to RP1’s defense, claiming that the FDA had made a mistake in its rejection.

In an open letter to the FDA, the physician leading the IGNYTE trial and 22 other oncology researchers noted that, as a condition for being admitted to the trial, participants had tried drugs like nivolumab alone without improvement and that “this real-world patient population will be, by necessity, heterogeneous.”

“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 gave Replimune the opportunity to resubmit the application this year and provide additional data and analyses from the ongoing IGNYTE phase 3 trial. Replimune resubmitted in October of 2025, with officials feeling confident about soon being able to release the drug, Patel says. And once again, the company received a rejection.

The second CRL, issued on April 10, outlined many of the same trial-design concerns as the 2025 letter—concerns that the company believed further communication with the review team before and during the resubmission process had alleviated. Upon closely reading the April 10 letter, however, Replimune realized it said the FDA review team that had been overseeing the application for several years had been replaced before the resubmission was evaluated “to maintain objectivity and account for potential bias,” which is not typical of resubmissions.

“This is all unexpected,” Patel says, noting that the second CRL was released online before Replimune had a chance to analyze the FDA’s new list of concerns and discuss it with the company’s employees. “It’s been a very disturbing situation..., just the shifting goalposts of FDA regulations and requirements.”

This second rejection has been met with new backlash from clinicians and patients, and even Secretary of Health and Human Services Robert F. Kennedy, Jr., has distanced himself from the controversial decision. For the research community, the rejection is especially bewildering, given the trial’s apparent success in treating patients with few other approved therapies left to try.

“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 oncologists’ support, the rejection puts Replimune in a “very difficult position,” Patel says. In April the company, whose stock took a nosedive after the CRLs, laid off employees working on the marketing and manufacturing of the new drug. Now Replimune officials must determine whether there is a feasible path forward for RP1. Meanwhile others in the field are growing concerned that RP1’s rejection might point to broader shifts at the FDA that will make it more difficult for new melanoma drugs to get approved.

“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 undergone several shifts in staffing and leadership, many of which appear to explain the changing 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 shift away from the approval process that the agency has used for decades: instead of requiring two phase 3 trials, one “pivotal” trial—a type that is typically randomized and controlled—will suffice. The goal of this shift, the announcement said, was to streamline and accelerate drug development.

Getting trials of drugs for advanced cancers to fit the new specifications would be difficult. For instance, drugs such as RP1 are intended for patients for whom other cancer therapies have not worked. That means a randomized controlled trial would not be feasible because participants in a control group would have to continue to use medications that previously had not worked for them. For now, many researchers and clinicians in the oncology space are still waiting for 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.