•Crizotinib is active as second-line therapy against MET-mediated resistance to alectinib in anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer and can be used in combination. •Repeat molecular analyses including assessment of MET amplification can help guide therapy in ALK-positive non–small-cell lung cancer. •Crizotinib is active as second-line therapy against MET-mediated resistance to alectinib in anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer and can be used in combination. •Repeat molecular analyses including assessment of MET amplification can help guide therapy in ALK-positive non–small-cell lung cancer.