The Concept of Functional Cure in Advanced/metastatic Melanoma Treated with Combined Nivolumab and Ipilimumab or Nivolumab Alone

BACKGROUND:Immune-Checkpoint-Inhibitors (ICIs) have significantly improved the course of advanced/metastatic melanoma and the concept of ICIs curative potential began to appear. To use statistical approaches to determine whether advanced/metastatic melanoma patients treated with nivolumab alone or in combination with ipilimumab may be considered as functionally cured. METHODS:Individual patient data were reconstructed from published Kaplan-Meier curves of the anti-PD1 arms of the Checkmate-067. The assumption of functional cure was assessed using three approaches based on a flexible-parametric survival model. Once the hypothesis of functional cure was confirmed, the time to functional cure (TTFC) was determined using an intuitive approach based on flexible survival model. RESULTS:The three complementary approaches were consistent and confirmed the functional cure assumption. The TTFC (the shortest time defined by fewer than 1% of patients progressing or dying) was estimated to be 61 (95%CI,50.7;79.4) and 63 m (95%CI,51.1;71.4) for nivolumab alone or in combination, respectively. CONCLUSIONS:We showed that metastatic melanoma patients, treated with the combination or nivolumab alone who were alive and had not progressed by the five-year time-point, can be considered as functionally cured. The robust statistical approach proposed could be applied to other clinical settings when the plausibility of cure is to be validated.