The effect of CYP2C19 polymorphism on the tolerability of ARQ 197: Results from phase I trial in Japanese patients with metastatic solid tumors.

Abstract

2516 Background: ARQ 197 is a selective, non-ATP competitive inhibitor of c-MET, a receptor tyrosine kinase implicated in tumor cell migration, invasion and proliferation. ARQ 197 is mainly metabolized by CYP2C19. The ratio of the poor metabolizer (PM) of CYP2C19 in Asians is reported to be around 20 % while it is very low in Caucasians. Recommended phase II dose (RP2D) of ARQ 197 in western countries was determined to be 360 mg bid.In this monotherapy phase I study in Japanese patients (pts) with metastatic solid tumors, we examined the drug's safety profile, pharmacokinetics and preliminary antitumor activity and determined RP2D in PM pts as well as extensive metabolizer (EM) pts. Methods: ARQ 197 was administered orally at 8 dose levels from 70 to 360 mg bid in a standard 3+3 dose escalation design. We enrolled PM and EM pts separately from 120 mg bid. Results: Forty-seven pts consisted of 33 EM pts (median age: 61.0 yrs; ECOG PS 0/1: 15/18; median prior therapies: 4) and 14 PM pts (median age: 59.5 yrs; ECOG PS 0/1: 6/8; median prior therapies: 4) were treated. The most common drug-related adverse events were fatigue, leukopenia, anemia, neutropenia and anorexia. Gr.4 neutropenia occurred in 1 of 6 EM pts at 360 mg bid and 3 of 7 PM pts at 240 mg bid, which identified each dosage as RP2D for EM and PM respectively. Cmax and AUC0-12 increased in a dose-dependent manner up to 300 mg bid in the EM cohorts and up to 240 mg bid in the PM. At 240 mg bid, the ARQ 197 Cmax and AUC0-12 of PM pts were 1.5-fold and 1.9-fold higher than those of EM pts respectively. Pts who had a relatively high exposure of ARQ 197 such as Cmax > 4,000 ng/mL or AUC0-12 > 40,000 ng.h/mL on day 1 tended to experience Gr.4 neutropenia regardless of CYP2C19 genotype. Two NSCLC pts, both of whom were PM at 240 mg bid, achieved partial response and 16 pts (34.0%) had stable disease (SD) for >= 16 weeks, especially 6 of 25 pts (24.0 %) in NSCLC had SD for >= 28 weeks. Conclusions: ARQ 197 was well tolerated in PM pts as well as EM pts. CYP2C19 genotype clearly affected the exposure to ARQ 197 which led different RP2Ds, 360 mg bid for EM pts and 240 mg bid for PM pts. ARQ 197 monotherapy showed a clear sign of activity. Further study is warranted.