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.