Tivantinib added to erlotinib in nonsmallcell lung cancer: The primary end point was not MET..

The transmembrane tyrosine kinase receptor mesenchymal–epithelial transition (MET) factor, activated by its ligand hepatocyte growth factor (HGF), is involved in cell proliferation, survival, motility, and metastasis [1]. The MET pathway is known to crosstalk with the epidermal growth factor receptor (EGFR) and KRAS signaling pathways, which are critical in the molecular pathogenesis of many solid tumors, including nonsmall-cell lung cancer (NSCLC) with intrinsic or acquired resistance to EGFR inhibitors [2]. While MET amplification is a quite uncommon event in lung cancer, MET protein overexpression has been detected, by immunohistochemistry, in 27%–77% of NSCLC samples with nonsquamous histology and 1%–57% of NSCLC samples with squamous cell histology [1]. Tivantinib is an oral drug that binds to the dephosphorylated MET kinase [3]. Although it has shown cytotoxic activity via molecular mechanisms that are independent from its ability to bind MET [4], the drug is under clinical development as a highly selective MET inhibitor. A pivotal randomized phase II study of tivantinib plus erlotinib versus erlotinib alone was conducted in 167 patients with advanced NSCLC, chemotherapy-pretreated and naive to EGFR tyrosine kinase inhibitors [5]. The study did not meet its primary end point, because no significant prolongation of progression-free survival (PFS) was shown, but interesting results were observed in exploratory analyses according to tumor histology and molecular characteristics: in detail, the addition of tivantinib seemed to be associated with a better outcome in both PFS and overall survival (OS) in the nonsquamous NSCLC subgroup, with better PFS in patients with wild-type EGFR and with a statistically significant PFS improvement in the small subgroup of patients with KRAS mutations [5]. In the article accompanying this editorial, Yoshioka et al. present the results of the ATTENTION phase III randomized trial comparing