We have generated a series of next-generation ALK inhibitors with novel three-dimensional
macrocyclic structures and potent inhibition of wildtype and a large variety of mutated ALKs, including the solvent-front mutation, ALK G1202R, and the solvent-front/gatekeeper compound mutation, ALK G1202R/L1196M. We plan to select an ALK inhibitor candidate for IND-enabling studies in 2019.
In 2019, five FDA-approved ALK inhibitors are available to patients for the treatment of ALK+ NSCLC, yet all of these options are vulnerable to solvent-front mutations that lead to drug resistance. Sequential therapy with a next-generation ALK inhibitor effective against the common solvent-front mutations is a key development strategy.
Targeting Known Mechanisms of Resistance
ALK G1202R confers resistance to crizotinib and is also the most frequently occurring resistant mutation (approximately 50%) in patients treated with ceritinib, alectinib and brigatinib. In addition, compound mutations have been reported in patients after treatment with two or three ALK TKIs. One such example is the compound mutation ALK G1202R/L1196M, which confers resistance to currently approved therapies, including lorlatinib. Lorlatinib is the only approved ALK inhibitor that has demonstrated clinical efficacy in ALK+ NSCLC patients who developed the ALK G1202R mutation from a prior ALK TKI.