Response to capmatinib in a patient with neuroendocrine carcinoma of the gallbladder origin harboring MET amplification

Abstract

Neuroendocrine carcinoma (NEC) of the gallbladder origin is particularly rare, accounting for only 0.38% of primary malignancies of the gallbladder, and standard therapies are limited. The MET gene encodes the tyrosine kinase receptor, c-Met. Pathogenic variants of MET, such as MET exon 14 skipping and MET amplification, result in excessive downstream signaling that promotes tumor progression. A MET inhibitor, capmatinib, blocks signaling of c-Met and has been approved by the Food and Drug Administration for non-small cell lung cancer with MET exon 14 skipping. The effectiveness of capmatinib has been reported in other cancers with MET amplification, but NEC with MET variants has not been reported. Here, we present a case of a 72-year-old woman with NEC of the gallbladder with multiple liver and lymph node metastases, who was resistant to conventional chemotherapy including carboplatin plus etoposide as first-line treatment and irinotecan as second-line treatment, but she responded to capmatinib. After 6 weeks of treatment, CT scan showed a partial response (80% reduction in size), but after 13 weeks, regrowth of liver metastasis was observed. Herein, we report a meaningful efficacy of capmatinib to the patient of NEC of the gallbladder origin with MET amplification.

Introduction

Neuroendocrine carcinoma (NEC) develops in a variety of organs, including the head and neck, lung, breast, digestive tract, and urinary regions; however, NEC of gallbladder origin is rare, accounting for approximately 0.38% of primary malignancies of the gallbladder [1].

The MET gene encodes the tyrosine kinase receptor, c-Met. Pathogenic variants of MET, such as MET exon 14 skipping or MET amplification, lead to oncogenic activity of c-Met. Furthermore, loss of function of the juxtamembrane domain, which plays a role in signal downregulation and receptor degradation, occurs secondary to MET exon 14 skipping, and MET amplification leads to overexpression of c-Met [2–4]. Hence, these variants result in excessive downstream signaling via phosphoinositide 3-kinase (PI3K), signal transducer and activator of transcription (STAT), and mitogen-activated protein kinase (MAPK), promoting tumor progression. A MET inhibitor, capmatinib, can bind to the adenosine triphosphate (ATP) site of the catalytic domain of c-Met and block its downstream signaling pathway [5, 6]. The Food and Drug Administration (FDA) approved capmatinib for non-small cell lung cancer (NSCLC) with MET exon 14 skipping in May 2020 [6]. Capmatinib has been reported to be efficacious in a patient with intrahepatic cholangiocarcinoma harboring MET amplification [7]. However, to the best of our knowledge, NEC with MET variants has not been reported thus far. Here, we report a patient with NEC of gallbladder origin harboring MET amplification, who manifested resistance to conventional chemotherapy but responded to capmatinib. MET inhibitors, such as capmatinib, may be effective in NEC of the gallbladder harboring MET amplification.

