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After multi-line treatment, immunohistochemistry detected MET overexpression of lung cancer patients with brain metastasis, and cevotinib + third-generation EGFR-TKI strongly reversed the condition.
This case was initially diagnosed as a patient with left pulmonary adenosquamous cell carcinoma (T3N3M0 stage IIIc) with mutation in exon 21 of EGFR. After surgical resection and postoperative adjuvant chemotherapy, multiple intracranial metastasis were found. After that, the patient underwent five-line treatment, including first-generation EGFR-TKI, third-generation EGFR-TKI, anti-angiogenic therapy combined with chemotherapy, etc., and underwent two intracranial surgeries. At this time, the patient's physical condition was extremely poor, with a PS score of 4 points. After immunohistochemistry (IHC) detection found that MET overexpression, the patient used six-line treatment with sevotinib + third-generation EGFR-TKI, and the tumor achieved partial remission (PR), and the thinking response gradually returned to normal, and no adverse reactions related to treatment occurred. The case was provided by Professor Su Meng, the First Affiliated Hospital of Wenzhou Medical University, and Professor Zou Changlin, the First Affiliated Hospital of Wenzhou Medical University, and was invited to comment on .
case introduction
basic information
female, 53 years old.
Past history: deny the history of chronic diseases such as hypertension , diabetes , infectious diseases such as hepatitis , tuberculosis , history of food allergies, denied the history of surgery, trauma and blood transfusion, and planned immunization according to local conditions. History of penicillin allergies.
Current medical history: In April 2015, a basal nodule (15*13mm) in the lower lobe of the left lung was found.
case provides expert
Professor Su Meng: IHC detects brain metastasis patients with MET overexpression, sevotinib + third-generation EGFR-TKI six-line treatment achieves PR
In recent years, lung cancer diagnosis and treatment has developed rapidly, and has gradually changed from the previous "one-size-fits-all" model to individualized and precise treatment under the guidance of molecular typing. EGFR mutation is the most common driver gene mutation in lung cancer patients in my country, and it exists in about half of the patients. The advent of EGFR-TKI brings long-term survival hope for such patients, but targeted therapy will inevitably lead to drug resistance in the end. Patients with EGFR-TKI resistant may develop tumor progression for different reasons, blind use of chemotherapy or other targeted drugs may have little effect and reduce survival expectations. At present, domestic and foreign guidelines recommend gene detection such as MET amplification after EGFR-TKI to clarify the causes of drug resistance and guide subsequent precise treatment. Therefore, clinicians should improve their awareness of genetic testing after drug resistance and confirm the root causes of drug resistance. Accurate targeted treatment is the key to improving patients' survival benefits.
This patient was initially diagnosed as a left lung adenosquamous cell carcinoma (T3N3M0 stage IIIc) with EGFR 21L858R mutation, and underwent "thoracoscopic left inferior lobe resection + lymph node dissection" and received adjuvant chemotherapy after surgery. Unfortunately, the review found that the patient had multiple intracranial metastasis. The patient was treated with first-line treatment with first-generation EGFR-TKI and obtained CR in the intracranial lesion 2 months later. After PD, genetic testing found a T790M mutation, so the second-line treatment of osimertinib was used, but the effect was not ideal. After that, the patient received third-line treatment of temozolomide + anlotinib, deep tumor resection of Mushang, fourth-line treatment of pemetrexed + bevacizumab, fifth-line treatment of cisplatin + vinorelbine and right frontal lobe lesions resection.
Then the patient had seizures , and the patient improved after emergency sedation treatment. However, afterwards, he became slow to respond, repeated headaches and dizziness, and his symptoms continued to worsen. He was given mannitol 250ml q8h maintenance treatment. In addition, the patient's PS score was 4 points and his physical condition was extremely poor. All of these pose great challenges to the choice of subsequent treatment options. Fortunately, the patient used the first intracranial metastasis surgical specimen MET IHC to detect MET overexpression (>50% of tumor cells with strong positive). After the dual target treatment of sevotinib + third-generation EGFR-TKI, the patient's thinking response gradually returned to normal after treatment, without headache or dizziness. The mannitol injection is gradually reduced until the medication is stopped. PR was achieved in the intracranial lesions, and have achieved a progression-free survival of 4 months (PFS), and no treatment-related side effects occurred during the treatment period.
From the treatment process of this case, it can be seen that for patients with lung cancer brain metastasis who are overexpressed after EGFR-TKI resistance, the dual-target precise treatment of cevotinib + third-generation EGFR-TKI have significant intracranial efficacy and is safe, and can be tolerated even in patients with PS scores as low as 4. This case further confirms the important value of MET overexpression as a guide to in biomarker, and also reminds clinicians that IHC detection of MET overexpression should not be ignored after EGFR-TKI resistance.
Comment Expert
Professor Zou Changlin: MET overexpression after EGFR-TKI resistance, MET+EGFR dual-target treatment helps patients benefit more
MET abnormality in non-small cell lung cancer (NSCLC) includes exon jump mutation of MET14, MET amplification, MET fusion, MET overexpression, etc. The study showed that the proportion of MET overexpression in NSCLC is 13.7% to 63.7%, and the incidence rate in patients with advanced EGFR mutation NSCLC treated with EGFR-TKI was 30.4% to 37.0% [1].
