The FDA issued a complete response letter for Replimune’s RP1 oncolytic virus therapy, causing its stock to plunge by 75%. Despite promising Phase II data showing response rates surpassing existing oncolytic treatments in anti-PD-1 refractory melanoma, regulatory expectations appear to have become more stringent. This rejection suggests a paradigmatic change in oncology drug approvals, emphasizing rigorous methodological standards over breakthrough therapy designations. RP1’s sophisticated dual mechanism involving tumor destruction and immune activation had previously generated optimism for accelerated approval pathways.