Effective Treatment With Endostar and Crizotinib Sequential Alectinib in a Lung Adenocarcinoma Patient With Brain Metastases Harboring a Novel CLHC1/RNT4 Intergenic Region- ALK Fusion

doi:10.21203/rs.3.rs-1008103/v1

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Effective Treatment With Endostar and Crizotinib Sequential Alectinib in a Lung Adenocarcinoma Patient With Brain Metastases Harboring a Novel CLHC1/RNT4 Intergenic Region- ALK Fusion

https://doi.org/10.21203/rs.3.rs-1008103/v1

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Background: Anaplastic lymphoma kinase (ALK) fusion, an important driven oncogene mutation, occurrs in 3%~7% non-small cell lung cancers (NSCLC), and EML4 is the most common partner gene. With the widespread application of next-generation sequencing (NGS), more gene breakpoint fusions have been discovered, and functional fusion transcripts can bring targeted clinical benefits. Clinical trials have shown that NSCLC patients with ALK fusion can obtain significant survival benefits through ALK tyrosine kinase inhibitor (ALK-TKI) treatment. In our case, a novel CLHC1/RNT4 intergenic region- ALK fusion was identified for the first time in a LUAD patient with BM, and the patient benefited from endostar and crizotinib sequential alectinib. Our case suggested the advantages of NGS for fusion detection and provided promising treatment options for NSCLC patients with BM harboring ALK fusions.

Drug Discovery, Design, & Development

Oncology

Laboratory Diagnostics

Lung adenocarcinoma. Brain metastases. CLHC1/RNT4 intergenic region- ALK fusion

Anaplastic lymphoma kinase (ALK) fusion, an important driven oncogene mutation, occurrs in 3%~7% non-small cell lung cancers (NSCLC), and EML4 is the most common partner gene [1]. With the widespread application of next-generation sequencing (NGS), more gene breakpoint fusions have been discovered, and functional fusion transcripts can bring targeted clinical benefits [2]. Clinical trials have shown that NSCLC patients with ALK fusion can obtain significant survival benefits through ALK tyrosine kinase inhibitor (ALK-TKI) treatment. So far, the FDA has approved five ALK-TKIs, namely Crizotinib, Ceritinib, Alectinib, Brigatinib, Ensartinib and Lorlatinib [3,4]. Herein, we firstly identified a novel CLHC1/RNT4 intergenic region- ALK fusion in a lung adenocarcinoma (LUAD) patient with brain metastases (BM), and the patient benefited from endostar and crizotinib sequential alectinib.

A 40-year-old woman admitted to the hospital on March 7, 2020 due to “cough and hemoptysis”. Chest computed tomography (CT) showed nodules in the upper lobe of the left lung with mediastinal lymph node metastasis (Fig. 1A). Further examination of brain magnetic resonance imaging (MRI) revealed BM (Fig. 1F), the neck lymph nodes were enlarged, and the pathology of neck lymph node biopsy showed LUAD. No driver gene mutation was found by ARMs-PCR using the patient’s blood in the hospital. Local brain radiotherapy (40Gy/20f) was performed with cisplatin (40mg/m² i.v. d1-3) and pemetrexed (800mg/m², d1) on April 2, 2020. Unfortunately, her condition worsened, her breath was difficulty, and chest and back pains were present. Positron emission tomography (PET)-CT revealed a significant increase in pericardial effusion. Pericardial effusion puncture drainage and local brain radiotherapy (40Gy/20f) were performed on April 10, 2020 concurrently. Endostar (30mg/m²/d, d1-7) was added to the treatment regimen on May 8, 2020.

A novel CLHC1/RNT4 intergenic region- ALK (Exon20-29) (abundance 39.97%) was identified using lung puncture tissue by NGS analysis (Simceredx) in June 2020, and results of immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) confirmed the ALK fusion (Fig. 2). Then the patient started oral crizotinib (250mg bid) combined with endostar (30mg d1-7) on June 18, 2020. The patient's condition was under control (Fig. 1C and H). Unfortunately, after 11 cycles, the patient felt dizzy and unwell in March 2021. The brain MRI showed multiple nodules in the left cerebellar hemisphere (Figure 1I) and chest CT showed no significant changes (Figure 1D), revealing the disease progressed. The patient's progression-free survival (PFS) was 9 months. Then alectinib (600mg bid) was administered from April 1, 2021, and which was evaluated as stable disease (SD). Timeline of the treatment and the changes of CT and MRI scan were shown in figure 1 (A-J).

In our case, we firstly identified a novel CLHC1/RNT4 intergenic region-ALK fusion in a LUAD patient with BM, which retained the whole kinase domain (exon 20-29) of ALK (Fig. 2B). The novel ALK fusion was confirmed as functional fusion transcripts by FISH and IHC (Fig. 1L). It has been reported that lung cancer patients with intergenic ALK fusions had response to ALK-TKIs [5-7]. Due to functional intergenic fusions can bring corresponding clinical benefits, intergenic fusions are receiving more and more attention. Compared with limited traditional detection methods, the application of NGS has accelerated the discovery of novel ALK fusions, and the requirements for samples have gradually become broader [8].

ALK fusion is a risk factor for brain metastasis in advanced NSCLC patients [9]. Clinical trials with TKI in NSCLC patients with BM have shown high percentage of objective responses, prolonged PFS, and improved quality of life. In patients with BM, simultaneously administer TKI and radiation therapy are attempted [10]. Endostar combined with radiotherapy has shown a good therapeutic effect on non-small cell lung cancer with BM in clinical practice [11]. The patients in our case with intergenic ALK fusion had a good response to ALK TKI plus endostar.

In conclusion, a novel CLHC1/RNT4 intergenic region- ALK fusion was identified for the first time in a LUAD patient with BM, and the patient benefited from endostar and crizotinib sequential alectinib. Our case suggested the advantages of NGS for fusion detection and provided promising treatment options for NSCLC patients with BM harboring ALK fusions.

Ethical approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

Consent for publication

A written informed consent was obtained from the patient for publication.

Availability of data and materials

Not applicable.

Competing interests

The authors have declared no competing interest.

Funding

The authors did not receive any funding for this study.

Authors' contributions

HX: treated the patient and writing the manuscript. NL, YQ, ML: analysis and interpretation of data. BL, GL: treated the patient, conceptualized the study, and approved the nal manuscript version.

Acknowledgement

Informed consent was obtained from the patient.

The authors thank Mr. Chuang Qi, Ms. Tingting Sun, Ms. Xueyu Yang, Mr. Wanglong Deng, Mr. Guanghua Lu and Mr. Ran Ding from Simceredx for the kindly assistance.

Compliance with ethical standards

Disclosure of potential conicts of interest

All authors have no conicts of interest to disclose.

Research involving Human Participants and/or Animals

This study does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was obtained from the patient for the publication of this case report.

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Effective Treatment With Endostar and Crizotinib Sequential Alectinib in a Lung Adenocarcinoma Patient With Brain Metastases Harboring a Novel CLHC1/RNT4 Intergenic Region- ALK Fusion

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