Case report

A 72-year-old woman was referred to a hospital by her family doctor for evaluation of a rapid increase in carcinoembryonic antigen (CEA) levels (1.4–30.2 ng/mL) over the past 5 months. Contrast-enhanced computed tomography (CT) scan revealed gallbladder wall thickening, multiple low-attenuation lesions in the liver, and lymphadenopathies in the perihilar lesion. She was then referred to our hospital for further evaluation. She had a history of diabetes, depression, and osteoporosis. Fluorodeoxyglucose (FDG)-positron emission tomography–CT showed FDG accumulation in the gallbladder, perihilar lymph nodes, and liver lesions. Upper and lower endoscopy showed no gross malignancy. Biopsies from the liver lesions showed malignant cells proliferating in sheets or rosette formation. Immunostaining showed positivity for chromogranin A (80%), synaptophysin (90%), insulinoma-associated protein 1 (50%), and negative for retinoblastoma protein and somatostatin receptor 2. The Ki-67 index was 53% (Fig. 1). Based on these findings, a diagnosis of NEC of the gallbladder with multiple liver and lymph node metastases was established. She was started on combination chemotherapy using carboplatin (CBDCA, AUC5, day1) and etoposide (ETP, 80 mg/m², days 1–3) every 3 weeks as first-line treatment according to the National Cancer Comprehensive Network guideline for NEC [8]. In parallel with chemotherapy initiation, a comprehensive gene panel (CGP) test was conducted for the liver biopsy sample (FoundationOne®CDx; F1CDx). After completion of 2 cycles of CBDCA/ETP, CT scan showed liver metastasis progression. Thereafter, second-line chemotherapy using irinotecan (CPT-11, 100 mg/m², days 1, 8, and 15) every 4 weeks was initiated; however, treatment was terminated in 4 weeks due to tumor progression. Furthermore, CGP test results (Table 1) showed MET amplification (copy number 98), suggesting tumor dependency to the c-Met signaling pathway. Since several studies reported the positive association between the efficacy of MET inhibitors and MET amplification [6, 7] and no standard treatment remained for this patient, our molecular tumor board proposed a treatment using a MET inhibitor, capmatinib, under a clinical trial (NCCH1901; jRCTs031190104). She was started on capmatinib (400 mg orally twice daily) as a third-line treatment. After capmatinib initiation, CEA and neurological singular enolase (NSE) levels began to decrease sharply (Fig. 2). On day 26, capmatinib was temporarily discontinued due to grade 2 anorexia, but was safely resumed with dose reduction (300 mg orally twice daily) on day 29. No other side effects associated with capmatinib were observed. After 6 weeks of capmatinib treatment, CT scan showed a partial response (80% reduction in size). However, 13 weeks after treatment initiation, CT scan showed regrowth of liver metastasis (100% increase in size) (Fig. 3). Since her general condition remained unchanged, she decided to continue capmatinib treatment. However, her general condition deteriorated rapidly within the next 2 weeks due to tumor progression, and capmatinib treatment was terminated. The patient was placed on best supportive care and died 6 months after capmatinib treatment.

Fig. 1.

Patient’s tumor pathology. A Malignant cells proliferating in sheets or forming rosettes; hematoxylin and eosin stain, 400×. B Ki-67 labels 53% of tumor cell nuclei in many areas; immunostaining for Ki-67, 400×. C Tumor cells are immunoreactive for chromogranin A in 80% of the areas; immunostaining for chromogranin A, 400×. D Tumor cells are not immunoreactive for retinoblastoma protein; immunostaining for retinoblastoma protein, 400×

Table 1.

The table shows the results of the comprehensive gene panel test (FoundationOne®CDx; F1CDx): there is no biomarker findings (microsatellite status, stable; tumor mutational burden, 6 Muts/Mb)

Genome variant	Allele fraction (AF) or copy number (CN)
MET amplification	CN 98
ARID1A G 388 fs*3	AF 37.83%
ATRX R781*	AF 16.58%
RICTOR amplification	CN 8
RB1 L607fs*5	AF 40.32%
TP53 R282W	AF 46.87%

MET amplification (CN 98), ARID1A G 388 fs*3 (AF 0.3783), ATRX R781* (AF 0.1658), RICTOR amplification (CN 8), RB1 L607fs*5 (AF 0.4032), TP53 R282W (AF 0.4687). Only MET amplification was a druggable variant

Fig. 2.

Disease responded to capmatinib, and tumor marker levels dropped. The patient was started on capmatinib (400 mg orally twice daily), but capmatinib was temporarily discontinued on day 26 due to grade 2 anorexia. It was safely resumed with dose reduction (300 mg orally twice daily) on day 29

Fig. 3.

Contrast-enhanced computed tomography: A Before capmatinib treatment. The arrow shows carcinoma of the gallbladder origin with extensive liver metastases; B 1.5 months after capmatinib treatment. Both primary and metastatic lesions shrunk markedly

