Crotchety crizotinib.

Not too long ago alectinib was replacing crizotinib as the coolest ALK-targeted kid on the block. But now there’s an even younger tyrosine-kinase inhibitor (TKI) in town, and it touts double the blockade power. Lorlatinib is a third-generation TKI targeting both the ALK oncogene and the C-ros oncogene 1 (ROS1), and it’s built up major street cred for a purported ability to cross the blood-brain barrier. The second generation alectinib has excellent upfront efficacy in ALK-rearranged non-small cell lung cancer (NSCLC), but it inherited from its forefather crizotinib an Achilles heel of quick tumor resistance pathways. Pfizer is currently placing big bets on lorlatinib proving it can step in when the older versions fail, with initial clinical trial reporting this week in Lancet. Lorlatinib was put to the test in a phase 1 study of 54 patients with advanced NSCLC with ALK and/or ROS1 oncogene derangements. It was deemed to have both safety and activity, but we’ll wait for the phase 3 head-to-head comparison before we put crizotinib to bed (at 8 o’clock with a glass of milk).