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Simple Summary  The prognosis of non-small cell lung cancer (NSCLC) is poor as more than half of the patients are diagnosed at an advanced stage. The outcomes have greatly improved in the recent two decades due to the introduction of target therapy. Anaplastic lymphoma kinase (ALK) rearrangement is the second most common driver mutation found in lung cancer, and several ALK inhibitors have shown excellent efficacy. However, head-to-head randomized controlled trials of these agents are lacking. We conducted this systematic review and network meta-analysis to indirectly compare the currently available ALK inhibitors. In summary, lorlatinib had the highest probability of the best progression-free survival in first-line treatment of ALK-positive NSCLC, followed by low-dose (300 mg twice daily) alectinib, high-dose (600 mg twice daily) alectinib, brigatinib, ensartinib, and ceritinib. Lorlatinib was associated with the best objective response rate and the highest probability of grade 3–5 adverse effects. Low-dose alectinib had the best safety profile.    Abstract  Several anaplastic lymphoma kinase inhibitors (ALKIs) have demonstrated excellent efficacy on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and also better adverse effect (AE) profiles compared to cytotoxic chemotherapy in advanced stage anaplastic lymphoma kinase (ALK) rearrangement-positive non-small cell lung cancer (NSCLC) in phase III randomized clinical trials (RCTs). We conducted this systematic review and network meta-analysis to provide a ranking of ALKIs for treatment-naïve ALK-positive patients in terms of PFS, ORR, and AEs. In addition, a sub-group analysis of treatment benefits in patients with baseline brain metastasis was also conducted. Contrast-based analysis was performed for multiple treatment comparisons with the restricted maximum likelihood approach. Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being the best (Prbest) reference. All next-generation ALKIs were superior to crizotinib in PFS but lorlatinib and brigatinib had increased AEs. The probability of lorlatinib being ranked first among all treatment arms was highest (SUCRA = 93.3%, Prbest = 71.8%), although there were no significant differences in pairwise comparisons with high- (600 mg twice daily) and low- (300 mg twice daily) dose alectinib. In subgroup analysis of patients with baseline brain metastasis, low-dose alectinib had the best PFS (SUCRA = 87.3%, Prbest = 74.9%). Lorlatinib was associated with the best ranking for ORR (SUCRA = 90.3%, Prbest = 71.3%), although there were no significant differences in pairwise comparisons with the other ALKIs. In addition, low-dose alectinib had the best safety performance (SUCRA = 99.4%, Prbest = 97.9%). Lorlatinib and low-dose alectinib had the best PFS and ORR in the overall population and baseline brain metastasis subgroup, respectively. Low-dose alectinib had the lowest AE risk among the available ALKIs. Further head-to-head large-scale phase III RCTs are needed to verify our conclusions.

Systematic Review and Network Meta-Analysis of Anaplastic Lymphoma Kinase (ALK) Inhibitors for Treatment-Naïve ALK-Positive Lung Cancer