Ensartinib is effective in the treatment of advanced non-small-cell lung cancer with MET amplification after multi-line ALK-TKIs resistance: a case report

Abstract

Although patients with ALK-positive non-small cell lung cancer (NSCLC) are initially effective on treatment with ALK tyrosine kinase inhibitors (TKIs), resistance will inevitably develop. Of these patients, 2/3 will develop ALK-independent resistance and little is known about the mechanisms of ALK-independent resistance. In pre-clinical studies, the activation of several bypass signaling pathways has been implicated in the development of resistance, including the MET, EGFR, SRC and IGF1R pathways. Among these, the MET pathway is one of the signaling pathways that has recently been extensively studied, and activation of this pathway is one of the mechanisms of ALK-independent drug resistance. Here, we report a successful case of an advanced NSCLC patient who was resistant to treatment with ALK TKIs and developed MET amplification, who achieved 23 months of progression-free survival after post-line treatment with ensartinib.

Introduction

Anaplastic lymphoma kinase (ALK) is a potent oncogenic driver gene in lung cancer, and ALK tyrosine kinase inhibitors (TKIs) have provided survival benefits to patients with ALK-positive advanced non-small cell lung cancer (NSCLC). However, almost all patients with advanced ALK-positive lung cancer eventually experience disease recurrence due to both on-target and off-target resistance mechanisms [1]. Tumor cells with on-target resistance retain their dependence on ALK, while those with off-target mechanisms activate ALK-independent pathways to support proliferation and survival [2]. In recent years, the development of next-generation ALK TKIs has increased day by day with the in-depth exploration of ALK target resistance mechanisms, but overcoming ALK-independent resistance mechanisms remains a major clinical challenge. MET amplification or mutation is a common cause of ALK-independent resistance. The coexistence of amplification and mutation is rare.MET amplification has been shown to be a driver of drug resistance to TKI-treated advanced NSCLC, which activates alterations in ALK, EGFR, RET and ROS-1 [3]. Therefore, MET gene amplification may be an important independent target for lung cancer development. There are relatively few case reports for the occurrence of MET amplification after ALK TKI resistance, and this case reports a 68-year-old female patient who achieved 23 months of progression-free survival (PFS) after selecting ensartinib backline treatment after resistance to ALK TKIs, and had manageable side effects during the administration of the drug.

Case presentation

A 68-year-old female patient with no history of smoking did not have a specific medical history, family history, or psychosocial history. Chest CT on 17 November 2017 showed a subpleural nodule in the upper lobe of the right lung with calcifications in a portion of it showing mild enhancement, and CT-guided puncture biopsy was recommended (Fig. 1). Subsequently, soft thoracoscopy was performed to visualize the right posterior lower wall pleural and diaphragmatic surface nodules, postoperative pathology suggested that adenocarcinoma tissue was seen in the right intrathoracic tissue sent for examination, and immunohistochemistry suggested TTF-1 (+), Napsin A (+), CK7 (+), MC (+) foci, CB (−), and Ki67 index of approximately 20%, and the possibility of pulmonary origin was considered in conjunction with immunohistochemistry (Fig. 2). In 2017, he was diagnosed with lung adenocarcinoma (cTxNxM1 stage IV) and genetic testing suggested a positive ALK fusion.

Fig. 1.

Chest CT on 17 November 2017 showed a subpleural nodule in the upper lobe of the right lung with calcifications in a part of it, with mild enhancement, and a CT-guided puncture biopsy was recommended; and a pleural effusion on the right side.

Fig. 2.

The postoperative pathology suggested that adenocarcinoma tissue was seen in the right intrathoracic tissue sent for examination, and immunohistochemistry suggested that TTF-1 (+), Napsin A (+), CK7 (+), MC (+) foci, CB (−), and Ki67 index of about 20%, and the possibility of lung origin was considered in conjunction with immunohistochemistry.

First-line treatment: Based on CSCO guidelines, crizotinib is recommended as first-line treatment for patients with stage IV ALK fusion gene-positive NSCLC. From 21 December 2017 to 30 July 2019, 250 mg of crizotinib was administered orally twice daily, and multiple follow-up chest CTs were performed between the start of oral crizotinib and 15 April 2019, all of which were unchanged compared with the previous slides, indicating disease stabilization (Fig. 3a).

Fig. 3.

(a) Multiple follow-up chest CTs between 21 December 2017, when oral crizotinib was initiated, and 15 April 2019 were virtually unchanged from the previous films. (b) Progression of a nodule in the upper lobe of the right lung on chest CT on 30 July 2019 compared to 15 April 2019. (c) Multiple follow-up chest CTs between the start of oral ceritinib on 31 July 2019 and 24 December 2019, were all unremarkable compared with the change on the previous film.

