Replimune’s oncolytic immunotherapy RP1, engineered from a modified herpesvirus, has faced additional FDA hurdles after the agency declined approval twice despite the program holding breakthrough therapy designation. The controversy centers on why the FDA rejected the proposed pathway for RP1 as a second-line option for melanoma patients who have not responded to initial treatments. The reporting notes that RP1’s early trials generated strong responses in clinical settings, which is precisely why developers expected a fast regulatory outcome under the breakthrough designation and fast-track-like posture. Instead, developers say the agency has behaved “like this” in a way they have not previously seen, underscoring the gap between early signals and regulatory expectations. UPMC Hillman Cancer Center director Yana Najjar said the decision leaves a patient population without clear second-line options. She characterized the affected group as “left behind” due to the lack of alternatives. For Replimune, the episode heightens uncertainty around oncolytic virotherapy acceptance and may sharpen scrutiny of endpoints, response durability, and benefit-risk in treatment-resistant metastatic disease.