The FDA twice declined to approve Replimune Group’s RP1 oncolytic immunotherapy program for melanoma despite earlier breakthrough therapy designation and fast-track signals. Replimune’s CEO, Sushil Patel, said he had not seen the regulator behave this way. The decision has renewed pressure on developers aiming to bring a second-line option for patients whose melanoma does not respond to traditional treatments. Clinicians speaking about the effort argued that some patients have limited or no standard second-line alternatives. RP1 is delivered intratumorally using an engineered herpesvirus designed to trigger tumor cell lysis and immune activation, but the FDA’s recent outcomes show that fast-track designations do not guarantee approval pathways.