KIF5B-MET Gene Rearrangement with Robust Antitumor Activity in Response to Crizotinib in Lung Adenocarcinoma

A stage IV lung adenocarcinoma (LADC) (cT2N3M1b) with left axillary lymph node metastasis was diagnosed in a 51-year-old female never-smoker. The patient presented in November 2013 with a 1-month history of dry cough. There were no driver mutations with regard to EGFR mutation and echinoderm microtubule associated protein like 4 gene (EML4)–ALK receptor tyrosine kinase gene (ALK) rearrangement. Because we failed to detect other driver mutations (i.e., KRAS, ROS1, BRAF, or ret proto-oncogene gene [RET]) using basic screening tests for LADC, the patient was treated with bevacizumab plus pemetrexed and cisplatin followed by pemetrexed maintenance for 26 months. We performed targeted next-generation sequencing and found a fusion gene between exon 24 of the kinesin family 5B gene (KIF5B) and exon 14 of MNNG HOS Transforming gene (MET) (Fig. 1 and Supplementary Data 1). After we identified disease progression during pemetrexed maintenance, various salvage therapies, including cytotoxic chemotherapy (gemcitabine plus carboplatin), an immune checkpoint inhibitor (pembrolizumab), and a mesenchymal-epithelial transition factor (c-MET) inhibitor (SAIT301) were tried, but a poor response was exhibited. At that time, crizotinib was not allowed to use, we tried clinical trial, another c-MET inhibitor. Because we identified the KIF5B-MET fusion gene, the patient was treated in June 2016with crizotinib, which was originally developed as a c-MET inhibitor after various salvage therapies. The patient exhibited a dramatic response with a long duration (10 months) (Fig. 2), after which disease progression developed. Since then, various salvage therapies, including cytotoxic chemotherapy (gemcitabine plus carboplatin, docetaxel, and vinorelbine), an immune checkpoint inhibitor (pembrolizumab), and another c-MET inhibitor (SAIT301) were tried, but a poor response was exhibited.

MET fusions are rare in LADC, and this is the first documented case of a patient with a MET fusion–positive tumor that exhibited a significant and sustained antitumor response to treatment with the MET inhibitor crizotinib. We detected a fusion gene between exon 24 of KIF5B and exon 14 of MET showing robust antitumor activity in response to crizotinib in LADC. This fusion gene was originally reported in one out of 513 LADC samples. However, whether this fusion gene serves as oncogenic driver has not been fully evaluated. In our case, the dramatic tumor shrinkage and duration of response to crizotinib suggests that this fusion gene has oncogenic activity in LADC.

MET is a receptor tyrosine kinase activated by binding of its ligand hepatocyte growth factor. Activating mutations, gene amplification, and aberrant overexpression of MET have been found in subsets of NSCLC. MET gene amplification occurs in 2% to 4% of adenocarcinomas and 15% to 20% of EGFR mutation–positive NSCLC with acquired resistance to EGFR inhibitors.^,  Patients with high MET gene amplification show a high rate of response to the MET inhibitor crizotinib. Oncogenic mutations in MET exon 14 splice sites can cause exon 14 skipping and lead to impaired Casitas B-cell lymphoma family E3 ubiquitin ligase binding and decreased MET degradation, which accounts for 3% to 4% of lung adenocarcinomas. Clinical response to crizotinib or capmatinib has been reported previously in patients with MET exon 14 alterations.^, 

Given the robust antitumor activity of crizotinib in a patient with KIF5B-MET gene rearrangement in our case, a subset of NSCLC could be generated by a fusion of KIF5B and MET, and this gene may thus be a promising molecular target for personalized diagnosis and treatment of LADC. The case presented in this study highlights the fact that comprehensive next-generation sequencing tests could prove useful in detecting alternate therapeutic targets in patients without known driver mutations.