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Randomised controlled trials (RCTs) published up to 3 November 2021 were retrieved from PubMed, EMBASE, Cochrane Library and ClinicalTrials.gov.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Setting<\/jats:title>\n                    <jats:p>RCTs from any country and healthcare setting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Participants<\/jats:title>\n                    <jats:p>Patients with advanced ALK-positive NSCLC with or without brain metastases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interventions and comparisons<\/jats:title>\n                    <jats:p>\n                      The interventions were ALK-2\n                      <jats:sup>nd<\/jats:sup>\n                      G\/3\n                      <jats:sup>rd<\/jats:sup>\n                      G; the control arm was ALK-1\n                      <jats:sup>st<\/jats:sup>\n                      G or crizotinib.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Primary and secondary outcome measures<\/jats:title>\n                    <jats:p>Primary outcomes included median progression-free survival and median OS. Secondary outcomes included systemic objective response rate, intracranial response rate and rate of grade \u22653 adverse events (AEs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 12 RCTs involving 3156 patients were analysed. Compared with ALK-1\n                      <jats:sup>st<\/jats:sup>\n                      G (crizotinib), ALK-2\n                      <jats:sup>nd<\/jats:sup>\n                      G (alectinib, brigatinib, ceritinib and ensartinib) significantly improved the OS (HR: 0.72, 95%\u2009CI: 0.57 to 0.90, p=0.004) and intracranial response of patients with any brain metastases, especially with measurable (diameter \u226510\u2009mm) brain metastases. Network meta-analysis demonstrated that ALK-3\n                      <jats:sup>rd<\/jats:sup>\n                      G (lorlatinib) had superior efficacy for patients with brain lesions, but performed a distinct side-effect profile. Moreover, alectinib showed superior efficacy and lower toxicity in ALK-positive NSCLC.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Treatment with ALK-2\n                      <jats:sup>nd<\/jats:sup>\n                      G inhibitors significantly improved OS compared with crizotinib, and alectinib has less severe AEs than any other ALK inhibitors with moderate-high efficacy. The limited OS follow-up and inadequate sample sizes might contribute to having no statistically significant difference in OS of lorlatinib versus crizotinib. More high-quality and longer follow-up RCTs are warranted to prove our findings.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PROSPERO registration number<\/jats:title>\n                    <jats:p>CRD42021292245.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2022-060782","type":"journal-article","created":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T13:08:17Z","timestamp":1663592897000},"page":"e060782","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["ALK inhibitors in ALK-rearranged non-small cell lung cancer with and without brain metastases: systematic review and network meta-analysis"],"prefix":"10.1136","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5971-3174","authenticated-orcid":false,"given":"Jun","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Health 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