Remarkable response to capmatinib in a patient with intrahepatic cholangiocarcinoma harboring TFG-MET fusion

Abstract

Dysregulation of mesenchymal-epithelial transition factor (MET) gene due to amplification, mutation, and fusion has been reported in various types of human cancers. Recently, the efficacy of small-molecule tyrosine kinase inhibitors (TKIs) targeting MET has been demonstrated in a wide range of MET-dysregulated tumors. The majority of biliary tract cancers including intrahepatic cholangiocarcinoma (iCCA) are diagnosed at an advanced stage, and the utility of conventional chemotherapy is limited. Here, we present a case of metastatic iCCA harboring TFG-MET gene fusion, which demonstrated a remarkable response to treatment with capmatinib, a selective MET inhibitor. The patient was a 46-year-old man diagnosed with iCCA with hepatic, intraabdominal lymph nodes, and peritoneal metastases. Comprehensive genomic profiling (CGP) revealed TFG-MET gene fusion in his tumor. After becoming refractory to standard chemotherapy, he received capmatinib, which resulted in a marked shrinkage of the liver masses and lymph node metastases, as well as a drastic decrease in serum CA19-9 level. Our case reinforces the importance of CGP in exploring targeted therapy and supports the potential role of capmatinib in the treatment of tumors harboring MET fusions.

Introduction

Mesenchymal-epithelial transition factor (MET) is the high-affinity tyrosine kinase receptor for hepatocyte growth factor. MET is known as a driver of oncogenesis that functions in tumor growth, local invasion, and distant metastasis [1]. Dysregulation of MET has been reported in various types of human cancers, which is attributed to multiple mechanisms such as amplification, mutation, and fusion [1]. Recently, the clinical implementation of comprehensive genomic profiling (CGP) enabled to detect tumors which is driven by MET dysregulation more frequently. Besides, the emergence of MET-targeting therapeutics has expanded the clinical significance of MET dysregulation in human cancers. In fact, the efficacy of small-molecule tyrosine kinase inhibitors (TKIs) targeting MET such as capmatinib, tepotinib, and crizotinib has been demonstrated in a wide range of MET-dysregulated tumors [1, 2]. Among these TKIs, capmatinib and tepotinib are highly selective to MET in contrast to crizotinib, which is a multitarget TKI inhibiting ALK, ROS1, and MET [1, 2].

Gene fusions represent an important class of genetic alterations that lead to aberrant activation of oncogenes, including MET [3, 4]. A number of genes are known as fusion partners with MET [1, 3]. Among them, TFG-MET fusions have been reported in thyroid carcinoma [5, 6], infantile spindle cell sarcoma [7], and secretory carcinoma of the salivary gland [8].

The incidence of biliary tract cancers (BTCs) including intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma, and gallbladder cancer has been increasing, especially in South America and Asia. The majority of BTCs are diagnosed at an advanced stage and unresectable [9]. So far, a combination of gemcitabine, cisplatin, and durvalumab is considered to be the standard chemotherapy for advanced inoperable BTCs, although its efficacy is limited, as the median overall survival was 12.8 months [10]. Thus, there is an urgent need for the development of novel systemic therapy against advanced BTC.

Here, we present a case of metastatic iCCA harboring TFG-MET gene fusion, which demonstrated a remarkable response by treatment with capmatinib, a selective MET inhibitor.

Case report

A 46-year-old man with no significant medical history presented at his nearby hospital complaining chiefly of back pain. Initial examinations revealed hepatic masses accompanied by enlargement of multiple intraabdominal lymph nodes. He was referred to our hospital for further examination and treatment. Contrast-enhanced computed tomography (CE-CT) revealed a mass measuring 4.0 × 5.0 × 5.2 cm (Fig. 1a) and a daughter nodule in the right lobe of the liver. CE-CT imaging also showed lymph node swellings in the hepatic hilar and para-aortic regions and a nodule in the pelvic cavity. Consistent with the metastatic spread of the cancer, positron emission tomography with ¹⁸F-fluorodeoxyglucose (FDG-PET) exhibited abnormal accumulations of FDG in hepatic masses, intraabdominal lymph nodes, and a peritoneal nodule. Liver needle biopsy taken from the main liver tumor revealed moderately to poorly differentiated adenocarcinoma. Based on these findings, a diagnosis of iCCA with hepatic, abdominal lymph nodes, and peritoneal metastases was made. In addition, serum level of CA19-9 was elevated to 38,328.0 U/mL (normal range 0–37 U/mL) (Fig. 1d). Systemic chemotherapy was indicated, and he received chemotherapy with a gemcitabine/cisplatin/S-1 (GCS) combination regimen (gemcitabine 1000 mg/m² and cisplatin 25 mg/m² on day 1 and S-1 orally twice daily at a dose of 60 mg on days 1–7, every 2 weeks) [11]. After 12 courses of GCS therapy, CE-CT showed increased size of iCCA along with further elevation of serum CA19-9 level (Fig. 1b, d).

Fig. 1.

