485P - Correlation of sorafenib exposure with safety and efficacy from pivotal clinical trials in hepatocellular carcinoma (HCC) and renal cell cancer (RCC)

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anticancer Agents
Renal Cell Cancer
Hepatobiliary Cancers
Biological Therapy
Presenter John Lettieri
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors J. Lettieri1, D. Mitchell2, C. Pena1, I. Molnar1, G. Meinhardt1
  • 1Clinical Pharmacology, Bayer HealthCare, 07981-0915 - Whippany/US
  • 2Pharmacology, Mitchell Pharmaceutical Consulting, 80026 - Lafayette/US



Sorafenib is approved for the treatment of advanced RCC and HCC. Retrospective analyses were conducted of 2 Phase III pivotal clinical trials of sorafenib in RCC (TARGET, NCT00073307) and HCC (SHARP, NCT00105443) to examine the relationship between sorafenib exposure and efficacy or safety outcomes.


For TARGET, trough plasma concentrations were obtained in 67 of 451 patients with RCC after 21 days of uninterrupted dosing with sorafenib. Patients were categorized as having low (<3.2 mg/L) or high (≥3.2 mg/L) exposure, with 3.2 mg/L being the median. For SHARP, 164 of 299 patients with HCC treated with sorafenib provided up to 3 samples on Day 21. An area under the curve (AUC(0-&tgr;)) was derived by population pharmacokinetics for each patient, and assignment to low- (Q1), medium- (Q2 + Q3), and high- (Q4) exposure groups was based on AUC (<37, 37-59, and >59 mg*h/L).


In TARGET, there was no difference in progression-free survival (PFS) based on high versus low sorafenib exposure; hazard ratio (HR) was 0.84 (95% confidence interval [CI] 0.43-1.64; median PFS 219 vs. 167 days, respectively). Rates of hand-foot skin reaction (HFSR), rash, and hypertension were similar in the high- and low-exposure groups, and the severity of adverse events was also independent of exposure in patients with RCC. In SHARP, overall survival (OS; primary clinical endpoint) for HCC patients in different exposure groups showed no meaningful differences in HRs (high vs. medium exposure: HR = 0.88, 95% CI 0.49-1.58, median OS 426 vs. 339 days, respectively; medium vs. low exposure: HR = 0.74, 95% CI 0.44-1.25, median OS 339 vs. 290 days, respectively). Rates of alopecia, HFSR, and diarrhea were numerically higher in the high-exposure group compared with the low-exposure group (alopecia 23% vs. 7%, HFSR 33% vs. 24%, diarrhea 69% vs. 40%). No increase in incidence rate in the high-exposure group was observed for fatigue, hypertension, and pruritus.


Exposure-response analysis of RCC and HCC patients enrolled in pivotal sorafenib trials indicates that no clear or consistent relationship exists between plasma concentrations or exposure of sorafenib with safety or efficacy outcomes.


J. Lettieri, C. Pena, I. Molnar and G. Meinhardt: is an employee of Bayer Healthcare; D. Mitchell: has provided consultancy for Bayer healthcare.