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

Abstract

Background: 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. Methods: We performed fluorescence in-situ hybridization and/or next-generation sequencing on 207 post-treatment 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 two 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 re-sensitized 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 select for MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET.

The METeoric rise of MET in lung cancer

“…In patients with NSCLC with ALK rearrangements, MET amplifications were detected in approximately 12% of patients who developed resistance to second‐generation inhibitors and 22% of those who experienced disease progression while receiving lorlatinib. Early results of targeting MET in this context are promising 48 …”

Detecting Resistance to Therapeutic ALK Inhibitors in Tumor Tissue and Liquid Biopsy Markers: An Update to a Clinical Routine Practice

“…Moreover, no significant differences in PFS were observed between patients with primary or acquired MET amplifications. Amplification in MET , and more rarely rearrangement in MET , emerge during treatment with ALK TKI [ 78 , 79 ]. So, about 15% of patients treated with new generation inhibitors develop MET amplifications [ 78 ].…”

“…Amplification in MET , and more rarely rearrangement in MET , emerge during treatment with ALK TKI [ 78 , 79 ]. So, about 15% of patients treated with new generation inhibitors develop MET amplifications [ 78 ]. Moreover, in the study by Dagogo-Jack et al, around 12 and 22% of tissue biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively showed a MET amplification [ 78 ].…”

“…So, about 15% of patients treated with new generation inhibitors develop MET amplifications [ 78 ]. Moreover, in the study by Dagogo-Jack et al, around 12 and 22% of tissue biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively showed a MET amplification [ 78 ]. In the same study lung cancer patients treated with a second-generation ALK inhibitor in a first-line setting were more likely to develop a MET amplification than those who had received next-generation ALK inhibitors after crizotinib.…”

Overcoming MET-Dependent Resistance to Selective RET Inhibition in Patients with RET Fusion–Positive Lung Cancer by Combining Selpercatinib with Crizotinib

“…Mechanisms of acquired resistance to treatment with selective RET inhibitors are not well understood. While a secondary mutation in the RET kinase domain has recently been reported 11 , activation of bypass tracts, such as MET amplification, also represent a recurring mechanism of resistance to driver genotypes in NSCLC 12,13 . Here we piloted combination therapy to target MET amplification detected in four RET-positive NSCLC patients (of a total 79 patients with NSCLC enrolled at all three sites) with resistance to selpercatinib.…”