First-line ALK inhibitors in treatment-naive advanced ALK rearranged non-small cell lung cancer: systematic review and network meta-analysis

Background: With multiple next-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) demonstrating improved outcomes in phase III randomized controlled trials (RCTs) against chemotherapy or crizotinib, there is an expanding list of first-line options. In the absence of head-to-head comparisons between next-generation ALK TKIs, we conducted a network meta-analysis (NMA) to compare the relative efficacy and toxicity of different ALK TKIs in treatment-naïve patients with ALK rearranged advanced non-small cell lung cancer (NSCLC). Methods: A systematic review and NMA of published phase III RCTs in MEDLINE evaluating an ALK TKI in treatment-naive patients with ALK rearranged advanced NSCLC. Outcomes of interest were progression-free survival (PFS) by independent review criteria (IRC), PFS by investigator assessment (IA), overall survival (OS), PFS by IRC for patients both with and without baseline brain metastases, objective response rate (ORR), intracranial response rate and toxicities. The surface under the cumulative ranking curve (SUCRA) was used to determine the overall ranking of each treatment. Risk of bias was assessed using Cochrane Collaboration’s tool. Results: Nine RCTs were identified as eligible and included in the final analysis, evaluating crizotinib (PROFILE 1014, PROFILE 1029), alectinib (ALEX, ALESIA, J-ALEX), brigatinib (ALTA-1L), ceritinib (ASCEND-4), ensartinib (eXalt3) and lorlatinib (CROWN). Overall trials were assessed to be at low risk of bias. For IRC PFS, ALK TKIs were found to be superior to chemotherapy. Lorlatinib showed IRC PFS benefit compared with all other ALK TKIs, which was reflected by the highest SUCRA of 99%. Lorlatinib compared to alectinib, brigatinib and ensartinib demonstrated NMA IRC PFS HR [95% credible interval (CrI)] of 0.63 (0.40–0.99), 0.54 (0.32–0.91) and 0.60 (0.35–1.03) respectively. Lorlatinib had the highest SUCRA for ORR (90%), and IRC PFS in patients with (97%) and without (95%) baseline brain metastases. Alectinib (92%) followed by lorlatinib (71%) had the highest SUCRA for OS outcomes. Conclusions: In this NMA, lorlatinib had the greatest PFS benefit compared with other ALK TKIs. Alectinib was superior in regards to OS, although immature OS outcomes may be a confounding factor. In real-world clinical practice however, numerous additional clinical considerations may also influence the selection of upfront ALK TKI.