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Case sharing of good efficacy in the first-line treatment of MET inhibitors.
The patient was advanced lung sarcoma-like carcinoma with exon-jump mutation in META14, and the first-line treatment was treated with cevotinib, which had a good response, achieved partial remission (PR), and obtained a 7-month progression-free survival (PFS), and adverse reactions were tolerated. After sevotinib resistance, cabotinib was used in second-line therapy and crizotinib in third-line therapy, both of which showed rapid disease progression (PD) and the overall survival (OS) of the patient reached 15 months. The case was provided by Professor Han Sen of Peking University Cancer Hospital and reviewed by Professor Fang Jian of Peking University Cancer Hospital.
Case profile
▎Basic information:
Patient, male, 74 years old.
Main complaint: Right chest pain in May.
Chest enhancement CT: a large soft-tissue mass in the upper lobe of the right lung, about 138×83 mm at a large axial level, and an upper and lower diameter of about 126 mm, mildly strengthened, involving the right 1st to 3rd ribs, with significant superior vena cava compression, with the establishment of collateral circulation.
Ultrasound B of abdominal and superficial lymph nodes: multiple enlarged lymph nodes on the right clavicle, considering metastasis.
Systemic bone scan: the right side of the 1st and 4th rib salt metabolism is vigorous, metastasis may occur.
Head MRI: no significant metastases are seen.
Right upper lung mass aspiration biopsy: carcinoma with poor differentiation (upper right lung), morphological and immunomarker support non-small cell lung carcinoma (NSCLC), but fail to clearly distinguish between glandular and squamous differentiation.
Immunohistochemistry shows: ALK-Ventana(-), CK5/6(-), NapsinA(-), P 40(-), ROS-1(-), TTF-1(-), Kahong (-), CK(+), Syn(-), CD56(-), CgA(-).
Clinical diagnosis: stage IV. right upper lung NSCLC (T4N3M1).
Genetic testing: There is a deletion of short fragments in the intron 13 region of the MET gene (NM_000245.2:c.2888-35_2888-20del), which causes a jump in exon 14 at mRNA level.
▎Diagnosis and treatment:
In this case, an elderly patient presented with chest pain, the initial diagnosis was meton-14 exon-jumping mutation NSCLC. On August 31, 2018, the first-line treatment was used cevotinib, and the patient complained of a significant reduction in back pain on the day of medication, the pain symptoms were completely alleviated after 1 week of medication, and the painkiller was discontinued. After 6 weeks of treatment, the chest enhancement CT showed that the upper lobe of the right lung had shrunk to 88 mm, a 36% reduction compared with before treatment. The overall evaluation is PR. Superior vena cava compression is completely relieved, and the collateral circulation is no longer filled with contrast. After 12 weeks and 18 weeks of medication, the efficacy was confirmed, both were to maintain PR, and the tumor continued to shrink. Adverse reactions during treatment can be tolerated.
Figure 1. Re-evaluation of efficacy before and during treatment of sivatinib
On March 8, 2019, the tumor progression was reviewed and evaluated, and the PFS was 7 months. Patients with no obvious symptoms and considering clinical benefit, continue oral sivotinib. To explore the causes of drug resistance in sivotinib, a secondary biopsy is performed. Pathological examination of the upper right lung shows poorly differentiated carcinoma with necrosis, consistent with sarcoma-like carcinoma. The genetic test results showed that compared with the baseline period, the amplification of the newly occurred BRAF gene increased from 58.5% to 69.8% and the AMPL of MET 14 exon increased from 58.5% to 69.8%, and the MET amplification increased from 2.4-fold to 3.1-fold.
The tumor continued to progress, and in June 2019, the patient's second-line treatment regimen was switched to cabozantinib, and after one month of treatment, the efficacy was evaluated as PD. In July 2019, the third-line conversion of zotinib was treated for more than 1 month, and the efficacy was evaluated as PD. The patient died on October 29, 2019 at an OS of 15 months due to persistent tumor progression.
Cases are provided by specialists
Professor Han Sen: Make good use of genetic testing to make accurate diagnosis and treatment throughout the entire course of lung cancer
Studies have shown that the driving gene plays an extremely important role in the continuous growth, infiltration and metastasis of lung malignant tumor cells, and the inactivation of the driving oncogene can lead to apoptosis of cancer cells, that is, cancer cells have a high sensitivity to inhibitors of the driving gene. The discovery of the driving gene provides a strong theoretical basis for molecularly targeted therapy of tumors[1]. With the development of molecular biology, the detection of gene mutations and the application of corresponding targeted drugs have greatly improved the therapeutic level of NSCLC. Today, the detection of targeted genes has become a routine test in major hospitals.
MET is considered to be another important NSCLC molecular therapeutic target after EGFR and ALK, MET14 exon jump mutation accounts for 3%-4% in NSCLC, and accounts for a higher proportion of lung sarcoma-like carcinoma, 4.9%-31.8%; the incidence of MET14 exon jump mutation in the Caucasus population is slightly higher than that of Japanese and Chinese (3.0% -4.9% vs 0.9% -2. 8%); the incidence of EXON-jump mutations in MET14 is higher than in younger patients in older patients; EXON-jumping mutations in MET14 are almost always mutually exclusive with other gene mutations, suggesting that they represent an independent tumor driver gene[2].
At the initial diagnosis, the patient underwent genetic testing and showed a meta-14 exon-jumping mutation. With long-term treatment of sivotinib, after 7 months of progression-free survival, patients eventually develop drug resistance. Genes in tumor tissue are undergoing new mutations all the time, and various treatments may affect the frequency of mutations and the site of mutations. Therefore, after drug resistance and disease progression, it is necessary to consider genetic testing again as appropriate and try to find the mechanism of drug resistance. The second genetic test of this patient found that a new BRAF gene amplification occurred, the abundance of MET14 exon mutation increased, and the MET amplification multiple increased. However, the resistance mechanism of MET inhibitors is more complex, and further research is currently underway, and the treatment after MET inhibitor resistance also needs to be further explored.
