[PMC free article] [PubMed] [Google Scholar] 24. (1) erlotinib, (2) erlotinib plus MK-2206, (3) MK-2206 plus AZD6244, or (4) sorafenib. Tumor gene expression profilingCtargeted next-generation sequencing was performed to evaluate predictive and prognostic biomarkers. Results Two hundred patients, 27% with mut+) tumors, were adaptively Nutlin 3a 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 mut+ patients, DCR was 20%, 25%, 62%, and 44% whereas for status, 1.8 months for arm 1, and 2.5 months for arms 2 versus arms 3 and 4 in mut+ patients (= .04). Median overall survival was 6.5 months, 9.0 and 5.1 months for arms Pramlintide Acetate 1 and 2 versus arms 3 and 4 in wild-type patients (= .03). Median overall survival was 7.5 months in mesenchymal versus 5 months in epithelial tumors (= .02). Conclusion Despite improved progression-free survival on therapy that did not contain erlotinib for mut+ patients and improved prognosis for mesenchymal tumors, better biomarker-driven treatment strategies are still needed. INTRODUCTION NonCsmall-cell lung cancer (NSCLC) is the leading cause of cancer-related death and accounts for more than a million deaths per year worldwide.1 The disease is usually diagnosed at later stages, when curative treatment is not available.2 The benefit from platinum-based doublet chemotherapy is modest.3 Lung cancers are biologically and molecularly diverse4 and have various responses to both traditional chemotherapy and targeted therapy designed to address molecular alterations that drive cancer progression.5 The rapid evolution of genomic profiling has dramatically accelerated our knowledge of the diversity of lung cancer4 and has generated the impetus for using genotyping as a guide for clinical care of patients with lung cancer and for creating novel design paradigms in genomics-driven clinical trials. In the phase II Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) program of personalized medicine (ClinicalTrials.gov numbers “type”:”clinical-trial”,”attrs”:”text”:”NCT00409968″,”term_id”:”NCT00409968″NCT00409968, “type”:”clinical-trial”,”attrs”:”text”:”NCT00411671″,”term_id”:”NCT00411671″NCT00411671, “type”:”clinical-trial”,”attrs”:”text”:”NCT00411632″,”term_id”:”NCT00411632″NCT00411632, “type”:”clinical-trial”,”attrs”:”text”:”NCT00410059″,”term_id”:”NCT00410059″NCT00410059, and “type”:”clinical-trial”,”attrs”:”text”:”NCT00410189″,”term_id”:”NCT00410189″NCT00410189) previously reported6,7 by our group, we prospectively biopsied tumors and, on the basis of tumor markers, we used adaptive randomization to assign patients with NSCLC to the treatment with the greatest potential benefit on the basis of cumulative data. The trial established the feasibility of performing core biopsies in pretreated patients with advanced disease and of using real-time biomarker analysis for treatment assignments,8 and it represented a major step toward personalizing therapy for patients with NSCLC. On this basis, the BATTLE-2 trial (BATTLE-2 Nutlin 3a Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer) capitalized on activity observed with sorafenib,9-11 on enhanced understanding of lung cancer biology, and on the availability of several promising brokers, including MK-2206, an allosteric AKT inhibitor,12 and AZD6244, an MEK inhibitor.13 We could thus test novel hypotheses derived from a mut+) NSCLC refractory to platinum-based regimens. Here we report the results of the first stage of the BATTLE-2 trial. PATIENTS AND METHODS Patient Population Patients with pretreated NSCLC at the University of Texas MD Anderson Cancer Center and Yale Cancer Center who agreed to a baseline tumor biopsy, who had Eastern Cooperative Oncology Group performance status Nutlin 3a (ECOG PS) of 0 to 2, and who had multiple prior lines of therapy and stable or treated brain Nutlin 3a metastases were enrolled (details for eligibility are provided in the Data Supplement). Patients were excluded if their tumor harbored sensitizing mutations or gene fusions, and they were erlotinib or crizotinib na?ve. All participants provided written informed consent. The MD Anderson Cancer Center and Yale Cancer Center Institutional Review Boards approved the study. The trial was monitored by an independent data and safety monitoring board. Study Design BATTLE-2 was a randomized, phase II, multicenter, open-label study in patients with advanced NSCLC refractory to prior platinum-based chemotherapy (Fig 1). After molecular tumor biomarker assessments, patients were adaptively randomly assigned to four arms: arm 1, erlotinib 150 mg once per day (OSI Pharmaceuticals, Farmingdale, NY; Genentech, San Francisco, CA); arm 2, erlotinib 150 mg once per day and the AKT inhibitor MK-2206 135 mg once per week (Merck, Kenilworth, NJ); arm 3, MEK inhibitor AZD6244 100 mg per day (AstraZeneca, Wilmington, DE) and AKT inhibitor MK-2206 100 mg once per week; and arm 4, sorafenib 400 mg orally twice per day (Bayer, Whippany, NJ). Patients who received prior erlotinib were randomly assigned to one of arms 2, 3, or 4. Tumor evaluation studies were performed after two cycles (one cycle is 28 days) and every two cycles thereafter. mutation status was a stratification factor. All patients who received at least one cycle of treatment (4 weeks) were considered evaluable.