First-line lorlatinib for advanced ALK-positive non-small-cell lung cancer

The treatment framework for advanced non-small-cell lung cancer harbouring anaplastic lymphoma kinase (ALK) fusions has changed substantially since the discovery of crizotinib, a first-generation ALK tyrosine-kinase inhibitor (TKI). Three generations of ALK TKIs have since been developed, with increasing potency, CNS penetrance, and ability to overcome ALK-resistance mutations with each successive generation. 1 Cooper AJ Sequist LV Lin JJ Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management. Nat Rev Clin Oncol. 2022; 19: 499-514 Crossref PubMed Scopus (48) Google Scholar Multiple phase 3 trials have shown superior efficacy of second-generation ALK TKIs (alectinib, brigatinib, and ensartinib) compared with crizotinib, establishing next-generation ALK TKIs as preferred initial therapy. 1 Cooper AJ Sequist LV Lin JJ Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management. Nat Rev Clin Oncol. 2022; 19: 499-514 Crossref PubMed Scopus (48) Google Scholar More recently, interim analysis of the phase 3 trial CROWN showed favourable efficacy of first-line lorlatinib, a third-generation ALK TKI, compared with crizotinib. 2 Shaw AT Bauer TM de Marinis F et al. First-Line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020; 383: 2018-2029 Crossref PubMed Scopus (419) Google Scholar With this rich therapeutic landscape, clinicians now face the key question of which next-generation ALK TKI to select. Efficacy and safety of first-line lorlatinib versus crizotinib in patients with advanced, ALK-positive non-small-cell lung cancer: updated analysis of data from the phase 3, randomised, open-label CROWN studyThese updated, long-term data from CROWN show the durable benefit of lorlatinib over crizotinib in patients with treatment-naive, ALK-positive non-small-cell lung cancer and support the use of first-line lorlatinib in patients with and without baseline brain metastases. Full-Text PDF