Current Management and the New Paradigm for ALK+ NSCLC After CROWN.

The 7-year update of the phase 3 CROWN study is the most impressive milestone in anaplastic lymphoma kinase (ALK)+ non-small-cell lung cancer (NSCLC) since the discovery of the oncogene 20 years ago and inaugurates an entire new paradigm. The progression-free survival (PFS) plateau at a high level > 50%, with an estimated very low annual progression rate < 2% after the third year, suggests that lorlatinib can inactivate the disease in most patients. The complete abrogation of on-target resistance abolishes ALK tyrosine kinase inhibitor (TKI) sequencing and will seriously impact future drug development. In the new era of extraordinary drug efficacy, the design of clinical trials, pathways of marketing authorization, and dosing optimization policies will also need to be reconsidered. Lorlatinib will dominate the therapeutic landscape of ALK+ NSCLC until the advent of combination therapies, which are the most reasonable next step. Further strengthening of the ALK blockade with additional ALK-directed drugs could likely eliminate the small residual "leak" of late off-target resistance after the third year, while combination with emerging neoantigen-directed immunotherapies may also help control the highly aggressive and more immunogenic early-progressing tumors and facilitate cure of the disease. Universal state-of-the-art DNA/RNA NGS for newly diagnosed NSCLC is now imperative to identify and treat all ALK+ patients according to the latest therapeutic advances, which will hopefully soon also spread to earlier stages and other oncogenic drivers.