LUNG CANCER: In tumours harbouring ALK fusions, MET amplification (detected by FISH or DNA/ctDNA analysis) was identified as potential mechanism of resistance to targeted therapy in 15% of cases

Kevin Sovet

June 17, 2020

SCIENTIFIC

LUNG CANCER

In tumours harbouring ALK fusions, MET amplification (detected by FISH or DNA/ctDNA analysis) was identified as potential mechanism of resistance to targeted therapy in 15% of cases

 

MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer

DOI: 10.1158/1078-0432.CCR-19-3906

Abstract

Purpose

Most ALK-positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. MET amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed.

 

Experimental Design

We performed FISH and/or next-generation sequencing on 207 posttreatment tissue (n = 101) or plasma (n = 106) specimens from patients with ALK-positive lung cancer to detect MET genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with MET alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 patients with MET-driven resistance.

 

RESULTS

MET amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation ALK inhibitor in the first-line setting were more likely to develop MET amplification than those who had received next-generation ALK inhibitors after crizotinib (P = 0.019). Two tumor specimens harbored an identical ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition resensitized a patient-derived cell line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET alterations achieved rapid responses to ALK/MET combination therapy.

 

CONCLUSIONS

Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET.

more info: https://clincancerres.aacrjournals.org/content/26/11/2535