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

• Published in: Clinical cancer research 2020-06, Vol.26 (11), p.2535-2545
• Main Authors: Dagogo-Jack, Ibiayi, Yoda, Satoshi, Lennerz, Jochen K, Langenbucher, Adam, Lin, Jessica J, Rooney, Marguerite M, Prutisto-Chang, Kylie, Oh, Audris, Adams, Nathaniel A, Yeap, Beow Y, Chin, Emily, Do, Andrew, Marble, Hetal D, Stevens, Sara E, Digumarthy, Subba R, Saxena, Ashish, Nagy, Rebecca J, Benes, Cyril H, Azzoli, Christopher G, Lawrence, Michael S, Gainor, Justin F, Shaw, Alice T, Hata, Aaron N
• Format: Article
• Language: English
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-19-3906

Most -positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. 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 ( = 101) or plasma ( = 106) specimens from patients with ALK-positive lung cancer to detect genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 patients with MET-driven resistance. 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 amplification than those who had received next-generation ALK inhibitors after crizotinib ( = 0.019). Two tumor specimens harbored an identical rearrangement, one of which had concurrent amplification. Expressing 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 and amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired 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 alterations may derive clinical benefit from therapies that target both ALK and MET.