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J Clin Oncol. 2016 Oct 20;34(30):3638-3647. doi: 10.1200/JCO.2015.66.0084.

The BATTLE-2 Study: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer.

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Vassiliki Papadimitrakopoulou, J. Jack Lee, Ignacio I. Wistuba, Anne S. Tsao, Frank V. Fossella, Neda Kalhor, Sanjay Gupta, Lauren Averett Byers, Julie G. Izzo, Ximing Tang, Ferdinandos Skoulidis, Don L. Gibbons, Li Shen, Caimiao Wei, Lixia Diao, S. Andrew Peng, Jing Wang, Alda L. Tam, John V. Heymach, and Waun Ki Hong, The University of Texas MD Anderson Cancer Center, Houston, TX; Scott N. Gettinger, Sarah B. Goldberg, Ja Seok Koo, and Roy S. Herbst, Yale University, New Haven, CT; Vincent A. Miller, Foundation Medicine, Cambridge, MA; Kevin R. Coombes, Ohio State University College of Medicine, Columbus, OH; and David J. Mauro and Eric H. Rubin, Merck, North Wales, PA.



By applying the principles of real-time biopsy, biomarker-based, adaptively randomized studies in non-small-cell lung cancer (NSCLC) established by the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, we conducted BATTLE-2 (BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer), an umbrella study to evaluate the effects of targeted therapies focusing on KRAS-mutated cancers.


Patients with advanced NSCLC (excluding sensitizing EGFR mutations and ALK gene fusions) refractory to more than one prior therapy were randomly assigned, stratified by KRAS status, to four arms: (1) erlotinib, (2) erlotinib plus MK-2206, (3) MK-2206 plus AZD6244, or (4) sorafenib. Tumor gene expression profiling-targeted next-generation sequencing was performed to evaluate predictive and prognostic biomarkers.


Two hundred patients, 27% with KRAS-mutated (KRAS mut+) tumors, were adaptively randomly assigned to erlotinib (n = 22), erlotinib plus MK-2206 (n = 42), MK-2206 plus AZD6244 (n = 75), or sorafenib (n = 61). In all, 186 patients were evaluable, and the primary end point of an 8-week disease control rate (DCR) was 48% (arm 1, 32%; arm 2, 50%; arm 3, 53%; and arm 4, 46%). For KRAS mut+ patients, DCR was 20%, 25%, 62%, and 44% whereas for KRAS wild-type patients, DCR was 36%, 57%, 49%, and 47% for arms 1, 2, 3, and 4, respectively. Median progression-free survival was 2.0 months, not different by KRAS status, 1.8 months for arm 1, and 2.5 months for arms 2 versus arms 3 and 4 in KRAS mut+ patients (P = .04). Median overall survival was 6.5 months, 9.0 and 5.1 months for arms 1 and 2 versus arms 3 and 4 in KRAS wild-type patients (P = .03). Median overall survival was 7.5 months in mesenchymal versus 5 months in epithelial tumors (P = .02).


Despite improved progression-free survival on therapy that did not contain erlotinib for KRAS mut+ patients and improved prognosis for mesenchymal tumors, better biomarker-driven treatment strategies are still needed.

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