Acquired Resistance Mechanism for MET Tyrosine Kinase Inhibitor

To the Editor:

We read with great interest the article entitled “Acquired resistance to osimertinib plus savolitinib is mediated by MET D1228 and Y1230 mutations in EGFR-mutated, MET-amplified lung cancer” by Piper-Vallillo et al.¹ recently published in JTO Clinical and Research Reports. In this article, the authors postulated that MET D1228N/Y/H and Y1230C secondary mutations could be the mechanisms of acquired resistance to type I MET inhibitor, savolitinib, along with EGFR tyrosine kinase inhibitor (TKI) treatment. There are two types of MET TKI, which are as follows: type I (e.g., capmatinib, tepotinib, and savolitinib) that binds to an active form of MET and type II (e.g., cabozantinib, merestinib, and glesatinib) that binds to an inactive form of MET. We previously reported that MET D1228 and Y1230 are the hotspots for the secondary resistant mutation for type I MET TKIs for NSCLC carrying MET exon 14 skipping mutation using in vitro models.² Concentrations that inhibit 50% (IC₅₀s) of most of the type I TKI to D1228X and D1230X were more than several 100 folds of that of the wild-type MET. Piper-Vallillo et al.¹ noted that this was also true for the combination therapy of type I MET TKI and EGFR TKI for EGFR-mutated, MET-amplified NSCLC. We also reported that switching from type I to type II MET TKI may be effective to overcome MET D1228 and Y1230 mutations.² However, Piper-Vallillo et al.¹ also reported that the treatment with a type II MET inhibitor, cabozantinib, could only eliminate Y1230C, whereas D1228N/Y/H mutant alleles remained. Similarly, in earlier reports on the sequential treatment of type I to type II MET TKI for patients with MET-driven NSCLC on resistance from D1228X and Y1230X,3, 4, 5 biopsies at the time of disease progression were found to carry D1228X. Altogether, these facts indicate that D1228X is more resistant than Y1230X to the currently available type II inhibitors. Indeed, the analysis of our in vitro data suggested that the IC₅₀s of cabozantinib to D1228Y, merestinib to D1228Y, or glesatinib to D1228A was 78-fold, 18-fold, or 10-fold of the corresponding IC₅₀s to wild-type MET, respectively, whereas the IC₅₀s for any Y1230X was a maximum of threefold increase.² Because the clinical development of type I MET TKIs preceded that of type II TKIs for MET-driven lung cancer, we will often witness the proclamation of MET D1228X and Y1230X as resistance mechanisms in the near future. Hence, the establishment of an effective treatment against D1228X is urgently awaited.