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

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.

Fig 1.

BATTLE-2 trial schema. AKTi, AKT inhibitor; MEKi, MEK inhibitor.

Fig 2.

CONSORT flow diagram of patient population and treatment assignments.

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.

(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).