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*For medical professionals to read and reference Wonderful case sharing~ This case is a 65-year-old female who was initially diagnosed with adenocarcinoma of the anterior segment of the right upper lobe (T4N1M0, stage IIIb) with EGFR 19del mutation
.
After gefitinib treatment, the tumor progressed to stage IV and developed secondary resistance to EGFR, and the gene test was EGFR 19del with MET amplification
.
The patient was enrolled in the clinical trial of the MET inhibitor sivotinib, and has been treated with sivotinib in combination with gefitinib until now
.
The best curative effect is partial remission (PR).
As of January 2022, the patient's current progression-free survival (PFS) is 58 months, and the follow-up is ongoing
.
This case was provided by Professor Xu Jiali of the First Affiliated Hospital of Nanjing Medical University, and invited Professor Guo Renhua of the First Affiliated Hospital of Nanjing Medical University to comment
.
Case introductionFig 1 After gefitinib treatment, the curative effect reached PRFig 2 After 8 months of gefitinib treatment, chest CT examination showed enlarged lesions in the right upper lobe, and head MR examination showed localized osteolytic bone in the right parietal bone Quality destruction with enhancementFig 3 After radiotherapy + gefitinib treatment, CT examination results showed that the lung lesions were significantly smaller, and the left adrenal nodules were significantly enlarged, and metastasis was considered; MR examination results of skull lesions SDFig 4 After adrenalectomy, CT The examination results showed lung SD and adrenal lesions were shrunkFig 5 After gefitinib combined with chemotherapy: efficacy evaluation SDFig 6 After sivotinib + gefitinib treatment: efficacy evaluation PR The patient was unresectable at the time of consultation Stage IIIb, EGFR 19del mutant lung cancer
.
After 8 months of treatment with EGFR-TKI gefitinib, the lung lesions enlarged and cranial metastases occurred, and the tumor progressed to stage IV
.
After radiotherapy, the patient's headache was relieved, and she continued oral gefitinib for 2 months
.
The patient's lung lesions were significantly smaller, but adrenal metastasis occurred, so left adrenalectomy was performed
.
The patient's adrenal tissue NGS test results showed EGFR 19del, cMET amplification
.
One month later, the patient developed adrenal metastases and was treated with gefitinib and pemetrexed
.
But just over 2 months later, the left adrenal nodule had enlarged
.
The results of genetic testing were still EGFR 19 del and MET amplification
.
Because previous studies suggested that patients with EGFR 19 del and cMET amplification may benefit from dual-target therapy, the patients were enrolled in clinical trials
.
She has been treated with "savatinib 600mg po qd + gefitinib 250mg po qd" until now
.
The best curative effect is PR.
As of January 2022, the patient's current PFS has reached 58 months, and the follow-up is ongoing
.
Professor Xu Jiali, a case provider: After NSCLC patients are resistant to EGFR-TKI therapy, MET mutations should be detected.
In China, the incidence and mortality of lung cancer rank first among malignant tumors
.
The latest data shows that in 2020, more than 810,000 people in China were newly diagnosed with lung cancer, and more than 710,000 people died of lung cancer [1], which seriously threatens the health of the people
.
In recent years, with the rapid development of molecular biology technology and the discovery of different tumor driver genes, the treatment of non-small cell lung cancer (NSCLC) has entered the era of targeted therapy
.
At present, abnormal driver genes of NSCLC have been found including EGFR, KRAS, ALK, etc.
[2]
.
With the application of targeted drugs such as EGFR-TKI and ALK-TKI, the survival time of NSCLC patients has been prolonged, but it is almost inevitable that the tumor usually develops drug resistance
.
EGFR-TKI acquired resistance mutations are very complex, including EGFR secondary mutations, such as T790M mutation; bypass activation, such as MET gene amplification, HER2 amplification or mutation, ALK gene fusion, ROS1 gene fusion, AXL gene amplification, etc.
