The Combined Therapy of Cabozantinib, Crizotinib, and Osimertinib in a Lung Cancer Patient with Acquired MET Amplification and Resistance Mutations

Curr Oncol. 2023 Sep 27;30(10):8805-8814. doi: 10.3390/curroncol30100635.

Abstract

EGFR-mutant lung cancers develop a wide range of potential resistance alterations under therapy with the third-generation EGFR tyrosine kinase inhibitor osimertinib. MET amplification ranks among the most common acquired resistance alterations and is currently being investigated as a therapeutic target in several studies. Nevertheless, targeted therapy of MET might similarly result in acquired resistance by point mutations in MET, which further expands therapeutic and diagnostic challenges. Here, we report a 50-year-old male patient with EGFR-mutant lung adenocarcinoma and stepwise acquired resistance by a focal amplification of MET followed by D1246N (D1228N), D1246H (D1228H), and L1213V (L1195V) point mutations in MET, all detected by NGS. The patient successfully responded to the combined and sequential treatment of osimertinib, osimertinib/crizotinib, and third-line osimertinib/cabozantinib. This case highlights the importance of well-designed, sequential molecular diagnostic analyses and the personalized treatment of patients with acquired resistance.

Keywords: D1228H; D1228N; D1246H; D1246N; L1195V; L1213V; NGS; c-MET; cabozantinib; copy number calling; crizotinib; focal amplification; hybrid capture; osimertinib; resistance; sequential therapy.

Publication types

  • Case Reports

MeSH terms

  • Crizotinib / therapeutic use
  • Drug Resistance, Neoplasm / genetics
  • ErbB Receptors / genetics
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / pathology
  • Male
  • Middle Aged
  • Mutation
  • Protein Kinase Inhibitors / adverse effects
  • Proto-Oncogene Proteins c-met / genetics

Substances

  • cabozantinib
  • Crizotinib
  • ErbB Receptors
  • osimertinib
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-met

Grants and funding

This research received no external funding.