Background: New strategies incorporating a personalized medicine approach for NSCLC treatment are increasingly explored and were pioneered in the prospective, biomarker-driven clinical program titled Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE-1) (Kim et al Cancer Discov 2011;1:44). Effective therapeutic strategies for mutant KRAS and other biomarkers of resistance in refractory NSCLC remain an unmet medical need. The BATTLE-2 clinical study is using EGFR, PI3K/AKT and MEK inhibitors and is designed to identify biomarkers for optimal patient selection for these therapies, with a long-term goal to significantly improve the survival of NCSLC patients (pts) (ClinicalTrials.gov NCT01248247). Methods: This is a four-arm, open-label, multi-center, biopsy-driven, adaptive randomization, phase II clinical trial in refractory NSCLC pts (failed at least 1 prior line of therapy). After a study-entry tumor biopsy, pts are adaptively randomized, based on KRAS status, to 4 trial arms: erlotinib, erlotinib plus the AKT inhibitor MK-2206, MK-2206 plus the MEK inhibitor selumetinib, and sorafenib. The primary objective is 8-week disease control rate (DCR). Baseline tumor testing includes KRAS and EGFR mutations and EML4/ALK translocation, the latter two being exclusion criteria. The trial is conducted in 2 stages. In Stage 1, 200 evaluable pts are adaptively randomized (AR) based on observed 8-week DCR and KRAS status while predictive biomarkers are being developed. In Stage 2, the AR model is refined to include the most predictive biomarkers tested in Stage 1, with subsequent Stage 2 AR based on the new algorithm, to a total of 400 evaluable pts. Selection of Stage 2 single and/or composite markers (“signatures”) follows a rigorous, internally and externally reviewed statistical analysis. All Stage 1 and 2 randomization biomarker assays are CLIA-certified. 219 pts have been enrolled and 124 pts randomized. 100 pts are evaluable for the 8-week DCR endpoint. Accrual updates, demographics, and further details will be presented at the meeting. Supported by NCI R01CA155196-01A1. Clinical trial information: NCT01248247.