In a study published online in The New England Journal of Medicine, Alice T. Shaw and coauthors presented the results of CROWN, a phase III trial evaluating the third-generation tyrosine kinase inhibitor (TKI) lorlatinib in patients with advanced non–small cell lung cancer (NSCLC) harboring an ALK translocation.  ALK translocation and mutations occur in 2% to 7% of NSCLC, mostly adenocarcinoma. Several first-generation (crizotinib) and second-generation ALK TKIs (ceritinib, alectinib, brigatinib, ensartinib) have been developed and approved since 2011. ALK TKIs have been practice-changing and are now the standard first-line treatment of ALK-positive NSCLC as recommended in guidelines.

Multiple ALK TKIs are available for upfront treatment, and second-generation ALK TKIs have shown improved results when compared with crizotinib in randomized trials; chronologically, these include alectinib, brigatinib, ensartinib, and, this month, lorlatinib as a third-generation ALK TKI. With the exceptions of crizotinib and ceritinib compared with platinum-based chemotherapy, the most recent second- and third-generation ALK TKIs were challenging crizotinib as the standard treatment.

Population characteristics in all these trials were very similar: mostly ALK-positive adenocarcinoma, previously untreated for advanced disease in most of the trials except for brigatinib (ALTA-L1; 27% pretreated) and lorlatinib (CROWN; 7% pretreated), brain metastasis were allowed, with an incidence ranging from 26% to 40% depending on the trials. Progression-free survival (PFS) was always the primary endpoint.

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