Abstract
Abstract Despite all of the success in targeted therapies for NSCLC, treatment of KRAS mutant NSCLC has been much more challenging. In Caucasian patients, KRAS mutant NSCLC is the most common subset of NSCLC. Therapeutic development of agents specifically targeting KRAS have been unsuccessful. However, recent preclinical and clinical studies suggest that targeting MEK may have some efficacy in KRAS mutant NSCLC. MEK inhibitors selumetinib (AZD6244) and trametinib (GSK1120212) are undergoing clinical development in previously treated KRAS mutant NSCLC patients. A randomized phase II clinical trial of selumetinib/docetaxel vs. docetaxel demonstrated a significant improvement in radiographic response (RR) rate (37% vs. 0%) and progression free survival (PFS) (5.3 vs. 2.1 months) and a numerical increase in overall survival (OS) (9.4 vs. 5.2 months) all in favor of the selumetinib combination. A phase III trial comparing selumetinib/docetaxel to docetaxel alone is currently underway. The trametinib study compared single agent trametinib to docetaxel in a similar patient population. In this study, the PFS was similar for both trametinib and docetaxel (11.7 and 11.4 weeks, respectively) as was the RR (12% in each arm). Additional studies are underway. Recent preclinical studies also suggest that the presence or absence of the tumor suppressor gene, LKB1, may impact the efficacy of selumetinib/docetaxel in a murine model of KRAS mutant NSCLC. LKB1 loss is detected in ∼ 30% of KRAS mutant cancers. In addition, there may be differences in patient outcomes based on the subtype of KRAS mutations. The impact and strategies to evaluate LKB1 loss and the subtypes of KRAS mutations in ongoing clinical trials of MEK inhibitors will be discussed. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL04-02. Citation Format: Pasi A. Jänne. Targeting MEK in KRAS mutant lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL04-02.
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