Newly diagnosed metastatic ALK+ NSCLC (ECOG 0–2)

Authored by Gilberto Lopes, published on 2026-04-17 07:50:21.0

As of 2025, NCCN and ASCO list alectinib, brigatinib, ensartinib, and lorlatinib as preferred first-line options for metastatic ALK+ NSCLC. ESMO living guidelines similarly support alectinib, brigatinib and lorlatinib (and ensartinib in some regions) as standard first-line ALK TKIs.Global 2025 consensus: Use a next-generation ALK TKI (alectinib, brigatinib, ensartinib, or lorlatinib) in all fit metastatic ALK+ patients, not crizotinib (unless it is the only available option).Main Clinical Trials Lorlatinib – CROWN 5-year data 5-year PFS still not reached, ~60% progression-free at 5 years vs 9.1 months PFS with crizotinib; best intracranial control seen with any TKI. Alectinib – ALEX & long-term follow-up Marked PFS and OS advantage vs crizotinib; mature 5-year OS showing durable benefit and excellent CNS activity. In most recent update PFS with alectinib improved by almost 2 years to 34.8 months with a favorable toxicity profile. Secondary endpoint: final overall survival (OS) analysis showed an encouraging median OS of 81.1 months versus 54.2 months in patients receiving alectinib versus crizotinib (hazard ratio 0.78, 95% confidence interval 0.56-1.08) with almost 50% versus 40% of the patients still alive after 7 years, respectively. Brigatinib & ensartinib – Both improve PFS vs crizotinib and have strong CNS penetration; all four TKIs hold NCCN category 1 preferred status in 2025. (but are less commonly used than alectinib and lorlatinib). Real-world and comparative data (ASCO/ESMO 2025). Large US claims and registry studies suggest broadly comparable OS for frontline alectinib, brigatinib and lorlatinib; all are superior to crizotinib; lorlatinib often shows numerically best CNS outcomes, but CNS AEs are also more pronounced. Non-Small Cell Lung Cancer, Version 4.2024, NCCN Clinical Practice Guidelines in Oncology