Uncommon MET mutational landscape in a non-small cell lung cancer patient treated with crizotinib: Case report

TL;DR

A rare MET mutation in a lung cancer patient responded briefly to crizotinib but developed resistance through new genetic changes.

Contribution

Reports a novel MET R1022L mutation and identifies resistance mechanisms like MET D1246H and KRAS amplification in NSCLC.

Findings

The patient had a novel METex14 mutation (R1022L) with initial response to crizotinib.

Resistance emerged via MET D1246H and wild-type KRAS amplification.

Systematic analysis of tumor samples is critical for identifying resistance mechanisms.

Abstract

MET exon 14 (METex14) skipping mutations are oncogenic drivers observed in approximately 3–4% of non-small cell lung cancers (NSCLC). Several distinct genetic alterations leading to METex14 have been reported but clinical significances of rare mutations are not well defined as well as outcomes of patients upon MET inhibitors (METi).

This report presents the case of a patient with metastatic NSCLC harboring an uncommon MET mutational landscape including notably a novel METex14 mutation (R1022L). Dramatic but transient efficacy was observed under crizotinib, due to early occurrence of acquired both on- and off-target mechanisms of resistance such as MET D1246H mutation and wild-type KRAS amplification.

Our case provides additional data on MET rare oncogenic variants and their sensitivity to METi. Systematic assessment of post-tyrosine kinase inhibitor tumor sample remains critical to identify on- and off-target mechanisms that may represent therapeutically targetable drivers in resistant patients.

•Resistance to MET inhibitors inevitably occurs in MET exon 14-dependent NSCLC.•Acquired on and off-target resistance mechanisms are not fully elucidated.•Data on MET rare oncogenic variants are lacking, especially their sensitivity to MET inhibitors.•Additional data on R1022L MET new variant are provided in this report.•D1246H second-site mutation and wild-type KRAS amplification emerged as resistance mechanisms to crizotinib.

Resistance to MET inhibitors inevitably occurs in MET exon 14-dependent NSCLC.

Acquired on and off-target resistance mechanisms are not fully elucidated.

Data on MET rare oncogenic variants are lacking, especially their sensitivity to MET inhibitors.

Additional data on R1022L MET new variant are provided in this report.

D1246H second-site mutation and wild-type KRAS amplification emerged as resistance mechanisms to crizotinib.

Figures