Recondo et al. reported a patient harboring MET exon 14 skipping who experienced PD on crizotinib, and a resistance MET mutation of Y1230C was detected both in plasma and tumor tissue at the time of progression. This patient had a PR after switched to merestinib.55 These results supported that merestinib may provide a therapeutic option to patients with METex14. The first-in-human phase I study was to evaluate the safety and tolerability of merestinib including three types of tumor without NSCLC. Overall, 60 (32%) of the 186 patients enrolled in the study had a best response of SD, and recommended a dosing of merestinib at 120 mg once daily based on acceptable exposure and safety.56 A phase II study conducted by Awad et al. was to evaluate the safety and efficacy of merestinib in patients with advanced METex14 NSCLC or patients with advanced cancer with NTRK rearrangements (NCT02920996).54
Glesatinib Glesatinib (MGCD265; Mirati Therapeutics) is another orally bioavailable, type II, multi-targeted inhibitor with potential anti-tumor activity. Glesatinib binds to and inhibits the phosphorylation of several RTKs, including the MET receptor, the TEK/TIE-2 receptor, RON, SMO, and VEGFR types 1, 2, and 3. Preclinical studies showed that glesatinib resulted in a dose-dependent inhibition of cancer cell growth with an IC50 value of 80 nM on NSCLC H1299 cells.57 A patient with METex14 NSCLC showed response to glesatinib after relapsing to crizotinib, including a reduction in size of a MET Y1230H mutation-positive liver metastases and concurrent loss of detection of this mutation in plasma DNA. |
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