OP1-2Sorafenib Exposure and Clinical Outcomes in Hepatocellular, Renal Cell, and Differentiated Thyroid Carcinomas

Background: Sorafenib is approved for the treatment of advanced hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and differentiated thyroid carcinoma (DTC). The relationship between sorafenib exposure and efficacy and safety from Phase 3 trials of sorafenib in RCC (TARGET), HCC (SHARP), and DTC (DECISION) were examined based on retrospective analyses. Methods: Plasma pharmacokinetic samples were collected from patients after ≥14 days of sorafenib treatment. Sorafenib AUC was derived from population pharmacokinetic modeling adjusted for dose reductions and categorized by quartiles as low (1st quartile: <34 mg*h/L for TARGET; <37 mg*h/L for SHARP; <79 mg*h/L for DECISION), medium (2nd plus 3rd quartiles), or high (4th quartile: >55 mg*h/L; >59 mg*h/L; and >118 mg*h/L, respectively). A multivariate Cox regression analysis was performed based on exposure levels. Results: Sorafenib steady-state concentration was determined in 86/451, 164/299, and 156/207 sorafenib patients from TARGET, SHARP and DECISION, respectively. There were no significant differences in PFS (TARGET and DECISION) or overall survival (OS; SHARP) among AUC groups. In TARGET, median PFS in the high, medium and low exposure groups was 181, 219 and 126 days, respectively (HR = 0.90, 95% CI 0.48–1.70, for low vs medium and HR = 0.77, 95% CI 0.29–2.06, for high vs medium). In DECISION, numerically longer PFS was observed in the high- (509 days) vs medium- or low-exposure groups (293 days, 305 days) (HR = 0.61; 95% CI 0.21–1.77 high vs low). In all 3 trials, the type and incidence of the most common adverse events was similar to the known safety profile irrespective of sorafenib exposure. Conclusion: There were no clinically significant safety concerns with higher sorafenib exposure. We observed numerical trends for shorter PFS and OS with lower exposure, though the differences were not significant.