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.

• Authors: Ronan J Kelly, Arun Rajan, Jeremy Force, Ariel Lopez-Chavez, Corrine Keen, Liang Cao, Yunkai Yu, Peter Choyke, Baris Turkbey, Mark Raffeld, Liqiang Xi, Seth M Steinberg, John J Wright, Shivaani Kummar, Martin Gutierrez, Giuseppe Giaccone
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 5 Pg. 1190-9 (Mar 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21224376 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Intramural)
• Copyright: ©2011 AACR.

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Benzenesulfonates
• Biomarkers, Tumor
• Cytokines
• KRAS protein, human
• Phenylurea Compounds
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Pyridines
• Niacinamide
• Sorafenib
• EGFR protein, human
• ErbB Receptors
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Proto-Oncogene Proteins p21(ras)
• ras Proteins

Topics

• Adult
• Aged
• Aged, 80 and over
• Angiogenesis Inhibitors
• Antineoplastic Agents (therapeutic use)
• Benzenesulfonates (therapeutic use)
• Biomarkers, Tumor
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Cytokines (analysis, metabolism)
• Disease-Free Survival
• Drug-Related Side Effects and Adverse Reactions
• ErbB Receptors (genetics)
• Female
• Genes, ras
• Humans
• Lung Neoplasms (drug therapy, genetics, pathology)
• Magnetic Resonance Angiography
• Male
• Middle Aged
• Mutation
• Neovascularization, Pathologic
• Niacinamide (analogs & derivatives)
• Phenylurea Compounds
• Prognosis
• Protein Kinase Inhibitors (therapeutic use)
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins B-raf (genetics)
• Proto-Oncogene Proteins p21(ras)
• Pyridines (therapeutic use)
• Sorafenib
• ras Proteins (genetics)