; may also be transformed from NSCLC to small cell lung cancer (SCLC) [3]
.
The complexity of EGFR-TKI acquired resistance mutations suggests the importance of genetic testing
.
The patient in this case had an EGFR mutation at the initial stage.
After two lines of first-generation EGFR-TKI therapy, secondary drug resistance developed.
The mutation type of the secondary drug resistance is related to the patient's subsequent treatment
.
After NGS detection, the patient had EGFR 19 del and MET amplification double gene mutations
.
After a multidisciplinary discussion, the patient was enrolled in a clinical trial and treated with a dual-target strategy of the MET inhibitor sivotinib 600 mg po qd combined with gefitinib 250 mg po qd so far
.
The best curative effect is PR.
As of January 2022, the patient's current PFS has reached 58 months, and the follow-up is ongoing
.
The premise of precise treatment of NSCLC is accurate diagnosis.
In addition to the clearly required testing items, including EGFR, ROS1, ALK, etc.
, if necessary, the target range of genetic testing can be expanded
.
From this case, after EGFR-TKI resistance, MET amplification must become a must-check item
.
Expert comments on Professor Guo Renhua: EGFR mutation combined with MET amplification, MET-TKI can be used in combination with EGFR-TKIMET gene is a proto-oncogene, located on the long arm of chromosome 7
.
MET amplification has a low incidence in NSCLC and is considered to be one of the resistance mechanisms of EGFR-TKI [2]
.
About 20% of patients with secondary resistance to EGFR-TKIs have MET amplification
.
According to statistics, MET amplification accounts for about 5% of patients with resistance to first-generation EGFR-TKIs, so some researchers believe that MET amplification is one of the potential resistance mechanisms of third-generation EGFR-TKIs [4]
.
For the treatment after MET amplification, there is currently no drug approved in China, mainly chemotherapy, but it can be enrolled in clinical trials and treated with MET inhibitors
.
The patient in this case has EGFR 19 del and MET amplification double gene mutation.
For this mutation type, dual-target inhibition of EGFR and MET pathways may bring synergistic therapeutic benefit
.
In an analysis of gefitinib-resistant cells [5], MET can also phosphorylate HER3, leading to activation of the PI3K-Akt pathway
.
Therefore, neither EGFR nor MET inhibitors alone are sufficient to inactivate the HER3-PI3K-Akt axis or to resist stall cell growth
.
Combination of EGFR and MET inhibitors prevented HER3 phosphorylation and Akt activation in resistant cells, thereby reducing cell survival
.
Most of the previous studies targeting the MET locus targeted primary mutations in MET, but in the international multicenter TATTON study [6], the researchers targeted the treatment of patients with locally advanced or metastatic NSCLC who developed MET amplification after previous EGFR-TKI treatment.
explored to fill a gap in the population with MET resistance mutations who have progressed after EGFR-TKI use
.
In the expansion cohort of the TATTON study, patients were randomly divided into groups B and D after enrollment, and group B was further divided into groups B1, B2 and B3, except that group B1 had previously used third-generation osimertinib treatment, B2 and B3 None of the groups were treated with third-generation EGFR-TKIs.
Group B2 had drug resistance combined with MET amplification but T790M was negative, and group B3 had drug resistance combined with MET amplification and T790M mutation
.
The study design basically achieved full coverage of MET amplification in the first, second and third generation EGFR-TKI treatment resistance
.
The results of the study showed that both PFS and objective response rate (ORR) showed very good results
.
The entire group B patients achieved a PFS of 7.
6 months and an overall ORR of 49%
.
In addition, the 2021 ORCHARD study [7] published the efficacy data of the MET gene variant group after osimertinib resistance
.
Among them, 17 patients were all detected with MET amplification and received osimertinib 80 mg QD + sivotinib 300/600 mg QD treatment, 7 patients achieved PR by the investigator's assessment, ORR was 41%, and all achieved remission of patients are continuing to receive treatment
.