At present, MET overexpression has shown potential guiding value in the clinical treatment of NSCLC MET inhibitors, but the benefit thresholds of different populations need further research. TATOON and other studies showed that patients with 3+ tumor cells with MET IHC ≥50% after EGFR-TKI resistance may benefit from the treatment of EGFR-TKI combined with MET inhibitors, while the moderately positive (2+) subgroup of tumor cells with IHC ≥50% responded poorly to combined targeted therapy [2]. In addition, SAVANNAH study showed that for patients with advanced NSCLC after MET amplification/overexpression after osimertinib, the objective response rate (ORR) of the total population (IHC ≥50% tumor cells 3+ and/or FISH GCN ≥5) was 32%, the median duration of remission (DoR) was 8.3 months, and the median PFS was 5.3 months; and the population with high MET amplification/high overexpression (IHC ≥90% tumor cells 3+ and/or FISH GCN ≥10) benefited more, with an ORR of 49%, a median DoR of 9.3 months, and a median PFS of 7.1 months [3]. This data once again affirms the efficacy of sevotinib combined with osimertinib dual-target treatment of MET overexpression, and also provides a reference for determining the MET overexpression threshold for potential benefit populations.
In addition, since celerotinib is not a substrate for P-glycoprotein (P-gp), it is theoretically not easily discharged by the blood-brain barrier efflux pump, which can maintain the concentration of drugs in the brain, which lays the theoretical foundation for celerotinib to be used in clinical patients with brain metastasis. Its strong brain-entering effect has also been confirmed in many clinical studies.
This case of brain metastasis after lung cancer has undergone five-line treatment including first-generation and third-generation EGFR-TKI, as well as two intracranial surgeries, with a PS score of 4 points. After the failure of fifth-line treatment, the MET IHC test used the first intracranial metastasis surgical specimen to indicate MET overexpression (>50% of tumor cells). After six-line treatment with Sevotinib + third-generation EGFR-TKI dual target, the intracranial lesion obtained PR, and the thinking response gradually returned to normal, without headache or dizziness, and no treatment-related side effects have occurred so far, which once again confirmed the intracranial efficacy and safety of this dual-target combination therapy regimen, which may be a better treatment option for patients with MET overexpression in clinical practice.
IHC is a commonly used MET overexpression detection method in clinical practice. It is easy to use and relatively cheap. If it can be widely used in clinical practice to detect MET overexpression and guide clinical MET targeted treatment, it will be expected that more patients can benefit from precise diagnosis and treatment. At the same time, it is also hoped that the consistency comparison study of different MET detection antibodies can be carried out in the future, and further clarify the interpretation standards for MET overexpression and the benefit threshold , providing guidance for clinical standardized diagnosis and treatment.
case review expert profile
Zou Changlin Professor
Chief physician, professor, master's supervisor
Director of the Department of Radiotherapy, First Affiliated Hospital of Wenzhou Medical University
Director of the Radiation Oncology Regulatory Training Base of Wenzhou Medical University
Deputy Chairman of the Oncology Branch of Zhejiang Medical Association
Vice Chairman of the Oncology Branch of Zhejiang Medical Association Tumor Radiation Therapy Physician Branch of Zhejiang Medical Association
Vice Chairman of the Radiation Oncology Professional Committee of Zhejiang Anti-Cancer Association
Vice Chairman of the Radiation Oncology Professional Committee of Zhejiang Anti-Cancer Association
html l0 Member of the Standing Committee of the Small Cell Lung Cancer Professional Committee of Zhejiang Anti-Cancer AllianceMember of the Standing Committee of the Evidence-Based Medicine Professional Committee of Zhejiang Mathematical Medicine Society
Member of the Radiation Tumor Treatment Branch of Zhejiang Medical Association
Member of the Nasopharyngeal Carcinoma Professional Committee of Zhejiang Anti-Cancer Association
presided over 15 key projects of the Ministry of Education, provincial natural science foundation and provincial and municipal scientific research projects, won the third prize of Zhejiang Province's health science and technology innovation, 1 third prize of provincial traditional Chinese medicine science and technology, and owned 3 national patents. More than 60 papers have been published as the first author or corresponding author, and more than 20 papers have been included in SCI.
cases provide an expert profile
Su Meng Professor
Department of Radiotherapy Department of Wenzhou Medical University First Affiliated Hospital Chief Physician MD
Publish more than ten SCI papers
Good at radiation therapy and comprehensive internal medicine treatment
Good at radiation therapy and comprehensive internal medicine treatment
References:
[1]. Pathology Branch of the Chinese Medical Association, National Pathology Quality Control Center, Lung Cancer Group of the Oncology Branch of the Chinese Medical Association, et al. MET clinical testing of non-small cell lung cancer [J]. Chinese Journal of Pathology, 2022, 51(11): 1094-1103.
[2].Lecia V Sequist, Ji-Youn Han, et al. Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study[J]. Lancet Oncol. 2020;21(3):373-386.
[3].Ann M J, et al. MET Biomarker-based Preliminary Efficacy Analysis in SAVANNAH: savolitinib+osimertinib in EGFRm NSCLC Post-Osimertinib. WCLC 2022. EP08.02-140.
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