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

Abstract

Most <i>ALK</i>-positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. <i>MET</i> amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed. We performed FISH and/or next-generation sequencing on 207 posttreatment tissue (<i>n</i> = 101) or plasma (<i>n</i> = 106) specimens from patients with ALK-positive lung cancer to detect <i>MET</i> genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with <i>MET</i> alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 patients with MET-driven resistance. <i>MET</i> 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 <i>MET</i> amplification than those who had received next-generation ALK inhibitors after crizotinib (<i>P</i> = 0.019). Two tumor specimens harbored an identical <i>ST7-MET</i> rearrangement, one of which had concurrent <i>MET</i> amplification. Expressing <i>ST7-MET</i> 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 <i>ST7-MET</i> and <i>MET</i> amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired <i>MET</i> alterations achieved rapid responses to ALK/MET combination therapy. Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired <i>MET</i> alterations may derive clinical benefit from therapies that target both ALK and MET.