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Phase I Study Evaluating Glesatinib (MGCD265), An Inhibitor of MET and AXL, in Patients with Non-small Cell Lung
Christian Kollmannsberger1, Herbert Hurwitz2,3, Lyudmila Bazhenova4
1British Columbia Cancer, 600 West 10th Ave, Vancouver, BC, V5Z 4E6, Canada. ckollmannsberger@bccancer.bc.ca.
Background:
Heightened signaling by mesenchymal epithelial transition factor (MET) is implicated in tumorigenesis. Glesatinib is an investigational, oral inhibitor of MET and AXL.
Objective:
This phase I study determined the maximum tolerated dose (MTD), recommended phase II dose (RP2D), and safety profile of glesatinib in patients with advanced or unresectable solid tumors. Antitumor activity and pharmacokinetics (PK) were secondary objectives.
Patients And Methods:
Four formulations of glesatinib glycolate salt (capsule, unmicronized, micronized, and micronized version 2 [V2] tablets) and two free-base formulations (free-base suspension [FBS] capsule and spray-dried dispersion [SDD] tablet), developed to enhance drug exposure and optimize manufacturing processes, were evaluated in patients with genetically unselected advanced/unresectable solid tumors. MTD, based on dose-limiting toxicities (DLTs) observed during the first 21-day treatment cycle, was further evaluated in dose-expansion cohorts comprising patients with overexpression of MET and/or AXL, MET/AXL amplification, MET-activating mutations, or MET/AXL rearrangements for confirmation as the RP2D.
Results:
Glesatinib was evaluated across 27 dose-escalation cohorts (n = 108). Due to suboptimal exposure with glesatinib glycolate salt formulations in the initial cohorts, investigations subsequently focused on the FBS capsule and SDD tablet; for these formulations, MTD was identified as 1050 mg twice daily and 750 mg twice daily, respectively. An additional 71 patients received glesatinib in the FBS and SDD dose-expansion cohorts. At MTDs, the most frequent treatment-related adverse events were diarrhea (FBS, 83.3%; SDD, 75.0%), nausea (57.1%, 30.6%), vomiting (45.2%, 25.0%), increased alanine aminotransferase (45.2%, 30.6%), and increased aspartate aminotransferase (47.6%, 27.8%). Exploratory pharmacodynamic analyses indicated target engagement and inhibition of MET by glesatinib. Antitumor activity was observed with glesatinib FBS 1050 mg twice daily and SDD 750 mg twice daily in tumors harboring MET/AXL alteration or aberrant protein expression, particularly in patients with non--small cell lung cancer (NSCLC). In patients with NSCLC, the objective response rate was 25.9% in those with MET/AXL mutation or amplification and 30.0% in a subset with MET-activating mutations. All six partial responses occurred in patients with tumors carrying MET exon 14 deletion mutations.
Conclusions:
The safety profile of single-agent glesatinib was acceptable. SDD 750 mg twice daily was selected as the preferred glesatinib formulation and dose based on clinical activity, safety, and PK data. Observations from this study led to initiation of a phase II study of glesatinib in patients with NSCLC stratified by type of MET alteration (NCT02544633).
Clinical Trials Registration:
ClinicalTrials.gov NCT00697632; June 2008.
Insights
Glesatinib, a MET and AXL inhibitor, showed acceptable safety and antitumor activity in patients with advanced solid tumors. The spray-dried dispersion (SDD) 750 mg twice daily formulation was selected for further study in non-small cell lung cancer (NSCLC).
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Heightened signaling by mesenchymal epithelial transition factor (MET) is implicated in tumorigenesis.
- Glesatinib is an investigational oral inhibitor targeting MET and AXL, key drivers in various cancers.
Purpose of the Study:
- Determine the maximum tolerated dose (MTD), recommended phase II dose (RP2D), and safety of glesatinib.
- Evaluate antitumor activity and pharmacokinetics (PK) of glesatinib in advanced solid tumors.
Main Methods:
- Phase I study evaluating four glesatinib glycolate salt and two free-base formulations (FBS capsule, SDD tablet).
- Dose-escalation and expansion cohorts in patients with advanced/unresectable solid tumors, including those with MET/AXL alterations.
- MTD determination based on dose-limiting toxicities (DLTs).
Main Results:
- MTD identified as 1050 mg twice daily for FBS capsule and 750 mg twice daily for SDD tablet.
- Frequent treatment-related adverse events included diarrhea, nausea, vomiting, and elevated liver enzymes.
- Observed antitumor activity, particularly in non-small cell lung cancer (NSCLC) with MET/AXL alterations, including MET exon 14 deletion mutations.
Conclusions:
- Glesatinib demonstrated an acceptable safety profile as a single agent.
- The SDD 750 mg twice daily formulation was chosen as the preferred dose and formulation based on clinical activity, safety, and PK.
- Results supported initiating a Phase II study of glesatinib in NSCLC patients stratified by MET alteration type.
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