ARQ 197 (also known as Tivantinib) is a selective, oral, non-ATP-competitive, small-molecule inhibitor of c-MET, and is mainly metabolized by CYP2C19. A Japanese phase I study evaluating ARQ 197 as a single agent demonstrated that the dose-limiting toxicity (DLT) of ARQ 197 was neutropenia, and that the recommended doses were 360 mg bid for CYP2C19 extensive metabolizers (EMs) and 240 mg bid for poor metabolizers (PMs). Nonclinical studies have shown synergism of c-MET ligand HGF with EGF. In addition, a Western phase 2 study demonstrated prolonged progression-free survival in metastatic non-small-cell lung cancer (NSCLC) patients treated with ARQ-197 in combination with an EGFR inhibitor Erlotinib. In this study, the safety and tolerability of ARQ 197 in combination with Erlotinib were evaluated in Japanese patients.Methods
Advanced or metastatic NSCLC patients received ARQ 197 as a single agent for single-dose analysis on day 1, and thereafter, started a repeating dose of ARQ 197 and Erlotinib combination for 29 days. ARQ 197 was administered at 300/360 mg bid for EMs (n = 4 and 12, respectively), and 120/240 mg bid for PMs (n = 3 and 6, respectively), whereas Erlotinib was administered at 150 mg/day for all patients. DLT-observation period was defined from the first dose to the end of the 29 days of the combinational treatments.Results
No DLTwas observed in the enrolled 25 patients (16 EMs, 9 PMs). Rash, dry skin, diarrhea, leukopenia, mucositis oral and nausea were the treatment emergent adverse events observed in >20% of the enrolled patients, including both EMs and PMs during the DLT observation period. Those adverse events were well manageable. Drug–drug interaction was not clearly observed in ARQ 197 metabolism in combination with Erlotinib. Of 25 patients evaluable for response, three patients (two EMs, one PMs) achieved a partial response and 10 patients maintained stable disease.Conclusion
ARQ 197, when combined with Erlotinib, was well tolerated up to 360 mg bid for EMs and 240 mg bid for PMs. A randomized, placebo-controlled, double-blind phase 3 trial is currently underway in Asian countries to evaluate the efficacy of ARQ 197 plus Erlotinib treatment over Erlotinib alone, on OS prolongation in non-squamous NSCLC with wild-type EGFR.