Evaluation of Kras mutations and angiogenic biomarkers in patients with advanced non-small cell lung cancer (NSCLC) receiving single-agent sorafenib (S).

Abstract

7626 Background: S is an oral multikinase inhibitor that targets the Ras/Raf/MEK/ERK pathway at the level of Raf kinase. At present there are no predictive biomarkers to improve patient selection and predict response to angiogenic inhibitors in NSCLC. Kras mutation status, angiogenesis markers (VEGF, bFGF, FLT-1, PLGF-1) and correlative imaging with DCE-MRI to determine early changes in tumor vascular characteristics were evaluated. Methods: Patients received S (400 mg po bid daily, in continuous 4 week cycles) in an effort to determine activity and tolerability and to measure its biological effects. Responses were evaluated every 8 weeks by RECIST. Kras mutations at codons 12, 13 and 61 were analyzed (n = 24). Two vascular permeability parameters Ktrans and Kep were measured by DCE-MRI at baseline and day 15 of cycle 1 (n = 27). Cytokine analysis was performed with serial plasma samples obtained on days 0, 14, 28 and 54 (n = 18). Results: 37 pts with previously treated stage IV NSCLC were enrolled in this single center phase II trial. Two pts (5%) had PRs and 19 had SD (51%) of 3-17 months. Drug related toxicity was consistent with the known side effects of S. Kras mutational status (17 wildtype, 7 mutations) and DCE-MRI were not associated with clinical outcome. In exploratory analyses with up to 18 pts, 3 plasma based parameters with levels below their respective median values in pg/mL demonstrated potential trends towards an association with improved OS by having univariate two-tailed p-values < 0.10: VEGF at day 0 < 150 had survival better than VEGF > 151+ (p = 0.014), bFGF at day 14 < 11.1 had survival better than bFGF > 11.2+ (p = 0.025) and FLT-1 at day 0 < 180 had survival better than FLT-1 > 181+ (p = 0.078). Conclusions: In this pt population with advanced NSCLC, Kras mutational status and DCE-MRI showed no correlation with response to S. Plasma based VEGF/FLT-1 and bFGF levels may act as biomarkers indicative of early angiogenesis inhibition. Confirmation of these findings would be worthwhile in a larger independent patient population. No significant financial relationships to disclose.