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Peer-reviewedCC BY-NC-NDJTO clinical and research reports

Brief Report: Combination Capmatinib and Trametinib in Metastatic MET-Driven NSCLC.

  • Tyiesha Brown1,2
  • Matthew S Lara3,4
  • Fei Jiang2,5
  • Edward B Garon6,7
  • Jonathan W Goldman6,7,8
  • Jonathan W Riess3,4,8
  • Collin M Blakely1,2,8
8 affiliations
  1. 1Department of Medicine, University of California San Francisco, San Francisco, California.
  2. 2University of California San Francisco Helen Diller Comprehensive Cancer Center, San Francisco, California.
  3. 3Department of Medicine, University of California Davis, Sacramento, California.
  4. 4University of California Davis Comprehensive Cancer Center, Sacramento, California.
  5. 5Department of Epidemiology & Biostatistics, Universiy of California San Francisco, San Francisco, California.
  6. 6Department of Medicine, University of California Los Angeles, Los Angeles, California.
  7. 7David Geffen School of Medicine at UCLA, Los Angeles, California.
  8. 8University of California Lung Cancer Consortium.
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Abstract

Introduction

MET tyrosine kinase inhibitor (TKI) therapy has improved outcomes in patients with NSCLC harboring MET alterations. Nevertheless, primary and acquired resistance ultimately limit the durability of response. This study evaluated the safety and efficacy of the MET inhibitor capmatinib with the MEK inhibitor trametinib in patients with metastatic MET-driven NSCLC who had progressed on prior treatment with at least one MET inhibitor.Methods

A multicenter phase I study evaluated capmatinib in combination with trametinib in patients with advanced-stage NSCLC harboring activating MET alterations and prior exposure to at least one MET TKI. A three-plus-three dose-escalation design was used to assess the safety and tolerability of the combination.Results

Three patients (N = 3) were enrolled in the study and completed a median of three cycles of therapy. Dose-limiting toxicities, including rash, edema, and nausea, necessitated dose reductions in the first two patients and the initiation of therapy in the third patient at a lower dose level. Ultimately, all patients discontinued therapy because of treatment-related adverse events (TRAEs). The study was terminated early because of poor accrual and TRAEs. No radiographic objective responses were observed.Conclusions

In this phase I trial, capmatinib plus trametinib was associated with marked TRAEs, and treatment was discontinued in all participants. On the basis of these findings, further investigation of this combination of MET and MEK inhibitors at the tested dose levels is not recommended. Future studies, if pursued, should consider modified dosing strategies, alternative MET and MEK inhibitor combinations, and MET-altered tumors with evidence of MAPK-mediated resistance.Clinicaltrialsgov identifier

NCT05435846.

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Cite

BibTeXRIS
BibTeX
@article{brown2026brief,
  title = {{Brief Report: Combination Capmatinib and Trametinib in Metastatic MET-Driven NSCLC.}},
  author = {Tyiesha Brown and Matthew S Lara and Fei Jiang and Edward B Garon and Jonathan W Goldman and Jonathan W Riess and Collin M Blakely},
  journal = {JTO clinical and research reports},
  year = {2026},
  month = aug,
  doi = {10.1016/j.jtocrr.2026.101072},
  url = {https://europepmc.org/article/MED/42898856},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Brief Report: Combination Capmatinib and Trametinib in Metastatic MET-Driven NSCLC.
AU  - Tyiesha Brown
AU  - Matthew S Lara
AU  - Fei Jiang
AU  - Edward B Garon
AU  - Jonathan W Goldman
AU  - Jonathan W Riess
AU  - Collin M Blakely
PY  - 2026
DA  - 2026/08/31
JO  - JTO clinical and research reports
DO  - 10.1016/j.jtocrr.2026.101072
UR  - https://europepmc.org/article/MED/42898856
AB  - Introduction  MET tyrosine kinase inhibitor (TKI) therapy has improved outcomes in patients with NSCLC harboring MET alterations. Nevertheless, primary and acquired resistance ultimately limit the durability of response. This study evaluated the safety and efficacy of the MET inhibitor capmatinib with the MEK inhibitor trametinib in patients with metastatic MET-driven NSCLC who had progressed on prior treatment with at least one MET inhibitor.Methods  A multicenter phase I study evaluated capmatinib in combination with trametinib in patients with advanced-stage NSCLC harboring activating MET alterations and prior exposure to at least one MET TKI. A three-plus-three dose-escalation design was used to assess the safety and tolerability of the combination.Results  Three patients (N = 3) were enrolled in the study and completed a median of three cycles of therapy. Dose-limiting toxicities, including rash, edema, and nausea, necessitated dose reductions in the first two patients and the initiation of therapy in the third patient at a lower dose level. Ultimately, all patients discontinued therapy because of treatment-related adverse events (TRAEs). The study was terminated early because of poor accrual and TRAEs. No radiographic objective responses were observed.Conclusions  In this phase I trial, capmatinib plus trametinib was associated with marked TRAEs, and treatment was discontinued in all participants. On the basis of these findings, further investigation of this combination of MET and MEK inhibitors at the tested dose levels is not recommended. Future studies, if pursued, should consider modified dosing strategies, alternative MET and MEK inhibitor combinations, and MET-altered tumors with evidence of MAPK-mediated resistance.Clinicaltrialsgov identifier  NCT05435846.
SN  - 2666-3643
ER  -