Resistance to MET inhibition in MET-dependent NSCLC and therapeutic activity after switching from type I to type II MET inhibitors

Richard Riedel; Jana Fassunke; Hannah L Tumbrink; Andreas H Scheel; Carina Heydt; Lena Hieggelke; Matthias Scheffler; Alena Heimsoeth; Lucia Nogova; Sebastian Michels; Jan-Phillip Weber; Rieke N Fischer; Anna Eisert; Theresa Westphal; Diana Schaufler; Janna Siemanowski; Michaela A Ihle; Svenja Wagener-Ryczek; Roberta Castiglione; Roberto Pappesch; Jan Rehker; Jessica Jürgens; Erich Stoelben; Anne Bunck; Carsten Kobe; Sabine Merkelbach-Bruse; Martin L Sos; Reinhard Büttner; Jürgen Wolf

doi:10.1016/j.ejca.2022.11.010

Resistance to MET inhibition in MET-dependent NSCLC and therapeutic activity after switching from type I to type II MET inhibitors

Eur J Cancer. 2023 Jan:179:124-135. doi: 10.1016/j.ejca.2022.11.010. Epub 2022 Nov 15.

Authors

Richard Riedel¹, Jana Fassunke², Hannah L Tumbrink³, Andreas H Scheel², Carina Heydt², Lena Hieggelke², Matthias Scheffler¹, Alena Heimsoeth³, Lucia Nogova¹, Sebastian Michels¹, Jan-Phillip Weber¹, Rieke N Fischer¹, Anna Eisert¹, Theresa Westphal¹, Diana Schaufler¹, Janna Siemanowski², Michaela A Ihle², Svenja Wagener-Ryczek², Roberta Castiglione⁴, Roberto Pappesch², Jan Rehker², Jessica Jürgens⁵, Erich Stoelben⁵, Anne Bunck⁶, Carsten Kobe⁷, Sabine Merkelbach-Bruse², Martin L Sos⁸, Reinhard Büttner⁹, Jürgen Wolf¹⁰

Affiliations

¹ University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology, Department I of Internal Medicine, Germany; Lung Cancer Group, Cologne, Germany.
² University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology, Department of Pathology, Molecular Pathology, Germany.
³ University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology, Department of Pathology, Molecular Pathology, Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Germany.
⁴ Institute of Pathology, Klinikum Stuttgart, Stuttgart, Germany.
⁵ Lung Clinic Merheim, Hospital of the City of Cologne, University of Witten-Herdecke, Germany.
⁶ University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology, Department of Radiology, Germany.
⁷ University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology, Department of Nuclear Medicine, Germany.
⁸ University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology, Department of Pathology, Molecular Pathology, Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Germany.
⁹ University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology, Department of Pathology, Molecular Pathology, Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Germany.
¹⁰ University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology, Department I of Internal Medicine, Germany; Lung Cancer Group, Cologne, Germany. Electronic address: juergen.wolf@uk-koeln.de.

PMID: 36521334
DOI: 10.1016/j.ejca.2022.11.010

Abstract

Objectives: Resistance to MET inhibition occurs inevitably in MET-dependent non-small cell lung cancer and the underlying mechanisms are insufficiently understood. We describe resistance mechanisms in patients with MET exon 14 skipping mutation (METΔ^ex14), MET amplification, and MET fusion and report treatment outcomes after switching therapy from type I to type II MET inhibitors.

Materials and methods: Pre- and post-treatment biopsies were analysed by NGS (next generation sequencing), digital droplet PCR (polymerase chain reaction), and FISH (fluorescense in situ hybridization). A patient-derived xenograft model was generated in one case.

Results: Of 26 patients with MET tyrosine kinase inhibitor treatment, eight had paired pre- and post-treatment biopsies (Three with MET amplification, three with METΔ^ex14, two with MET fusions (KIF5B-MET and PRKAR2B-MET).) In six patients, mechanisms of resistance were detected, whereas in two cases, the cause of resistance remained unclear. We found off-target resistance mechanisms in four cases with KRAS mutations and HER2 amplifications appearing. Two patients exhibited second-site MET mutations (p.D1246N and p. Y1248H). Three patients received type I and type II MET tyrosine kinase inhibitors sequentially. In two cases, further progressive disease was seen hereafter. The patient with KIF5B-MET fusion received three different MET inhibitors and showed long-lasting stable disease and a repeated response after switching therapy, respectively.

Conclusion: Resistance to MET inhibition is heterogeneous with on- and off-target mechanisms occurring regardless of the initial MET aberration. Switching therapy between different types of kinase inhibitors can lead to repeated responses in cases with second-site mutations. Controlled clinical trials in this setting with larger patient numbers are needed, as evidence to date is limited to preclinical data and case series.

Keywords: MET amplification; MET exon 14 skipping; MET fusion; NSCLC; Tyrosine kinase inhibitor resistance.

MeSH terms

Carcinoma, Non-Small-Cell Lung* / drug therapy
Carcinoma, Non-Small-Cell Lung* / genetics
Carcinoma, Non-Small-Cell Lung* / pathology
Drug Resistance, Neoplasm / genetics
Humans
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / pathology
Mutation
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins c-met / genetics

Substances

Proto-Oncogene Proteins c-met
Protein Kinase Inhibitors