Patients with ALK-positive advanced NSCLC, who received crizotinib or alectinib treatment in first line, were retrospectively reviewed....Clinical outcomes have been comprehensively analyzed between TKIs, ALK fusions, EML4-ALK variants, and next-generation TKIs after crizotinib failure....Patients in EML4 group had a better prognosis than those in non-EML4 group after alectinib administration (HR 0.13, 95% CI: 0.03–0.60, p = 0.009)....Our results revealed alectinib had better PFS and higher intracranial efficacy compared to crizotinib in ALK-positive NSCLC, and might improve PFS by comparison with ceritinib and brigatinib after crizotinib failure.