Second-line therapy: Review of chest CT on 30 July 2019 suggested progression of a nodule in the upper lobe of the right lung (Fig. 3b). Based on the results of the ASCEND 5 trial, which showed the median progress-free survival (mPFS) of 5.4 months for the overall population and 9.8 months for the Asian population after multiple lines of ceritinib therapy. Therefore, once-daily oral ceritinib 750 mg was administered from 31 July 2019 to 16 April 2020, and multiple follow-up chest CTs between the start of oral ceritinib and 24 December 2019, showed no significant change from the previous slides, and the disease was stable (Fig. 3c).

Third-line treatment: Chest CT on 16 April 2020 showed that the nodule in the upper lobe of the right lung had progressed again (Fig. 4d). The ALUR trial confirmed that the mPFS of aleitinib in the second line of treatment was 10.9 months and the mean OS (mOS) was 27.8 months. Therefore, aleitinib was administered orally 600 mg twice daily from 17 April 2020 to 2 July 2020.

Fig. 4.

(d) The nodule in the upper lobe of the right lung had again progressed from the previous film on the repeat chest CT on 16 April 2020. (e) A follow-up chest CT scan on 2 July 2020 showed that the right pleural effusion was significantly larger than before and disease progression was considered. (f) There were no significant changes in multiple follow-up chest CTs between 3 July 2020 for oral crizotinib and 26 August 2020.

Fourth-line treatment: 2 July 2020 Review of the chest CT scan suggested that the right pleural effusion had significantly increased compared with the previous one (Fig. 4e), taking into account the progression of the disease. The right thoracentesis tube was placed and the pleural fluid was aspirated and drained and sent for genetic testing, which suggested MET amplification with an amplification frequency of 4.6%, while the original ALK fusion positivity had disappeared. Based on the results of the AcSé trial, crizotinib had a clear inhibitory effect on MET amplification and clinical efficacy was precise, and crizotinib was administered orally at 250 mg twice daily from 3 July 2020 to 27 November 2020. Multiple follow-up chest CTs between oral crizotinib and 26 August 2020 showed little change from the previous slice and no progression (Fig. 4f).

Fifth-line therapy: Unfortunately, another disease progression occurred at the review on 27 November 2020 (Fig. 5g), but at that time, the patient refused to undergo systemic chemotherapy, and targeted drugs against MET amplification had not yet been applied in the clinic. Therefore, only the existing small molecule targeted drugs can be found from the follow-up treatment, we reviewed a large number of literature, and found that the 50% inhibitive concentration (IC50)value of ensatinib in the MET site is better than that of crizotinib, the patient was instructed to take ensatinib 225 mg orally once a day from 28 November 2020 to 18 November 2022 for the backline treatment. The patient was reviewed several times during the medication period, and the disease was stable, with no significant change from the previous slice in the chest CT (Fig. 5h) on 16 August 2021 and chest CT (Fig. 5i) on 18 November 2022, and the PFS was more than 23 months.

Fig. 5.

(g) A follow-up chest CT on 27 November 2020 showed further progression of a nodule in the upper lobe of the right lung. Oral ensartinib was started since 28 November 2020, and there was no significant progression in multiple follow-up chest CTs, and PFS was more than 23 months as shown in the chest CT of 16 August 2021 (h) and the chest CT of 18 November 2022 (i).

Discussion

Mesenchymal Epithelial Transition Factor (MET) is a proto-oncogene located on the long arm of chromosome 7, consisting of 21 exons and 20 introns. The gene encodes a protein tyrosine kinase, MET protein, which belongs to the hepatocyte growth factor (HGF) receptor family. MET protein binds to HGF and phosphorylates at tyrosine residues Y1234 and Y1235 in the structural domain of the tyrosine kinase, inducing kinase activity, which in turn activates these signaling molecules leading to downstream signal activation transduction such as PI3K, MAPK and STAT3 [4]. The end result is the promotion of cell transformation, cell invasion, cell proliferation, and cell cycle progression [5]. The types of abnormalities mainly include MET gene amplification, MET gene mutation, MET protein overexpression, MET rearrangement, as well as overexpression of its ligand, HGF, and point mutations [6,7]. The proportion of MET amplification at low levels that also carries abnormalities of other driver genes is about 50%, but no accompanying abnormalities of other drivers were found at high levels of amplification. Primary MET amplification occurs in 1–5% of lung adenocarcinomas [8–10] and secondary MET amplification is common in patients with EGFR mutations after prolonged treatment with EGFR TKIs. After an average of 9 months on the first three generations of EGFR TKIs, MET amplification occurs in 15–20% of patients [11]. Because MET gene copy number increase due to MET gene amplification then causes EGFR-TKI resistance. Therefore, MET gene amplification may be an important independent target for lung cancer development. At present, relevant drugs such as savolitinib and crizotinib have been applied in the treatment of MET amplification. However, there are relatively few reports of MET amplification after ALK-TKI resistance, and the patient experienced MET amplification after resistance to multiple lines of ALK-TKI therapy in this case.

