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Short Report
15 December 2025

Long-term efficacy and safety of lorlatinib versus alectinib in anaplastic lymphoma kinase-positive advanced/metastatic non-small cell lung cancer: matching-adjusted indirect comparison

Authors: Todd Bauer [email protected], Devin Abrahami, Anna Polli, Haitao Chu, Priya Ramachandran, Conor Chandler, Min Tan, James Truscott, Julien Mazieres, and Christine A GarciaAuthor Info & Affiliations
Volume 15, Number 1
https://doi.org/10.57264/cer-2025-0117
PDFFormats

Abstract

Aim: Lorlatinib demonstrated superior efficacy over alectinib as a first-line treatment for ALK-positive (ALK+) advanced/metastatic non-small cell lung cancer in a matching-adjusted indirect comparison (MAIC) using 3-year follow-up data from CROWN (lorlatinib). This study aimed to update these findings using the latest extended 5-year follow-up data from CROWN. Materials & methods: We conducted an anchored MAIC using data from CROWN and ALEX (alectinib). Patients were matched based on prespecified effect modifiers. We compared progression-free survival (PFS) using hazard ratios (HRs), restricted mean survival time and PFS probabilities and adverse events (AEs) using rate ratios and rate differences. PFS was analyzed in subgroups with and without baseline brain/CNS metastases. Results: Lorlatinib demonstrated superior PFS over alectinib, reducing the risk of progression or death by 45% (HR: 0.55, 95% CI: 0.34, 0.88). Lorlatinib extended restricted mean survival time by 8.5 months up to 4 years and 11.2 months up to 5.5 years, with generally higher annual PFS probabilities across years 1–5. While lorlatinib was associated with a higher incidence of grade ≥3 AEs, the rates of AEs leading to treatment discontinuation, dose interruption and dose reduction were similar between the treatments. In patients with baseline brain/CNS metastases, lorlatinib showed a numerical PFS benefit, with significant improvement at year 1. In patients without brain/CNS metastases, lorlatinib significantly improved PFS, with significant increases at years 2–4. Conclusion: This extended analysis reaffirms lorlatinib’s superior efficacy over alectinib in prolonging PFS. Despite the higher grade ≥3 AE incidence, similar rates of dose reduction, interruption, or discontinuation suggest these AEs are manageable. Lorlatinib remains a first-line treatment option for ALK+ metastatic non-small cell lung cancer, offering meaningful benefits to appropriate patients.

Plain language summary: Long-term efficacy & safety of lorlatinib versus alectinib in anaplastic lymphoma kinase-positive advanced/metastatic non-small cell lung cancer: matching-adjusted indirect comparison

What is already known about this subject?

Lorlatinib and alectinib are both recommended first-line treatment options for anaplastic lymphoma kinase (ALK+) metastatic non-small cell lung cancer. In the absence of a head-to-head randomized clinical trial directly comparing the efficacy and safety of these two treatments, indirect treatment comparisons, such as matching-adjusted indirect comparisons (MAIC), can help inform healthcare decision-making.
In a previous MAIC using 3-year follow-up data from the CROWN trial, lorlatinib outperformed alectinib in progression-free survival (PFS) for ALK+ metastatic non-small cell lung cancer.

What are the new findings?

Our updated MAIC based on extended follow-up data from the CROWN trial confirms lorlatinib’s PFS superiority over alectinib, showing a 45% reduction in the risk of progression or death.
Lorlatinib extended the restricted mean survival time by up to 11.2 months and maintained higher annual PFS probabilities over 5 years.
Lorlatinib significantly improved PFS in patients without baseline brain/CNS metastases and showed a numerical PFS benefit in those with baseline brain/CNS metastases, with significant improvement at year 1.
While lorlatinib had a higher incidence of grade ≥3 adverse events (AEs), rates of AEs leading to dose reduction, interruption or discontinuation were similar to alectinib.

How might it impact clinical practice in the foreseeable future?

The updated findings support lorlatinib as an effective first-line treatment option for ALK+ advanced/metastatic NSCLC, offering significant improvements in PFS and manageable AEs compared with alectinib.

Supplementary Material

File (supplementary materials.docx)

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