The study will continue to enroll approximately 30 patients as planned, with final efficacy data to be announced in the fourth quarter of 2022
.
The patient has been treated with EGFR-TKI and MET-TKI savatinib dual-target therapy so far, and the best response is PR.
Up to 58 months of PFS has been obtained, and the follow-up is still ongoing
.
Through this case, it can be seen that MET-amplified NSCLC patients with secondary resistance to EGFR-TKI have developed from the helpless in the past to the present
.
At present, the MET inhibitor sivotinib has been approved for the indication of MET exon 14 skipping mutation, and clinical research on the treatment of patients with MET amplification is also underway.
It is believed that patients with MET amplification will have better treatment options in the future
.
Case review expert Professor Guo Renhua Deputy Director of the Department of Oncology, Nanjing Medical University First Affiliated Hospital (Jiangsu Provincial People's Hospital) Deputy Director, Chief Physician Deputy Director of the Department of Oncology, Nanjing Medical University, Professor, Doctoral Supervisor Director of the Chinese Society of Clinical Oncology (CSCO) CSCO Non Member of the Small Cell Lung Cancer Expert Committee Member of the CSCO Small Cell Lung Cancer Expert Committee Member of the CSCO Translational Medicine Expert Committee Member of the Prevention and Treatment Professional Committee Member of the Thoracic Oncology Branch of the China Association for the Promotion of International Exchanges in Healthcare Deputy Head of the Lung Oncology Group, Biotherapy Branch, Case Provider Professor Xu Jiali, MD, Deputy Chief Physician of the Department of Medical Oncology, Jiangsu Provincial People's Hospital, Deputy Director and Working Secretary of the Oncology Branch of Nanjing Medical Association Young Member of the Academic Working Committee Member of the Chinese Society of Clinical Oncology Member of the Rescue Team of the Red Cross Society of Jiangsu Province The science experts of the Red Cross Society of Jiangsu Province have published nearly 20 SCI articles as the first or corresponding author, specializing in the diagnosis and comprehensive treatment of lung cancer References: [1] .
Sung H, Ferlay J, Siegel RL, et al.
Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].
CA: a cancer journal for clinicians, 2021, 71(3): 209-249.
[2].
Jiang Xiaoyun, Li Mengling, et al.
Research progress of small molecules targeting EGFR in the treatment of non-small cell lung cancer[J].
Pharmaceutical Research, 2021,40(11),753-759[3].
Camidge, D .
, Pao, W.
& Sequist, L.
Acquired resistance to TKIs in solid tumors: learning from lung cancer.
Nat Rev Clin Oncol 11, 473–481 (2014).
[4].
Pan Yaqiang, Li Zhenhua, et al.
The mechanism of secondary resistance to epidermal growth factor receptor tyrosine kinase inhibitors in patients with epidermal growth factor receptor mutant non-small cell lung cancer Research progress of new strategies for targeted therapy [J].
Journal of Practical Cardiovascular and Cerebrovascular Diseases 2019, 27(12), 21-27[5].
Arteaga, CL (2007).
HER3 and mutant EGFR meet MET.
Nature medicine , 13(6), 675-677[6].
Sequist LV, et al.
Lancet Oncol.
2020 Mar;21(3):373-386.
[7].
Sequist LV, Han JY, Ahn MJ, 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].
The Lancet Oncology , 2020, 21(3): 373-386.
*This article is only for providing scientific information to medical professionals and does not represent the views of this platform675-677[6].
Sequist LV, et al.
Lancet Oncol.
2020 Mar;21(3):373-386.
[7].
Sequist LV, Han JY, Ahn MJ, 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].
The Lancet Oncology, 2020, 21(3 ): 373-386.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform675-677[6].
Sequist LV, et al.
Lancet Oncol.
2020 Mar;21(3):373-386.
[7].
