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.

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.