Phase I Study Evaluating Glesatinib (MGCD265), An Inhibitor of MET and AXL, in Patients with Non-small Cell Lung Cancer and Other Advanced Solid Tumors

Christian Kollmannsberger, Herbert Hurwitz, Lyudmila Bazhenova, Byoung Chul Cho, David Hong, Keunchil Park, Karen L. Reckamp, Sunil Sharma, Hirak Der-Torossian, James G. Christensen, Demiana Faltaos, Diane Potvin, Vanessa Tassell, Richard Chao, Geoffrey I. Shapiro

Research output: Contribution to journalArticlepeer-review


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: NCT00697632; June 2008.

Original languageEnglish
Pages (from-to)105-118
Number of pages14
JournalTargeted Oncology
Issue number1
Publication statusPublished - 2023 Jan

Bibliographical note

Funding Information:
This study (NCT00697632) was supported by Mirati Therapeutics Inc. Funding for a professional medical writer with access to the data was provided by Mirati Therapeutics Inc.

Funding Information:
The authors thank the patients and their families who participated in this study, and also Josée Morin (Innovaderm Research, formally Excelsus Statistics Inc.) for assistance with data analysis and critical review of the manuscript draft, Mai Hang (formally of Mirati Therapeutics Inc.) for contributions to the study conception and design, and Manuela Juretic (formally of Mirati Therapeutics Inc.) for contribution to the study design. Medical writing services were provided by Siân Marshall (SIANTIFIX, Cambridge, UK) in accordance with Good Publication Practice (GPP3) guidelines ( and funded by Mirati Therapeutics, Inc.

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Switzerland AG.

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research
  • Pharmacology (medical)


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