Sequist LV, Han JY, Ahn MJ, 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].
The Lancet Oncology, 2020, 21(3 ): 373-386.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform
.
After gefitinib treatment, the tumor progressed to stage IV and developed secondary resistance to EGFR, and the gene test was EGFR 19del with MET amplification
.
The patient was enrolled in the clinical trial of the MET inhibitor sivotinib, and has been treated with sivotinib in combination with gefitinib until now
.
The best curative effect is partial remission (PR).
As of January 2022, the patient's current progression-free survival (PFS) is 58 months, and the follow-up is ongoing
.
This case was provided by Professor Xu Jiali of the First Affiliated Hospital of Nanjing Medical University, and invited Professor Guo Renhua of the First Affiliated Hospital of Nanjing Medical University to comment
.
Case introductionFig 1 After gefitinib treatment, the curative effect reached PRFig 2 After 8 months of gefitinib treatment, chest CT examination showed enlarged lesions in the right upper lobe, and head MR examination showed localized osteolytic bone in the right parietal bone Quality destruction with enhancementFig 3 After radiotherapy + gefitinib treatment, CT examination results showed that the lung lesions were significantly smaller, and the left adrenal nodules were significantly enlarged, and metastasis was considered; MR examination results of skull lesions SDFig 4 After adrenalectomy, CT The examination results showed lung SD and adrenal lesions were shrunkFig 5 After gefitinib combined with chemotherapy: efficacy evaluation SDFig 6 After sivotinib + gefitinib treatment: efficacy evaluation PR The patient was unresectable at the time of consultation Stage IIIb, EGFR 19del mutant lung cancer
.
After 8 months of treatment with EGFR-TKI gefitinib, the lung lesions enlarged and cranial metastases occurred, and the tumor progressed to stage IV
.
After radiotherapy, the patient's headache was relieved, and she continued oral gefitinib for 2 months
.
The patient's lung lesions were significantly smaller, but adrenal metastasis occurred, so left adrenalectomy was performed
.
The patient's adrenal tissue NGS test results showed EGFR 19del, cMET amplification
.
One month later, the patient developed adrenal metastases and was treated with gefitinib and pemetrexed
.
But just over 2 months later, the left adrenal nodule had enlarged
.
The results of genetic testing were still EGFR 19 del and MET amplification
.
Because previous studies suggested that patients with EGFR 19 del and cMET amplification may benefit from dual-target therapy, the patients were enrolled in clinical trials
.
She has been treated with "savatinib 600mg po qd + gefitinib 250mg po qd" until now
.
The best curative effect is PR.
As of January 2022, the patient's current PFS has reached 58 months, and the follow-up is ongoing
.
Professor Xu Jiali, a case provider: After NSCLC patients are resistant to EGFR-TKI therapy, MET mutations should be detected.
In China, the incidence and mortality of lung cancer rank first among malignant tumors
.
The latest data shows that in 2020, more than 810,000 people in China were newly diagnosed with lung cancer, and more than 710,000 people died of lung cancer [1], which seriously threatens the health of the people
.
In recent years, with the rapid development of molecular biology technology and the discovery of different tumor driver genes, the treatment of non-small cell lung cancer (NSCLC) has entered the era of targeted therapy
.
At present, abnormal driver genes of NSCLC have been found including EGFR, KRAS, ALK, etc.
[2]
.
With the application of targeted drugs such as EGFR-TKI and ALK-TKI, the survival time of NSCLC patients has been prolonged, but it is almost inevitable that the tumor usually develops drug resistance
.
EGFR-TKI acquired resistance mutations are very complex, including EGFR secondary mutations, such as T790M mutation; bypass activation, such as MET gene amplification, HER2 amplification or mutation, ALK gene fusion, ROS1 gene fusion, AXL gene amplification, etc.
; may also be transformed from NSCLC to small cell lung cancer (SCLC) [3]
.
