MET is an important primary oncogenic driver gene in non-small cell lung cancer (NSCLC). The most common MET aberrations are gene amplifications and exon 14 splice variants. MET fusion is a rare type of structural rearrangement; nine MET fusion partner genes have been identified, namely: PRKAR2B (1), KIF5B (2–4), STARD3NL (5), CDR2 (6), UBE2H (7), HLA-DRB1 (8), ATXN7L1 (9), CD47 (10), and SPECC1L (11). To date, eight cases of KIF5B-MET gene fusion have been reported in the literature, of which only a few have described the efficacy of crizotinib (Table 1). Continued reporting of these cases is necessary to inform clinical practice. Herein, we present the case of a patient who presented with neck pain and limb myasthenia persisting for more than 6 months. She was diagnosed with advanced lung adenocarcinoma with KIF5B-MET fusion and achieved partial response to crizotinib for 4 months. In addition, we identified a secondary MET mutation (MET Y1230H) after disease progression during crizotinib therapy. To the best of our knowledge, this is the first clinical report of a MET Y1230H mutation arising in a patient with KIF5B-MET fusion.

In May 2020, a 59-year-old woman who had never smoked presented to our hospital with neck pain and limb myasthenia persisting for more than 6 months. Her medical history was unremarkable. However, computed tomography and magnetic resonance imaging revealed a tumor in the lower lobe of her right lung with pleural effusion (Figure A1) and multi-organ metastasis, including the brain (Figure B1), vertebrae, and bone. Histopathological analysis of tissue biopsy samples obtained from the lower lobe of the right lung using bronchoscopy revealed poorly differentiated adenocarcinoma; the immunohistochemistry results were as follows: napsin A(-), TTF-1(-), CK5/6(-), P40(-), CgA(-), Syn(-), CK7(+), and Ki67(70%+). Next-generation sequencing of the lung biopsy tissue showed KIF5B-MET (K24::M15) fusion without other targeted oncogenic alterations such as EGFR, ALK, ROS1, BRAF, HER2, RET, and KRAS (Table 2). In addition, the programmed death-ligand 1(PD-L1) expression analysis revealed a tumor proportion score of 40%.

The patient refused chemotherapy; thus, crizotinib (250 mg, po. bid) was initiated as the first-line treatment in June 2020 without adverse effects.

After 3 weeks of crizotinib treatment alone, a reduction in the size of most lesions in the brain was observed, accompanied by a decrease in edema around the lesions (Figure B2). However, the lung mass and pleural fluid did not significantly change (Figure A2). Thus, crizotinib was continued owing to its clinical benefits, and bevacizumab was initiated in July 2020.

After crizotinib plus three cycles of bevacizumab, the lung mass shrank, and the pleural fluid decreased (Figure A3), but the brain lesions grew (Figure B3). Therefore, brain radiation therapy was started in September 2020 (gross tumor volume: 50 Gy/2.5 Gy/20 F, planning target volume: 36 Gy/1.8 Gy/20 F).

By October 2020, the disease had progressed; compared to that in the previous evaluation, the pleural fluid increased, the previously decreased tumor grew, and new lesions appeared in the liver (Figure A4). Targeted sequencing was performed on new blood samples using a panel of 483 cancer-related genes to identify new actionable mutations, revealing a novel point mutation in MET exon 19 (c.3688T> C; p. Y1230H) (Table 2).

The patient again refused chemotherapy after crizotinib plus bevacizumab failure. The MET Y1230H mutant may be sensitive to the type II MET TKI, cabozantinib; however, cabozantinib has not been listed in China. Therefore, we chose anlotinib [a vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor (VEGFR-2 TKI)] plus carrelizumab [an immune checkpoint inhibitor (ICI)] as salvage therapy, from which the patient did not benefit, and her condition worsened. The patient died of multiple organ dysfunction thereafter, surviving 6 months after the diagnosis.

The KIF5B-MET fusion gene was originally reported in one of 513 lung adenocarcinoma (LADC) samples (12). There are two known types of KIF5B-MET fusions in LADC – K24::M15 and K24::M14. We identified eight cases in the literature; six involved K24::M15 and two involved K24::M14 (Table 1). Thus, our patient with a gene fusion between exon 24 of KIF5B and exon 15 of MET is the ninth case to be reported.

