Overcoming Acquired Resistance Mutation MET D1228N to Crizotinib With Cabozantinib in NSCLC With MET Exon 14 Skipping Mutation

Abstract

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Non-small-cell lung cancer: how to manage MET exon 14 skipping mutant disease

“…60 Given the differential binding properties of type I and type II MET TKIs, resistance by acquired point mutations in the tyrosine kinase domain can be potentially overcome by switching to a different type of MET TKI. This strategy has been reported in several case reports, with patients achieving both stable disease and partial responses when switching from type Ib to type II inhibitors, such as cabozantinib or merestinib, in the setting of acquired MET mutations [59][60][61] and a partial response in a patient switching from a type II to a type Ia inhibitor in the setting of an acquired MET mutant-exon 14 allele amplification. 59 Given the biological rationale for this approach, there is an unmet need to conduct clinical trials that can shed a light on the optimal therapeutic sequencing strategy tailored according to resistance mechanisms.…”

Targeting MET in NSCLC: An Ever-Expanding Territory

“… 79 In our study, one patient exhibited responsiveness to savolitinib after exhibiting resistance to ensartinib. 61 In addition, cabozantinib reportedly can overcome crizotinib-induced resistance to the MET D1228N mutation, 80 and a patient with acquired MET Y1230C achieved PR with merestinib therapy after exhibiting resistance to crizotinib. 76 Moreover, preclinical studies have revealed that glesatinib and foretinib can overcome resistance induced by mutations of D1228N and Y1230C/H.…”

From osimertinib to preemptive combinations

“…Resistance mutations against type I MET inhibitors are sensitive to type II inhibitors, and vice versa [22][23][24][25][26]. In patients with METex14 NSCLC, cabozantinib can overcome resistance selected by type I MET inhibitors [27][28][29]. Furthermore, cabozantinib is effective in METex14-positive NSCLC with brain metastases [30].…”