Evaluation of KRAS mutations, angiogenic biomarkers, and DCE-MRI in patients with advanced non-small-cell lung cancer receiving sorafenib

Abstract

Purpose: Sorafenib, a multikinase inhibitor targeting Raf and VEGFR, has shown activity in unselected patients with non-small-cell lung cancer (NSCLC). At present there are no validated biomarkers indicative of sorafenib activity.

Experimental design: Patients received sorafenib 400 mg BID daily to determine activity and tolerability and to measure its biological effects. KRAS mutation status (N = 34), angiogenesis markers (VEGF, bFGF, FLT-1, PLGF-1) and imaging with DCE-MRI (dynamic contrast enhanced MRI) to determine early changes in tumor vascular characteristics were evaluated. Three parameters K(trans), K(ep), and V(e) were measured by DCE-MRI at baseline and day 14 of cycle 1. Cytokine analysis was done on days 0, 14, 28, and 54.

Results: Thirty-seven patients with previously treated stage IV NSCLC were enrolled in this single-center phase II trial. In 34 evaluable patients, 2 had partial responses and 20 had stable disease for 3 to 17 months, a disease control rate of 65%. The median progression-free survival (PFS) was 3.4 months, and median overall survival (OS) was 11.6 months. Toxicity was consistent with the known side effects of sorafenib. KRAS (32%) and EGFR mutations (22%) showed no correlation with response, PFS, or OS. K(ep), was significant in predicting an improvement in OS (P = 0.035) and PFS (P = 0.029). Cytokine analysis demonstrated an improved OS for bFGF day 0 (<6 vs. >6 pg/mL; P = 0.042), whereas a PFS benefit was seen with bFGF at day 28 (<6 vs. >6; P = 0.028).

Conclusions: KRAS and EGFR mutational status showed no correlation with response, PFS, or OS. Radiologic and cytokine changes may act as biomarkers indicative of early angiogenesis inhibition.

©2011 AACR.

Figures

Figure 1. Maximum percent reduction or best response of target lesions in patients (N=34) with available post baseline tumor measurements

PD, progressive disease; SD, stable disease; PR, partial responses. Two PRs measuring 60% and 43% and 20 patients (59%) with stable disease with a median duration of 5.4 months. Tumor shrinkage (1% to 24%) was seen in 12 patients with stable disease and tumor growth (2% to 16%) was seen in the remaining 8 patients. In total 8 patients (24%) had stable disease ≥ 6 months, with 3 patients on study for 6 months, 1 for 7 months, 2 for 8 months, 1 for 10 months and 1 patient for 17 months respectively. Progressive disease as best response was seen in 12 patients (35%), with 3 patients considered not evaluable.

Figure 2. Overall survival (OS) and Progression free survival (PFS)

Kaplan meier curves for (A) OS (B) PFS (C) OS according to KRAS wildtype or mutation (D) PFS according to KRAS wildtype or mutation. Median OS for all patients on study is 11.6 months. Median OS for KRAS wildtype is 13.2 months and 7.2 months for KRAS mutant (p=0.59). Median PFS for all patients on study is 3.4 months. Median PFS for KRAS wildtype is 3.6 months and 2.6 months for KRAS mutant.

Figure 3. Cytokine and DCE-MRI analysis

Exploratory analysis demonstrating potential trends towards an association with OS and PFS by having univariate two-tailed p-values 6 pg/ml. (B) Patients with lower bFGF levels 6 pg/ml, indicating a potential prognostic and predictive role for bFGF. Similarly Kep as measured by DCE-MRI may act as a radiological biomarker. Patients demonstrating a Kep difference of - 0.14 showed (C) an overall survival benefit and (D) a progression free survival benefit.