The 2021 edition of the Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Non-Small Cell Lung Cancer points out that for patients with advanced NSCLC, it is recommended to detect genes such as MET amplification and MET14 exon jump mutation, and free/circulating DNA (cf/ctDNA) can be considered if tissue specimens are not reachable. This recommendation is a grade II recommendation, which reflects the great importance attached by domestic lung cancer experts to the detection of MET targets [3].
In the era of precision medicine, genetic testing has played a positive guiding role in clinically more accurate and effective diagnosis and treatment. It is expected that in the future, genetic testing technology will continue to make breakthroughs to escort the precise treatment of lung cancer patients.
Expert reviews
Professor Fang Jian: The efficacy of traditional therapy on metaton jumping mutation lung cancer is limited, and patients can benefit from sivotinib treatment
Prior to the listing of cevotinib, the common treatment regimen for lung cancer patients with MET14 exon-jump mutation was chemotherapy and immunotherapy, but chemotherapy and immunotherapy had limited efficacy in the past for MET14 exon-jumping mutations. The results of one clinical study showed that patients with NSCLC with MET14 exon-jump mutations received only 6.7 months of first-line chemotherapy, much lower than the OS of driver-negative patients (11.2 months) [4]. In another clinical study, 24 patients with NSCLC with EXON-hopping mutations in MET14 received immunotherapy with an objective response rate (ORR) of 17 percent and a median PFS of only 1.9 months, which was less than expected [5].
In this case, the patient is lung sarcoma-like carcinoma, lung sarcoma-like carcinoma is a rare class of NSCLC, and the early patient is a comprehensive treatment mode based on surgery, but unfortunately, pulmonary sarcoma-like carcinoma is not sensitive to radiotherapy and chemotherapy, and is prone to recurrence and metastasis, the prognosis is poor, and the patient's treatment needs are far from being met.
In 2021, the journal Lancet Respiratory Medicine published the results of a Phase II clinical study of sivatinib for the treatment of metaton jump mutation lung sarcoma-like carcinoma of META14 or other NSCLC subtypes: Of all 70 patients, the orr of cevotinib treatment was 42.9%, the disease control rate (DCR) was 82.9%, the median PFS was 6.8 months, and the median OS was 12.5 months [6].
Notably, the proportion of patients with lung sarcoma-like cancer is as high as 36%, and 21% of patients develop brain metastases. The results of the subgroup analysis showed that the ORR assessed by the Independent Review Committee was 40.0% and the median PFS was 5.5 months in patients with lung sarcoma-like carcinoma. Patients with brain metastases were assessed by an independent review committee with an extracranial ORR of 46.7%, a DCR of 93.3%, and a median PFS of 6.9 months [6].
Based on the research results of sivotinib, the 2021 edition of the CSCO Non-Small Cell Lung Cancer Diagnosis and Treatment Guidelines recommends the use of EXON jump mutations in MET14, and in the level II recommendation, it is pointed out that cevotinib (3 types of evidence) is the treatment choice for patients with first-line untargeted therapy, which is the highest recommended level among MET-targeted drugs [3].
Case review specialist
Professor Fang Jian
Peking University Cancer Hospital, Director of the Second Department of Thoracic Oncology
Chief physician, master tutor
Vice President of Beijing Cancer Prevention and Control Research Association
Chairman of the Lung Cancer Branch Committee of the Beijing Tumor Prevention and Control Research Association
Vice Chairman of the Molecular Targeting Committee of the Geriatric Tumor Professional Committee of the Chinese Gerontological Society
Member of the Lung Cancer Committee of the Geriatric Oncology Professional Committee of the Chinese Gerontological Society
Member of the CSCO Expert Committee on Vascular Targeted Therapy
Member of the Chemotherapy Professional Committee of the Chinese Anti-Cancer Association
Executive member of the Geriatric Professional Committee of the Chinese Anti-Cancer Association
Drug evaluation expert of the State Food and Drug Administration
Professor Han Sen
Ph.D. in Oncology, Peking University Health Science Center
Department II of Thoracic TumorOlogy, Peking University Cancer Hospital
Attending
He is a member of the Lung Cancer Branch Committee of the Beijing Cancer Prevention and Control Research Association
Visiting Scholar, Indiana University-Purdue University, USA
As Sub-I, he is responsible for clinical research in multiple international and domestic multi-center countries
His professional direction is the comprehensive treatment of lung cancer, and he has published more than 30 academic papers
bibliography:
Zou Lili,Ke Qi. Research Progress on Targeted Genes and Their Detection for Non-Small Cell Lung Cancer[J]. Sichuan Journal of Anatomy,2020,28(3):196-200.
[2] ZHOU Ye,YU Yan. MET14 exon jump mutation and non-small cell lung cancer[J].International Journal of Oncology,2021,48(6):366-369.
3]2021 Edition of The Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Non-Small Cell Lung Cancer.
[4] Gow CH, Hsieh MS, Wu SG, Shih JY. A comprehensive analysis of clinical outcomes in lung cancer patients harboring a MET exon 14 skipping mutation compared to other driver mutations in an East Asian population. Lung Cancer. 2017;103:82-89.
[5] Sabari JK, Leonardi GC, Shu CA, et al. PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers. Ann Oncol. 2018;29(10):2085-2091.
[6] Lu S, Fang J, Li X, et al. Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study. Lancet Respir Med. 2021;9(10):1154-1164.
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