Discussion

In the N-terminus, c-Met binds to hepatocyte growth factor, and the catalytic region located in the C-terminus triggers downstream signaling via the phosphoinositide 3-kinase (PI3K), signal transducer and activator of transcription (STAT), and mitogen-activated protein kinase (MAPK) pathways. Its excessive signaling promotes tumor progression [2–4]. This over-activation can be blocked by MET inhibitors through binding to the catalytic domain of c-Met [5, 6, 9, 10]. Since May 2020, the Food and Drug Administration (FDA) has approved capmatinib [5] for non-small cell lung cancer (NSCLC) with MET exon 14 skipping, and tepotinib [11] has been approved for the same indication since February 2021. Outside the approved indication, in a phase 2 trial [6], capmatinib efficacy has been reported in NSCLC with MET amplification and cholangiocarcinoma with MET amplification and fusion in case reports [7, 12]. Similarly, in several clinical trials, the efficacy of tepotinib has been reported in hepatocellular carcinoma [13] and NSCLC [14] with MET amplification and for NSCLC [15] and gastric cancer [16] with oncogenic MET variants. However, no drugs have been reported to be effective for gallbladder NEC harboring MET amplification, and neither capmatinib nor tepotinib is approved in Japan for solid tumors harboring this variant. Hence, under a pan-cancer multidrug off-label treatment trial (NCCH1901; jRCTs031190104), the patient received capmatinib therapy, which supports patients receiving off-label treatments based on the CGP test results.

MET amplification could occur as an acquired mechanism of resistance after treatment of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). MET amplification is observed in approximately 10–15% of NSCLC cases who were treated with EGFR-TKIs [17–19]. The use of other TKIs can also lead to MET amplification [20, 21]. For instance, MET amplification was observed in 12–22% of patients with NSCLC who received pan-anaplastic lymphoma kinase inhibitors [22]. Since our patient had no history of TKI treatment, MET amplification was attributable to reasons other than a resistance mechanism.

In this case, the biopsy sample revealed neuroendocrine carcinoma, but elevated levels of NSE and CEA suggested the possibility of mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) or mixed adeno-neuroendocrine carcinoma (MANEC). Even if there were mixed adenocarcinoma components, the significant reduction in tumor size indicates therapeutic effect on both NEC and adenocarcinoma.

In other reports, the response duration to capmatinib for biliary tract cancers was limited to 4–6 months [23, 24], the resistance mechanisms to this drug may occur earlier in biliary tract cancers than in lung cancers [6].

According to the data of 76,639 cancer patients registered in cBioPortal [25], prevalence of MET amplification was highest in embryonal tumor (5.8%, 9/144) and mature B-cell lymphoma (5.83%, 6/103), followed by esophagogastric cancer (3.38%, 58/1717), intrahepatic cholangiocarcinoma (3.2%, 18/555), and liver hepatocellular carcinoma (2.5%, 28/1113) among cancer types including more than 100 cases. Prevalence of MET amplification was 1.7% (4/240) and 0.33% (1/304) in gallbladder carcinoma and gastrointestinal neuroendocrine tumor, respectively. NEC with MET amplification is deemed to be extremely rare as NEC of the gallbladder comprises only 0.38% of primary malignancies of the gallbladder.

In conclusion, we present a patient with NEC of the gallbladder harboring MET amplification whose tumor did not respond to conventional cytotoxic chemotherapies and the best response was progressive disease, but showed a partial response to capmatinib for at least 6–8 weeks. Further clinical trials are warranted to test the efficacy of capmatinib on patients with solid tumors harboring MET amplification.

Funding

This research was supported by a Grant-in-Aid for Scientific Research C (17K08413) from the Japan Society for the Promotion of Science and by the Japan Agency for Medical Research and Development, AMED, under Grant number 17kk0305006h0001.

Data availability

The datasets used during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of interest

Masashi Kanai own stocks in Therabiopharma and received honoraria from Chugai Pharmaceutical Co., Ltd. Taro Funakoshi belongs to an endowed chair sponsored partly by Yakult Honsha Co., Ltd. and Chugai Pharmaceutical Co., Ltd. Manabu Muto received research funding and honoraria from Chugai Pharmaceutical Co., Ltd. All remaining authors have no conflict of interest to declare.

Ethics approval

This report was supported by research on “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)” of the Clinical Research Review Committee, National Cancer Center Hospital, under Grant number CRB3180008.

Consent for publication

We obtained consent of the patient for participating in the NCCH1901 study and publication related to this study. A copy of the consent form with the patient's signature can be submitted.