Why the FDA rejected a ‘breakthrough’ melanoma drug

May 2, 2026

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Why the FDA rejected a ‘breakthrough’ melanoma drug

The FDA rejected the promising skin cancer drug RP1 twice, leaving many puzzled and worried about what this means for other drug approvals

By K. R. Callaway edited by Jeanna Bryner

The FDA has twice denied approval of a "breakthrough" drug to treat advanced melanoma.

Valerie Plesch/Bloomberg via Getty Images

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, heter