CE-CT imaging and serum level of CA19-9 during the chemotherapy. a-c: CE-CT imaging of iCCA before chemotherapy (a), after 6 months of gemcitabine/cisplatin/S-1 (GCS) therapy (b), and after 4 months of capmatinib monotherapy (c) are shown. Arrows in CE-CT images indicate the main tumor in the right lobe of the liver. d: Serum level of CA19-9 was elevated after 6 months of GCS chemotherapy and rapidly dropped after the initiation of capmatinib. a, b, and c below the graph indicate the timing when CE-CT images in panel a, b, and c, respectively, were taken. CE-CT contrast-enhanced computed tomography, iCCA intrahepatic cholangiocarcinoma

Meanwhile, CGP using FoundationOne® CDx (Foundation Medicine Inc., Cambridge, MA, USA) was performed utilizing the liver biopsy specimen, and revealed a fusion between exons 1–6 of TFG [NM_006070] and exons 15–21 of MET [NM_000245] (Fig. 2) as a probable driver of his iCCA cells. Otherwise, no remarkable genetic alterations were identified. Because the efficacy of MET-targeted therapy in tumors harboring MET fusion have been reported [12–21], treatment with capmatinib, a selective inhibitor of MET, 400 mg orally administered twice daily, was started under the prospective trial of patient-proposed healthcare services with multiple targeted agent based on the result of gene profiling by multigene panel test (NCCH1901; jRCTs031190104). He tolerated this dose well, with no significant adverse events. Three months after the start of capmatinib, serum CA19-9 level decreased drastically to 243.0 U/mL (Fig. 1d). Furthermore, CE-CT taken after 4 months of capmatinib monotherapy showed a remarkable response in terms of shrinkage of the liver masses as well as lymph node metastases (Fig. 1c). He received capmatinib for a total of more than 7 months and then stopped when CE-CT showed the disease progression indicated by enlarged liver masses and the emergence of bone metastasis at the right third rib.

Fig. 2.

Structural details of the TFG-MET fusion found in the current case. The TFG gene [NM_006070] fragment contains coiled-coil domain, whereas the MET gene [NM_000245] fragment contains a kinase domain. Sequence reads were mapped to the human reference genome (hg19/GRCh37)

Discussion

This case report presents an iCCA case that showed a remarkable response to capmatinib with no significant side effects. CGP revealed a gene fusion between exons 1–6 of TFG and exons 15–21 of MET, forming the fusion gene containing the coiled-coil domain of TFG and the kinase domain of MET (Fig. 2). To the best of our knowledge, this is the first report on iCCA harboring TFG-MET fusion. The coiled-coil domain of TFG presumably results in ligand-independent dimerization of the fusion gene products, and subsequently causes ligand-independent constitutive activation of the tyrosine kinase domain. Moreover, because this fusion gene does not contain exon 14 of MET, which is a regulator of the ubiquitination and decomposition of the protein, MET activity derived from this fusion gene might be further increased [1, 22]. In addition, the efficacy of MET inhibitors against tumors harboring MET fusions including iCCA [12–21] has been reported as summarized in Table 1. Collectively, we hypothesized that the TFG-MET fusion found in the current case was most likely to be an actionable target, and treatment with MET inhibitor could be beneficial. Capmatinib is a type Ib TKI shown to be a more selective and potent MET inhibitor than other TKIs such as crizotinib [1]. In a phase 2 clinical trial, capmatinib showed efficacy in patients with NSCLC with a MET exon 14 skipping mutation [23]. Consistent with the recent reports on lung adenocarcinoma [17] and iCCA [21], our case demonstrated a marked response to capmatinib, supporting the promising role of capmatinib in treatment of tumors harboring MET-fusions. Although MET alterations including amplifications (2–7%) and mutations (4.7%) are observed in a part of iCCA [24], fusions involving the MET gene are rare in iCCA and in other tumors [3]. Nevertheless, our case reinforces the importance of CGP in exploring targeted therapy.

Table 1.

Tumors harboring MET fusion treated with MET inhibitors

	Cancer type	MET fusion type	MET inhibitor	Outcome
Davies et al. [12]	NSCLC	HLA-DRB1-MET	Crizotinib	Mass shrinkage Response for 8 months
Blanc-Durand et al. [13]	NSCLC	HLA-DRB1-MET	Tepotinib	Mass shrinkage Improvement in physical function Response for 9 months
Ma et al. [14]	NSCLC	ARL1-MET	Crizotinib	Mass shrinkage Relief of respiratory symptoms Response for 5 months
Plenker et al. [15]	Lung adenocarcinoma	KIF5B-MET STARD3NL-MET	Crizotinib	Mass shrinkage
Cho et al. [16]	Lung adenocarcinoma	KIF5B-MET	Crizotinib	Mass shrinkage Response for 10 months
Lin et al. [17]	Lung adenocarcinoma	KIF5B-MET	Capmatinib	Mass shrinkage No significant AE Response for 9 months
Liu et al. [18]	Lung adenocarcinoma	CD47-MET	Crizotinib	Mass shrinkage Response for 8 months
Bender et al. [19]	Pediatric glioblastoma	PTPRZ1-MET	Crizotinib	Mass shrinkage Relief of symptoms
Yu et al. [20]	iCCA	EHBP1-MET	Crizotinib	Serum tumor marker decreasing Mass shrinkage Response for 8 months
Turpin et al. [21]	iCCA	CAPZA-2-MET	Capmatinib	Mass shrinkage Response for 4 months
Current case	iCCA	TFG-MET	Capmatinib	CA19-9 decreasing Mass shrinkage Response for 7 months

In summary, we report a case of iCCA harboring TFG-MET fusion that responded remarkably to treatment with capmatinib. Our case supports the potential role of capmatinib in the treatment of tumors harboring MET fusions.

Declarations

Conflict of interest

Atsushi Yamada was affiliated with an endowed chair funded by CHUGAI PHARMACEUTICAL CO. LTD. Masahiro Yoshioka, Masashi Kanai, and Manabu Muto received honoraria from CHUGAI PHARMACEUTICAL CO. LTD. Manabu Muto also received research funding and scholarship donations from CHUGAI PHARMACEUTICAL CO. LTD.

Informed consent

Informed consent was obtained from all individual participants included in the study.