Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 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

Vassiliki Papadimitrakopoulou  1 , J Jack Lee  1 , Ignacio I Wistuba  1 , Anne S Tsao  1 , Frank V Fossella  1 , Neda Kalhor  1 , Sanjay Gupta  1 , Lauren Averett Byers  1 , Julie G Izzo  1 , Scott N Gettinger  1 , Sarah B Goldberg  1 , Ximing Tang  1 , Vincent A Miller  1 , Ferdinandos Skoulidis  1 , Don L Gibbons  1 , Li Shen  1 , Caimiao Wei  1 , Lixia Diao  1 , S Andrew Peng  1 , Jing Wang  1 , Alda L Tam  1 , Kevin R Coombes  1 , Ja Seok Koo  1 , David J Mauro  1 , Eric H Rubin  1 , John V Heymach  1 , Waun Ki Hong  1 , Roy S Herbst  1
Affiliations

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

Vassiliki Papadimitrakopoulou et al. J Clin Oncol. .

Abstract

Purpose: 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 and methods: 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.

Results: 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).

Conclusion: 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.

PubMed Disclaimer

Conflict of interest statement

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
BATTLE-2 trial schema. AKTi, AKT inhibitor; MEKi, MEK inhibitor.
Fig 2.
Fig 2.
CONSORT flow diagram of patient population and treatment assignments.
Fig 3.
Fig 3.
(A) Progression-free survival (PFS) by treatment (P = .17), (B) overall survival (OS) by treatment (P = .46), (C) PFS of patients with KRAS wild-type (wt) tumors by treatment (P = .13), and hazard ratio (HR) for erlotinib-containing treatments versus treatments not containing erlotinib (HR, 0.76; 95% CI, 0.54 to 1.09). (D) PFS of patients with KRAS-mutated (KRAS mut+) tumors by treatment (HR, 1.95; 95% CI, 1.00 to 3.77; P = .04), (E) OS of patients with KRAS wt tumors by treatment (HR, 0.66; 95% CI, 0.45 to 0.97; P = .03), and (F) OS of patients with KRAS mut+ tumors by treatment (HR, 1.26; 95% CI, 0.65 to 2.46; P = .50). All P values were based on two-sided log-rank test.
Fig 4.
Fig 4.
(A) The epithelial mesenchymal transition gene expression signature classifies BATTLE-2 tumors (all treatment arms) into epithelial (E) and mesenchymal (M). Distribution of KRAS-mutated tumors is shown. (B) Progression-free survival among epithelial and mesenchymal tumors (log-rank test P = .12). (C) Overall survival was superior for patients with mesenchymal tumors (log-rank test P = .02).
See this image and copyright information in PMC

Comment in

References

    1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–2917. - PubMed
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29. - PubMed
    1. Le Chevalier T, Scagliotti G, Natale R, et al. Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: A meta-analysis of survival outcomes. Lung Cancer. 2005;47:69–80. - PubMed
    1. Ding L, Getz G, Wheeler DA, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008;455:1069–1075. - PMC - PubMed
    1. Toyooka S, Mitsudomi T, Soh J, et al. Molecular oncology of lung cancer. Gen Thorac Cardiovasc Surg. 2011;59:527–537. - PubMed