Phase 1 Study of AMG 337, a Highly Selective Small-Molecule MET Inhibitor, in Patients With Advanced Solid Tumors.

PURPOSE: This first-in-human, open-label phase 1 study evaluated AMG 337, an oral, highly selective small-molecule inhibitor of MET in advanced solid tumors.

EXPERIMENTAL DESIGN: Patients enrolled into dose-escalation cohorts received AMG 337 up to 400 mg once daily (QD) or up to 250 mg twice daily (BID), following a modified 3+3+3 design. Dose expansion was conducted in MET -amplified patients at the maximum tolerated dose (MTD). Primary endpoints included assessment of adverse events (AEs), establishment of the MTD, and pharmacokinetics; clinical response was a secondary endpoint.

RESULTS: The safety analysis set included 111 patients who received ≥1 dose of AMG 337. Thirteen patients had ≥1 AE qualifying as dose-limiting toxicity. The MTD was determined to be 300 mg QD; the MTD for BID dosing was not reached. Most frequent treatment-related AEs were headache (63%) and nausea (31%). Grade ≥3 treatment-related AEs occurred in 23 patients (21%), most commonly headache (n=6) and fatigue (n=5). Maximum plasma concentration occurred at 3.0 hours following 300-mg QD dosing, indicating AMG 337 absorption soon after treatment. Objective response rate was 9.9% (11/111; 95% CI, 5.1%-17.0%) in all patients and 29.6% (8/27; 95% CI, 13.8%-50.2%) in MET -amplified patients; median (range) duration of response was 202 (51-1430+) days in all patients and 197 (64-1430+) days in MET -amplified patients.

CONCLUSIONS: Oral AMG 337 was tolerated with manageable toxicities, with an MTD and recommended phase 2 dose of 300 mg QD. The promising response rate observed in patients with heavily pretreated MET -amplified tumors warrants further investigation.