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Clinical Trial
. 2024 Nov;25(7):634-642.
doi: 10.1016/j.cllc.2024.08.003. Epub 2024 Aug 13.

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

Christine Garcia  1 , Devin Abrahami  2 , Anna Polli  3 , Haitao Chu  4 , Conor Chandler  5 , Min Tan  6 , John Mark Kelton  7 , Despina Thomaidou  8 , Todd Bauer  9
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Free article
Clinical Trial

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

Christine Garcia et al. Clin Lung Cancer. 2024 Nov.
Free article

Abstract

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.

Keywords: Grade ≥3 adverse events; Indirect treatment comparison; Next-generation ALK TKI; Nonsmall cell lung cancer; Progression-free survival.

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Conflict of interest statement

Disclosure Devin Abrahami, Anna Polli, Haitao Chu, and Despina Thomaidou are employees of Pfizer and have stock ownership in Pfizer. John Mark Kelton was employed by Pfizer during the conduct of this study, and has stock ownership in Pfizer, Abbott and AbbVie. Christine Garcia receives consulting fees from Pfizer. Todd Bauer receives consulting fees from and is an ad board member of Pfizer, Bayer, and Lilly. Conor Chandler and Min Tan are employees of Evidera, which received financial support from Pfizer in connection with the study and the development of this manuscript.

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