Trial Shows Interactions Between KRAS Mutations, Erlotinib Therapy in NSCLC

Using a biopsy-mandated, targeted randomization approach, a new trial showed that KRAS wild-type advanced non–small-cell lung cancer (NSCLC) patients fare better with regimens containing erlotinib, while KRAS-mutated NSCLC patients had better outcomes without erlotinib and with MEK and AKT inhibitors.

“The rapid evolution of genomic profiling has dramatically accelerated our knowledge of the diversity of lung cancer 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,” wrote study authors led by Vassiliki Papadimitrakopoulou, MD, of the University of Texas MD Anderson Cancer Center in Houston.

Previously, the BATTLE study established the feasibility of performing core biopsies and using real-time biomarker analysis to guide treatment assignments. The new BATTLE-2 trial incorporated that method, and randomized 200 patients (27% with KRAS mutations) with advanced pretreated NSCLC to one of four study arms: group one received erlotinib; group two received erlotinib plus MK-2206, an AKT inhibitor; group three received MK-2206 plus AZD6244, a MEK inhibitor; and group four received sorafenib. The results were published in the Journal of Clinical Oncology.

In 186 patients eligible for analysis, the 8-week disease control rate (DCR) was 48%, and the median progression-free survival (PFS) was 2.0 months. The median overall survival (OS) was 6.5 months, and the 1-year survival rate was 28%. The DCRs in the four groups were 32%, 50%, 53%, and 46%, respectively. PFS and OS were no different across the four arms.

There was no significant association found between KRAS mutation status and 8-week DCR. In patients with KRAS mutations (52 evaluable patients), PFS was significantly longer if treated with therapy that did not contain erlotinib, with a hazard ratio (HR) of 1.95 (95% CI, 1.00–3.77; P = .04). In KRAS wild-type patients however, there was no difference in PFS between erlotinib-containing and non–erlotinib-containing regimens.

The KRAS wild-type patients did have better OS when treated with erlotinib-containing regimens, with an HR of 0.66 (95% CI, 0.45–0.97; P = .03). KRAS-mutated patients did not have a significant OS difference based on erlotinib therapy. In study group one, KRAS mutation–positive patients had significantly worse OS than those with wild-type tumors (5.5 months vs 11.1 months; P = .02); no such difference was seen in the other groups.

“The BATTLE-2 study showed the utility of real-time biopsies for broad profiling of tumors that serve as a discovery vehicle for better target selection,” the authors wrote. They added that better biomarker-driven treatments in this malignancy are still needed, and the information from BATTLE-2 will be used to guide development of such regimens.