Comprehensive biomarker analysis and final efficacy results of sorafenib in the BATTLE trial.

Abstract

PURPOSE:

To report the clinical efficacy of sorafenib and to evaluate biomarkers associated with sorafenib clinical benefit in the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) program.

PATIENTS AND METHODS:

Patients with previously treated non-small cell lung cancer (NSCLC) received sorafenib until progression or unacceptable toxicity. Eight-week disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. Prespecified biomarkers included K-RAS, EGFR, and B-RAF mutations, and EGFR gene copy number. Gene expression profiles from NSCLC cell lines and patient tumor biopsies with wild-type EGFR were used to develop a sorafenib sensitivity signature (SSS).

RESULTS:

A total of 105 patients were eligible and randomized to receive sorafenib. Among 98 patients evaluable for eight-week DCR, the observed DCR was 58.2%. The median PFS and OS were 2.83 [95% confidence interval (CI), 2.04-3.58] and 8.48 months (95% CI, 5.78-10.97), respectively. Eight-week DCR was higher in patients with wild-type EGFR than patients with EGFR mutation (P = 0.012), and in patients with EGFR gene copy number gain (FISH-positive) versus patients FISH-negative (P = 0.048). In wild-type EGFR tumors, the SSS was associated with improved PFS (median PFS 3.61 months in high SSS vs. 1.84 months in low SSS; P = 0.026) but not with eight-week DCR. Increased expression of fibroblast growth factor-1, NF-κB, and hypoxia pathways were identified potential drivers of sorafenib resistance.

CONCLUSION:

Sorafenib demonstrates clinical activity in NSCLC, especially with wild-type EGFR. SSS was associated with improved PFS. These data identify subgroups that may derive clinical benefit from sorafenib and merit investigation in future trials.

• Authors: George R Blumenschein Jr, Pierre Saintigny, Suyu Liu, Edward S Kim, Anne S Tsao, Roy S Herbst, Christine Alden, J Jack Lee, Ximing Tang, David J Stewart, Merrill S Kies, Frank V Fossella, Hai T Tran, L Mao, Marshall E Hicks, Jeremy Erasmus Jr, Sanjay Gupta, Luc Girard, Michael Peyton, Lixia Diao, Jing Wang, Suzanne E Davis, John D Minna, Ignacio Wistuba, Waun K Hong, John V Heymach, Scott M Lippman
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 24 Pg. 6967-75 (Dec 15 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 24166906 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2013 AACR.

Chemical References

• Biomarkers, Tumor
• Phenylurea Compounds
• Niacinamide
• Sorafenib
• EGFR protein, human
• ErbB Receptors

Topics

• Aged
• Biomarkers, Tumor (genetics, metabolism)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Disease-Free Survival
• ErbB Receptors (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Middle Aged
• Neoplasm Staging
• Niacinamide (administration & dosage, analogs & derivatives)
• Phenylurea Compounds (administration & dosage)
• Sorafenib