MET D1228N

In addition, TPX-0022 exhibited potent activity against the resistance-relevant c-Met L1195F mutant and moderate activity against the c-Met G1163R, F1200I and Y1230H mutants but weak activity against the c-Met D1228N and Y1230C mutants. Overall, our study reveals the structural mechanism underlying the potency and selectivity of TPX-0022 and the ability to overcome acquire resistance mutations and provides insight into the development of selective c-Met macrocyclic inhibitors.

Most pts (84%, 20/24) received a prior MET TKI (crizotinib, n=15; capmatinib, n=4; tepotinib, n=1); 16 pts (67%) and 13 pts (54%) received one or more prior lines of chemotherapy and immunotherapy, respectively...Due to its alternative type II binding mode, cabozantinib can be useful in the treatment of type I TKI resistance. As proof of concept, 3 of 4 responses were observed in patients with type I MET TKI progression.

MET fusions occur in a rare subset of patients with NSCLC and represent a promising therapeutic target. MET secondary mutations D1228H/N or D1246N present the potential resistance mechanisms of MET inhibitors in patients with de novo MET fusions.

"CONCLUSION Activating MET TKD mutations without concurrent MET exon 14 mutations were detected in ~ 0.2% of NSCLC, and occur in the absence of other known drivers in a subset of cases. Comprehensive genomic profiling to detect these alterations and guide treatment selection and clinical trial enrollment is warranted."

MET TKD mutations were identified in both baseline and patients treated with TKIs. MET-H1094Y might play an oncogenic role in NSCLC and may confer acquired resistance to EGFR-TKIs. Preliminary data indicates that EGFR-mutated NSCLC patients who acquired MET-V1092I or MET-H1094Y may benefit from combinatorial therapy with EGFR-TKI and MET-TKI, providing insights into personalized medical treatment.

We demonstrated that MET exon 14 skipping alterations and MET amplification are not mutually exclusive to other oncogenic co-mutations, and report the association of genomic MET alterations with PD-L1 expression. Since genomic MET alterations are emerging targets requiring upfront treatment, optimal understanding of the co-mutational landscape for this patient population is needed.

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Besides acquired resistance mutations, bypass mechanisms of resistance to EGFR-TKI treatment are common in patients with EGFR-mutations. Here we describe a patient with metastatic lung adenocarcinoma with CD74-ROS1 fusion who initially responded to crizotinib and then developed resistance by the acquired mutation of D1228N in the MET kinase domain, which showed short-term disease control for cabozantinib.