Early toxicity of sunitinib as a potential predictive biomarker in advanced hepatocellular carcinoma (HCC) patients.

Abstract

4081 Background: We previously reported efficacy and toxicity data from a phase II study of sunitinib (37.5 mg daily for 4 weeks followed by 2 weeks break) in patients with advanced HCC (Zhu et al, J Clin Oncol 2009). Sunitinib significantly decreased the number of circulating hematopoietic progenitor/stem cells, and that modulation of circulating inflammatory factors (e.g., IL-6) correlated with survival outcomes. Since hematologic toxicities are frequent after sunitinib therapy, we studied the early kinetics of these adverse events and explored their association with circulating biomarkers and clinical outcome. Methods: Toxicity of sunitinib was evaluated every two-weeks during the first cycle of therapy. Biomarker level changes from baseline were tested using the exact paired Wilcoxon test. P-values were adjusted for multiple comparisons over time, using the false discovery rate control method with weights proportional to the square root of the number of data points. Correlation between toxicities and overall survival or progression-free survival was evaluated in a Cox model using log-transformed levels of biomarkers or biomarker change after stratifying by Cancer of the Liver Italian Program (CLIP) score and for baseline biomarkers. Results: We found that sunitinib significantly and rapidly decreased all myeloid and lymphoid circulating cell populations (by 20%-50%), but increased erythropoiesis (p < 0.05 for all). The extent of the early decrease in neutrophils, platelets and monocytes, as well as the development of non-hematologic toxicities (i.e., skin toxicities), was significantly associated with improved survival outcomes (p < 0.05). Finally, circulating cell kinetics significantly associated with specific changes in plasma biomarkers (e.g., changes in platelets with changes in VEGF-C and soluble VEGFR3; changes in neutrophils with changes in IL-8, TNF-α and soluble VEGFR2). Conclusions: The adverse effects of sunitinib, particularly on the hematopoietic system, are rapid and may be directly related to its activity in advanced HCC. This exploratory study suggests that early hematopoietic toxicities from sunitinib may predict survival outcomes in advanced HCC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Dyax, Genentech, Genomic Health, ImClone Systems, Merck, Millennium, Pfizer, Regeneron, Roche, SynDevRx SynDevRx Genentech, Pfizer AstraZeneca, Dyax, Pfizer