Tivantinib (formerly ARQ 197, T) is a selective, oral, non-ATP-competitive, small-molecule inhibitor of c-MET. Erlotinib (E) is small-molecule inhibitor of EGFR, and is approved for NSCLC. As presented at ASCO 2011, a randomized, placebo-controlled, double blind phase 3 trial (MARQUEE) is currently underway in Western counties, targeting the prolongation of OS in E + T over E alone, in non-squamous NSCLC regardless of EGFR mutation status, as 2nd-3rd line treatments. The ATTENTION and MARQUEE share the same rationale based on a phase 2 study which demonstrated prolonged PFS in metastatic NSCLC treated with E + T, as compared with E alone. To translate the phase 2 study to Asians, genetic differences need to be considered. Firstly, the higher incidence of EGFR mutation in Asian NSCLC (∼50%), as compared with Caucasian (∼10%), should be taken into account, because PFS prolongation in the phase 2 study in E + T treated group was less clear in patients with EGFR mutation. Secondly, genetic polymorphism related to functional inferiority is known for CYP2C19 (2C19), the key metabolic enzyme for T, and the incidence of 2C19 poor metabolizers (PMs) is more frequent in Asians (∼20%) compared with Caucasians (∼3%). Japanese phase 1 studies of T as a single agent and in combination with E revealed that a differential dosing based on a pretreatment test of 2C19 genetic polymorphism was recommended for upcoming Asian phase 2/3 studies.Methods
An Asian multi-national (Japan, Korea and Taiwan), double-blind, placebo-controlled phase 3 trial has been initiated to evaluate the efficacy of E + T treatment on OS prolongation in non-squamous NSCLC with wild-type EGFR, in the 2nd-3rd line setting. The doses of T are determined by the pretreatment test of 2C19 polymorphism; 240 mg bid for PMs, and 360 mg bid for EMs as used in Western countries, whereas the dose of E is 150 mg daily in all patients. Patients (n = 460) will be randomized 1:1 to receive E + T or E + placebo until progression, unacceptable toxicity or other discontinuation criterion. Putative predictive biomarkers, such as c-MET/HGF expression, will be tested. The starting and estimated completion dates are Jul. 2011 and Dec. 2013, respectively. This study is sponsored by Kyowa Hakko Kirin Co., LTD (NCT01377376).