Better fourth-generation drugs than lorlatinib/lorlatinib

Lorlatinib/lorlatinib (Lorlatinib) is known as an effective third-generation ALK inhibitor. It has successfully overcome the resistance of first- and second-generation ALK inhibitors, especially the resistance caused by the G1202R mutation, and has also demonstrated excellent results in the treatment of brain metastases. Among patients who had previously received two or more ALK inhibitor treatments, the clinical response rate of lorlatinib was as high as 39%, and the median progression-free survival (PFS) reached 6.9 months.

Although the new generation of ALK tyrosine kinase inhibitors (TKIs) represented by lorlatinib has significantly improved kinase selectivity and anti-drug resistance, treatment resistance still inevitably emerges after long-term use. Recent studies have shown that approximately 35% of the mechanisms of resistance to lorlatinib can be attributed to compound mutations. Of the 14 compound mutations studied, 6 conferred de novo sensitivity to first- or second-generation ALK TKI inhibitors.

To address this challenge, Turning Point Therapeutics recently developed TPX-0131 (also known as zotizalkib) and repotrectinib (TPX-0005). Both drugs are small and compact macrocyclic compounds with lower molecular weights than the currently FDA-approved ALK TKIs. They are classified as fourth-generation ALK TKIs due to their high efficacy in inhibiting multiple resistance mutations generated by lorlatinib.

It is worth noting that although the fourth-generation drugsTPX-0131 and repotrectinib have shown clinical potential against lorlatinib resistance, so far, there has been no in-depth study to explore in detail the specific impact of mutations such as F1174C/L/V on the combination of these new-generation drugs with lorlatinib. Research in this area will contribute to a deeper understanding of resistance mechanisms and provide important guidance for future drug design and treatment options.