Phase I Study of AMG 337, a Highly Selective Small-molecule MET Inhibitor, in Patients with Advanced Solid Tumors

Abstract

Purpose: This first-in-human, open-label phase I study evaluated AMG 337, an oral, highly selective small-molecule inhibitor of MET in advanced solid tumors.Patients and Methods: Patients enrolled into dose-escalation cohorts received AMG 337 up to 400 mg once daily or up to 250 mg twice daily, 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 once daily; the MTD for twice-daily 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 once-daily 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 (51-1,430+) days in all patients and 197 (64-1,430+) days in MET-amplified patients.

Conclusions: Oral AMG 337 was tolerated with manageable toxicities, with an MTD and recommended phase II dose of 300 mg once daily. The promising response rate observed in patients with heavily pretreated MET-amplified tumors warrants further investigation.See related commentary by Ma, p. 2375.

©2018 American Association for Cancer Research.

Figures

Figure 1.

Study design and treatment schedule for once-daily (QD) and twice-daily (BID) dose-escalation (A) and dose-expansion cohorts (B). The once-daily dose-escalation cohorts included doses from 25 mg up to a maximum planned dose of 500 mg; twice-daily dose-escalation cohorts included doses from 100 to 250 mg. If no DLT occurred among the first 3 to 4 patients during the first 28 days of treatment, patients could be enrolled at the next dose level; if a single DLT occurred, 2 to 3 additional patients were added to that cohort; if a second DLT occurred, additional patients were added to that cohort for a total of up to 9 patients; if ≥3 DLTs occurred at any time, enrollment was stopped and a lower dose level considered. Sequential dose escalation continued until the MTD, defined as the highest dose at which <33% of patients experienced a DLT, was reached. During dose escalation, patients with MET amplification or mutation were allowed to enroll at the highest tolerable dose at any time, provided all other eligibility criteria were met. Up to 50 additional patients with MET amplification/mutation or MET overexpression could be enrolled in 3 dose-expansion cohorts at the MTD or maximum planned dose. BID, twice daily; DLT, dose-limiting toxicity; E1, MET-amplified gastric, gastroesophageal, or esophageal cancer; E2, MET-amplified non–small-cell lung cancer; E3, other MET-amplified cancer subtypes; ICF, informed consent form; PO, orally.

Figure 2.

Waterfall plot showing percentage change from baseline in target tumor dimensions (best response, central read) by dose. A, Response among all patients with available response data (n = 84). B, Response among MET-amplified patients with available response data. C, Swimmer plot showing duration of treatment and response by dose for all patients. D, Fluorodeoxyglucose positron emission tomography (FDG-PET) maximum intensity projections showing response in a 63-year-old male with gastroesophageal junction cancer and MET amplification at baseline (left) and at week 5 (right). This patient received AMG 337 200 mg once daily orally (QD PO) and achieved a CR at week 56.4. BID, twice daily; CR, complete response; E1, MET-amplified gastric, gastroesophageal, or esophageal cancer; E2, MET-amplified non–small-cell lung cancer; E3, other MET-amplified cancer subtypes; PD, progressive disease; PO, orally; PR, partial response; SD, stable disease; QD, once daily.