Comparative Efficacy and Safety of Lorlatinib Versus Alectinib and Lorlatinib Versus Brigatinib for ALK-Positive Advanced/Metastatic NSCLC: Matching-Adjusted Indirect Comparisons

Several treatments are available for ALK+ advanced/metastatic nonsmall cell lung cancer but have not been studied head-to-head. Lorlatinib was compared with alectinib and brigatinib using matching-adjusted indirect comparisons and was estimated to have superior efficacy (progression-free survival), but higher rates of Grade > 3 adverse events than alectinib. These findings indicate that lorlatinib should be considered a treatment for this indication. Introduction: The comparative efficacy and safety of lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), versus second-generation ALK TKIs as a first-line treatment for ALK+ advanced/metastatic nonsmall cell lung cancer (NSCLC) remains uncertain as there are no head-to-head clinical trials. Methods: Matching-adjusted indirect comparisons (MAICs) were conducted using phase III trial data demonstrating superior efficacy over crizotinib, a first-generation ALK TKI. MAICs were conducted to compare lorlatinib (CROWN) versus alectinib (ALEX and ALESIA) and brigatinib (ALTA-1L) with matching based on prespecified effect modifiers. Efficacy outcomes included progression-free survival (PFS), objective response (OR), and time to progression in the central nervous system (TTP-CNS). Safety outcomes included Grade >3 adverse events (AEs) and AEs leading to treatment discontinuation, dose reduction, or dose interruption. Results: Lorlatinib was estimated to improve PFS compared to alectinib (ALEX) (HR: 0.54 [95% CI: 0.33, 0.88]) and brigatinib (ALTA-1L) (HR: 0.51 [95% CI: 0.31, 0.82]). Lorlatinib was estimated to improve TTP-CNS compared with brigatinib (HR: 0.19 [95% CI: 0.05, 0.71]). The estimated Grade >3 AE rate was higher with lorlatinib than with alectinib (RR: 1.48 [95% CI: 1.13, 1.94]); however, no differences were observed in other safety endpoints (ie, AEs leading to discontinuation, dose reduction, or interruption) or compared to brigatinib. Conclusion: Lorlatinib was estimated to have superior efficacy over first- and second-generation ALK-TKIs, but a higher rate of Grade >3 AEs compared to alectinib. These data support the use of lorlatinib as a first-line treatment for ALK+ advanced/metastatic NSCLC.