The complexity of EGFR-TKI acquired resistance mutations suggests the importance of genetic testing
.
The patient in this case had an EGFR mutation at the initial stage.
After two lines of first-generation EGFR-TKI therapy, secondary drug resistance developed.
The mutation type of the secondary drug resistance is related to the patient's subsequent treatment
.
After NGS detection, the patient had EGFR 19 del and MET amplification double gene mutations
.
After a multidisciplinary discussion, the patient was enrolled in a clinical trial and treated with a dual-target strategy of the MET inhibitor sivotinib 600 mg po qd combined with gefitinib 250 mg po qd so far
.
The best curative effect is PR.
As of January 2022, the patient's current PFS has reached 58 months, and the follow-up is ongoing
.
The premise of precise treatment of NSCLC is accurate diagnosis.
In addition to the clearly required testing items, including EGFR, ROS1, ALK, etc.
, if necessary, the target range of genetic testing can be expanded
.
From this case, after EGFR-TKI resistance, MET amplification must become a must-check item
.
Expert comments on Professor Guo Renhua: EGFR mutation combined with MET amplification, MET-TKI can be used in combination with EGFR-TKIMET gene is a proto-oncogene, located on the long arm of chromosome 7
.
MET amplification has a low incidence in NSCLC and is considered to be one of the resistance mechanisms of EGFR-TKI [2]
.
About 20% of patients with secondary resistance to EGFR-TKIs have MET amplification
.
According to statistics, MET amplification accounts for about 5% of patients with resistance to first-generation EGFR-TKIs, so some researchers believe that MET amplification is one of the potential resistance mechanisms of third-generation EGFR-TKIs [4]
.
For the treatment after MET amplification, there is currently no drug approved in China, mainly chemotherapy, but it can be enrolled in clinical trials and treated with MET inhibitors
.
The patient in this case has EGFR 19 del and MET amplification double gene mutation.
For this mutation type, dual-target inhibition of EGFR and MET pathways may bring synergistic therapeutic benefit
.
In an analysis of gefitinib-resistant cells [5], MET can also phosphorylate HER3, leading to activation of the PI3K-Akt pathway
.
Therefore, neither EGFR nor MET inhibitors alone are sufficient to inactivate the HER3-PI3K-Akt axis or to resist stall cell growth
.
Combination of EGFR and MET inhibitors prevented HER3 phosphorylation and Akt activation in resistant cells, thereby reducing cell survival
.
Most of the previous studies targeting the MET locus targeted primary mutations in MET, but in the international multicenter TATTON study [6], the researchers targeted the treatment of patients with locally advanced or metastatic NSCLC who developed MET amplification after previous EGFR-TKI treatment.
explored to fill a gap in the population with MET resistance mutations who have progressed after EGFR-TKI use
.
In the expansion cohort of the TATTON study, patients were randomly divided into groups B and D after enrollment, and group B was further divided into groups B1, B2 and B3, except that group B1 had previously used third-generation osimertinib treatment, B2 and B3 None of the groups were treated with third-generation EGFR-TKIs.
Group B2 had drug resistance combined with MET amplification but T790M was negative, and group B3 had drug resistance combined with MET amplification and T790M mutation
.
The study design basically achieved full coverage of MET amplification in the first, second and third generation EGFR-TKI treatment resistance
.
The results of the study showed that both PFS and objective response rate (ORR) showed very good results
.
The entire group B patients achieved a PFS of 7.
6 months and an overall ORR of 49%
.
In addition, the 2021 ORCHARD study [7] published the efficacy data of the MET gene variant group after osimertinib resistance
.
Among them, 17 patients were all detected with MET amplification and received osimertinib 80 mg QD + sivotinib 300/600 mg QD treatment, 7 patients achieved PR by the investigator's assessment, ORR was 41%, and all achieved remission of patients are continuing to receive treatment
.