One study [12] tested ALK-positive lung cancer patients for MET gene abnormalities after treatment and found 11 (13%) biopsy specimens with MET amplification out of 86 specimens tested, including four low-level MET amplification (MET/CEP7 2.4–3.9) and six high-level FISH-based MET amplification (MET/CEP7 5.2 to >25). All 11 patients with MET amplification were second- or third-line relapsed ALK-TKI patients. MET amplification was found in 6 (12%) of 52 biopsies with second-generation ALK TKIs and in 5 (22%) of 23 biopsies with lorlatinib. No MET amplification was detected in patients with crizotinib relapse. In addition, 6 (55%) of the 11 patients with MET amplification had never received crizotinib. This study demonstrates that MET is an important bypass mechanism leading to next-generation ALK TKI resistance.

At present, in addition to crizotinib, related drugs have been developed for MET amplification, such as Gleesatinib (MGCD 265) [13]; Emibetuzumab (LY 2875358) [14]; Rilotumab (AMG 102) [15], etc., which have been shown to be effective in the treatment of MET amplification. However, these drugs were not yet available in the clinic in 2020, and this patient refused antitumor therapy such as systemic chemotherapy after crizotinib resistance. Ensartinib is a mesenchymal lymphoma kinase (ALK) inhibitor, the targets of action of ensatinib and similar drugs are shown in Table 1, it can be seen that ensartinib is a multi-target inhibitor of ALK, MET, ROS1 and AXL, and ensartinib ‘s IC50 value in the target of MET is 1.8 nmol/L, while crizotinib is 4 nmol/L [16]. Preclinical studies have confirmed that the IC50 for the inhibitory effect of enzatinib on c-MET-expanded gastric adenocarcinoma MKN-45 cells was 0.156 μmol/L [17]. Mechanistically, ensartinib can bind the structural domain of the kinase so that MET cannot be activated by phosphorylation, and both ALK and MET belong to the receptor tyrosine kinase, so some of the downstream signaling pathways are shared, such as the PI3K-AKT-mTOR or RAS-RAF-MEK pathway.

Table 1.

Targets of ensatinib and similar drugs

ALK-TKI	Targets	IC50 or Ki* (nmol/L)
Ensartinib	ALK	1.7
	ROS1	19
	MET	1.8
	AXL	35
Crizotinib	ALK	0.69*
	ROS1	N.D.
	MET	4*
Ceritinib	ALK	0.15
	IGF-1R	8
	INSR	7
	STK22D	23
Alectinib	ALK	1.9
	RET	4.8
Brigatinib	ALK	0.6
	ROS1	1.9
	FLT3	2.1
	EGFR L858R	1.5
Lorlatinib	ALK	1.3
	ROS1	<0.02*

*indicate Ki values, and without an *, indicate IC50 values.

MET gene amplification and activating mutations have been recognized as potentially important therapeutic targets in NSCLC [18–22], with very important therapeutic value. In the future, we will conduct in-depth research on the role of ensartinib in MET amplification, which is expected to find more and better therapeutic drugs for more patients with MET amplification.

Conclusion

In conclusion, we report here for the first time the successful treatment of this patient with MET-amplified advanced NSCLC with enzatinib, resulting in a 23-month PFS for this patient, demonstrating that ensartinib is an effective and tolerable treatment for patients with ALK-TKI-resistant advanced NSCLC with MET-amplified MET.

Acknowledgements

The authors would like to thank the patient’s family for providing the information about the patient. The Internal Medicine-Oncology Ethics Committee of Shaanxi Provincial People’s Hospital approved this study, and the patient’s family members provided informed written consent to publish the case details and relevant pictures. The authors are also deeply indebted to all the tutors and teachers for their direct and indirect assistance and helpful advice.

Shaanxi Provincial People’s Hospital Top Talent Program (2021BJ-01). Beijing Science and Technology Medical Development Fund (KC2021-JX-0186-86).

Conceptualization, Yi Liu, Jun Bai and Yanping Yang; methodology, Jun Bai; validation, Yanping Yang, Yi Liu and Jun Bai; investigation, Yanping Yang and Yi Liu;writing-original draft preparation, Yanping Yang; writing-review and editing, Yi Liu and JunBai; visualization, Xincheng He.; supervision, Wenxuan Xiao.; funding acquisition, Yi Liu.

The patient’s family gave informed consent to publish this report and related images.

Conflicts of interest

There are no conflicts of interest.