Characterization of ipilimumab exposure-efficacy/safety response relationships in subjects with previously treated or untreated advanced melanoma.
8541 Background: Ipilimumab (IPI) is a fully human monoclonal antibody directed against CTLA-4 that is being developed as a novel immunotherapeutic agent against melanoma and other solid tumors. The objective of this analysis was to retrospectively characterize the exposure-response (E-R) relationships for efficacy (overall survival, OS) in subjects with previously untreated advanced melanoma (pu-MEL), and safety (immune related adverse-events, irAEs) in subjects with previously treated advanced melanoma (pt-MEL) or pu-MEL. Methods: The E-R analysis of OS included 498 pu-MEL from a phase III study (CA184024) of IPI administered at 10 mg/kg + dacarbazine (DTIC) or DTIC + placebo; and the E-R analyses of irAE included 1036 subjects from a phase I study (CA184078), 4 phase IIstudies (CA184004/007/008/022) and CA184024 of IPI administered at doses of 0.3, 3 or 10 mg/kg. The relationship between steady‑state IPI trough concentration (Cminss) and OS was described using a Cox proportional hazards model, and the relationships between Cminss and incidence of irAEs were described by ordinal logistic regression models (separate models for any irAE, as well as skin, liver and GI irAE). Results: The risk of death decreased with increasing Cminss, and is higher for subjects with elevated baseline LDH level. The risk of death was higher for subjects with baseline ECOG status > 0 and was higher with increasing stage of disease (M1C>M1B>M1A>M0). The hazard ratio for OS corresponding to the median Cminss of 49.99 µg/mL was 0.745 relative to subjects in DTIC + placebo group. The probability of Grade 2+ or Grade 3+ GI, skin, liver and any irAEs also increases with Cminss. Prior anti-cancer therapy (including prior DTIC) or concomitant DTIC were the only significant covariates in the E-R irAE models. Conclusions: These model-based analyses suggest that higher Cminss of IPI appears to be associated with improved survival in pu-MEL (based on data from CA184024) and higher Cminss also appears to be associated with increased probability of irAEs in pu-MEL or pt-MEL.