The KIF5B-MET variant has oncogenic functions in cancer cells (4), but MET inhibitors have potential therapeutic effects on tumors expressing the KIF5B-MET fusion protein. Cho et al. (2) reported the first documented case of a KIF5B-MET (K24::M14) gene rearrangement in a patient with LADC who responded positively to treatment with crizotinib, a MET inhibitor. Plenker et al. (3) also reported positive results after 8 months of crizotinib treatment in a patient with a KIF5B-MET (K24::M15) gene fusion. In our case, the patient refused chemotherapy. Thus, crizotinib was taken orally with positive results after 3 weeks; most brain lesions decreased slightly. However, significant lung lesions or pleural fluid changes did not occur.

A multicenter Phase 3 study (CTONG1509) (13) reported that bevacizumab plus erlotinib provides superior progression-free survival compared to erlotinib alone in Chinese patients. In addition, bevacizumab with alectinib has been proven to be a safe and highly effective first-line therapy (14). Bevacizumab is a monoclonal antibody against VEGF; thus, VEGFR2 inhibition enhances the anti-tumor effect of molecularly targeted drugs in various oncogene-driven NSCLC models by inhibiting tumor angiogenesis and exerting a direct antiproliferative effect on cancer cells (15), which suggests that combination therapy with bevacizumab and molecularly targeted agents is a promising strategy for patients with NSCLC harboring oncogenic driver genes. Given the fact that the efficacy of using crizotinib alone was not very satisfactory, we also tried to administer bevacizumab. After treatment with crizotinib plus three cycles of bevacizumab, the lung lesions shrank and pleural fluid decreased; however, the brain lesions increased, possibly due to heterogeneity in the tumor’s response.

Unfortunately, disease progression occurred 1 month later. Therefore, to identify new actionable mutations, targeted sequencing was performed on fresh blood samples using a panel of 483 cancer-related genes, revealing a novel point mutation in MET exon 19 (c.3688T> C; p. Y1230H). MET Y1230H is a drug-resistance mutation in the MET activation loop, associated with secondary resistance mechanisms in preclinical studies (16). Clinical studies have shown that this mutation is associated with resistance to MET inhibitors (17), and structural analysis indicated that it destabilizes the auto-inhibitory conformation of MET and abrogates important aromatic stacking interactions with the inhibitor (18). Schrock et al. (19) reported that the MET Y1230 mutation is an acquired mechanism of crizotinib resistance in NSCLC with MET exon 14 skipping. Herein, we describe a similar case of a MET Y1230H mutation acquired after crizotinib treatment in a patient with NSCLC, driven by the KIF5B-MET (K24::M15) gene fusion. This patient developed resistance to crizotinib owing to an acquired MET Y1230H mutation. Based on the mechanism of action, MET TKIs are divided into two groups, type I and type II. As type I and II MET TKIs bind the ATP pocket of MET differently, they have distinct inhibition capacities for MET mutants. Engstrom and others confirmed that the MET Y1230H mutant was resistant to type I MET TKIs, such as capmatinib, lvotinib, and crizotinib, but remained sensitive to type II MET TKIs, glesatinib and cabozantinib (20). The switch from a type I MET TKI to a type II MET TKI, cabozantinib, can be an effective strategy to overcome acquired type I MET TKI resistance in NSCLC (21). Unfortunately, to date, cabozantinib has not been listed in China, and the patient was unable to purchase it in China in 2020.

Anlotinib is a small molecule multi-target TKI that can effectively inhibit kinases such as VEGFR, platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and C-Kit. It has anti-tumor angiogenesis and tumor growth inhibition effects. In May 2018, anlotinib hydrochloride capsules were approved for marketing by China National Medical Products Administration, making anlotinib hydrochloride the first drug in China to be approved for third-line treatment of advanced NSCLC. This drug is suitable for the treatment of patients with locally advanced or metastatic NSCLC who have experienced progression or recurrence after receiving at least two types of systemic chemotherapy in the past. The patient refused chemotherapy, hence we administered anlotinib as a third-line treatment. Meanwhile, an ICI was selected as salvage therapy but failed to yield positive outcomes. This is similar to the finding of previous studies that showed that ICIs are less effective for NSCLC with EGFR mutation or EML4-ALK fusion (22).

In summary, crizotinib can be effective for patients with KIF5B-MET fusion; however, cancer cells can develop resistance. In our patient with NSCLC with KIF5B-MET fusion, the MET Y1230H mutation was an acquired resistance mechanism to crizotinib. Preventing or overcoming resistance in these patients requires further exploration. ICIs may be ineffective for NSCLC with KIF5B-MET fusion.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. Written informed consent was obtained from the participant/patient(s) for the publication of this case report.

SD: Conceptualization, Writing – original draft. WD: Conceptualization, Writing – original draft. YT: Data curation, Writing – review & editing. QX: Data curation, Writing – review & editing. TW: Supervision, Validation, Writing – review & editing.