The study will continue to enroll approximately 30 patients as planned, with final efficacy data to be announced in the fourth quarter of 2022
.
The patient has been treated with EGFR-TKI and MET-TKI savatinib dual-target therapy so far, and the best response is PR.
Up to 58 months of PFS has been obtained, and the follow-up is still ongoing
.
Through this case, it can be seen that MET-amplified NSCLC patients with secondary resistance to EGFR-TKI have developed from the helpless in the past to the present
.
At present, the MET inhibitor sivotinib has been approved for the indication of MET exon 14 skipping mutation, and clinical research on the treatment of patients with MET amplification is also underway.
It is believed that patients with MET amplification will have better treatment options in the future
.
Case review expert Professor Guo Renhua Deputy Director of the Department of Oncology, Nanjing Medical University First Affiliated Hospital (Jiangsu Provincial People's Hospital) Deputy Director, Chief Physician Deputy Director of the Department of Oncology, Nanjing Medical University, Professor, Doctoral Supervisor Director of the Chinese Society of Clinical Oncology (CSCO) CSCO Non Member of the Small Cell Lung Cancer Expert Committee Member of the CSCO Small Cell Lung Cancer Expert Committee Member of the CSCO Translational Medicine Expert Committee Member of the Prevention and Treatment Professional Committee Member of the Thoracic Oncology Branch of the China Association for the Promotion of International Exchanges in Healthcare Deputy Head of the Lung Oncology Group, Biotherapy Branch, Case Provider Professor Xu Jiali, MD, Deputy Chief Physician of the Department of Medical Oncology, Jiangsu Provincial People's Hospital, Deputy Director and Working Secretary of the Oncology Branch of Nanjing Medical Association Young Member of the Academic Working Committee Member of the Chinese Society of Clinical Oncology Member of the Rescue Team of the Red Cross Society of Jiangsu Province The science experts of the Red Cross Society of Jiangsu Province have published nearly 20 SCI articles as the first or corresponding author, specializing in the diagnosis and comprehensive treatment of lung cancer References: [1] .
Sung H, Ferlay J, Siegel RL, et al.
Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].
CA: a cancer journal for clinicians, 2021, 71(3): 209-249.
[2].
Jiang Xiaoyun, Li Mengling, et al.
Research progress of small molecules targeting EGFR in the treatment of non-small cell lung cancer[J].
Pharmaceutical Research, 2021,40(11),753-759[3].
Camidge, D .
, Pao, W.
& Sequist, L.
Acquired resistance to TKIs in solid tumors: learning from lung cancer.
Nat Rev Clin Oncol 11, 473–481 (2014).
[4].
Pan Yaqiang, Li Zhenhua, et al.
The mechanism of secondary resistance to epidermal growth factor receptor tyrosine kinase inhibitors in patients with epidermal growth factor receptor mutant non-small cell lung cancer Research progress of new strategies for targeted therapy [J].
Journal of Practical Cardiovascular and Cerebrovascular Diseases 2019, 27(12), 21-27[5].
Arteaga, CL (2007).
HER3 and mutant EGFR meet MET.
Nature medicine , 13(6), 675-677[6].
Sequist LV, et al.
Lancet Oncol.
2020 Mar;21(3):373-386.
[7].
Sequist LV, Han JY, Ahn MJ, 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].
The Lancet Oncology , 2020, 21(3): 373-386.
*This article is only for providing scientific information to medical professionals and does not represent the views of this platform675-677[6].
Sequist LV, et al.
Lancet Oncol.
2020 Mar;21(3):373-386.
[7].
Sequist LV, Han JY, Ahn MJ, 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].
The Lancet Oncology, 2020, 21(3 ): 373-386.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform675-677[6].
Sequist LV, et al.
Lancet Oncol.
2020 Mar;21(3):373-386.
[7].
Sequist LV, Han JY, Ahn MJ, 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].
The Lancet Oncology, 2020, 21(3 ): 373-386.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform
