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*Only for medical professionals to read for reference MET inhibitors are safe and effective in treating lung sarcomatoid carcinoma with skipping mutations of MET14 exon
.
Many people are familiar with lung cancer, but when it comes to pulmonary sarcomatoid carcinoma (PSC), you may feel unfamiliar
.
PSC can be said to be the "king" in lung cancer
.
PSC is a general term for a rare type of non-small cell lung cancer (NSCLC), accounting for about 0.
1%-0.
5% of lung malignancies
.
According to the 2015 World Health Organization (WHO) classification standards for lung malignant tumors, PSC belongs to lung malignant epithelial cell tumors, which includes 5 subtypes, namely pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma and Pulmonary blastoma [1]
.
PSC is very "cunning" and has no typical clinical symptoms, but imaging has certain characteristics, and diagnosis requires pathological and immunohistochemical examinations
.
The treatment principle of PSC is similar to that of other NSCLC.
Early patients are treated with a comprehensive treatment model based on surgery
.
Unfortunately, PSC is not sensitive to radiotherapy and chemotherapy, and is prone to recurrence and metastasis, and the prognosis is poor
.
In recent years, with the development of detection technology and the exploration of PSC molecular pathology, mesenchymal-epithelial cell conversion factor (MET) tyrosine kinase inhibitor (TKI) is expected to bring a breakthrough in the treatment of PSC
.
The misdiagnosis rate of PSC is high, and the treatment options are limited.
PSC is more common in elderly, male, and smoking patients.
The average age of the patients is 65-75 years [1].
About 70% of patients have been diagnosed with locally advanced or distant metastases at the time of diagnosis.
To treatment is a clinical difficulty
.
The misdiagnosis rate of PSC is relatively high, and it is difficult to confirm the diagnosis of PSC only by clinical manifestations and imaging examinations, which means that tumor histopathological examination is very important for the differential diagnosis of PSC
.
However, due to the high heterogeneity of PSC, small biopsy or cytology samples cannot provide sufficient evidence for diagnosis
.
In terms of treatment, except for surgery, PSC patients have little benefit from radiotherapy and chemotherapy
.
On the whole, PSC is not only difficult to diagnose, but the greater dilemma lies in the limitations of treatment methods
.
In general, PSC is a type of NSCLC with a high degree of malignancy and a poor prognosis.
Compared with other types of NSCLC, the risk of death is significantly higher, and the treatment needs of patients are far from being met
.
PSC patients with skipping mutations in exon MET14 have a higher risk of recurrence.
With the continuous improvement of detection methods, the exploration of the molecular characteristics of PSC has also been intensified
.
Researchers found that PSC is a type of NSCLC with a high frequency of driving gene mutations, and mutations in EGFR, KRAS, ALK and MET genes are more common
.
In NSCLC, MET14 exon skip mutation rate is not as common as EGFR, but in PSC, MET14 exon skip mutation rate is very high, reaching 31.
8%
.
PSC is more aggressive than other NSCLC subtypes and has a worse prognosis
.
The protein c-MET encoded by the MET gene is a transmembrane tyrosine kinase receptor.
The MET pathway is involved in the regulation of cell proliferation, migration and angiogenesis
.
Mutations in the MET gene, including the 14th exon skipping and gene amplification, can cause abnormal activation of the MET pathway, thereby driving the proliferation and migration of cancer cells, and promoting tumor development [2]
.
It is understood that advanced PSC has low response to radiotherapy and is resistant to many chemotherapeutic drugs, and the treatment efficiency is low
.
Platinum-based combination chemotherapy is still the current standard treatment for advanced PSC, but the efficacy of first-line chemotherapy is not good
.
A study based on DNA and RNA NGS detected the driver gene mutation profile of 77 Chinese PSC patients, and collected and analyzed the demographic characteristics and clinical results of patients with MET14 exon jumping mutations
.
The results showed that MET14 exon skip mutation is one of the poor prognostic factors for patients with advanced PSC.
The disease recurrence time of MET14 exon skip mutation positive PSC patients was significantly shorter than that of negative patients (P=0.
017) [3]
.
This means that the existence of a jumping mutation in MET14 exon makes the treatment of PSC, which is already highly malignant, more difficult
.
MET inhibitors bring a turning point for MET14 exon skip mutation PSC.
The 2019 American Association for Cancer Research (AACR) annual meeting, a phase II clinical trial on the treatment of MET14 exon skip mutation PSC or other NSCLC subtypes The results of the study were announced for the first time; at the 2020 American Society of Clinical Oncology (ASCO) annual meeting, the study was unveiled again, astounding global experts with a disease control rate (DCR) of 93.
4%
.
This research was led by Professor Lu Shun from the Chest Hospital of Shanghai Jiaotong University
.
The full text was published in The Lancet·Respiratory Medicine in June 2021 [4]
.
The drug used in this study is Syvotinib, a highly selective MET-TKI that inhibits tumor growth and metastasis by blocking the MET signaling pathway
.
Saivotinib has been approved for marketing by the National Medical Products Administration (NMPA) of China in June 2021.
The indications are: disease progression after platinum-containing chemotherapy or intolerance to standard platinum-containing chemotherapy, with MET14 exon skip mutation Of adult patients with locally advanced or metastatic NSCLC
.
The approval of Syvotinib means that China has ushered in the first approved highly selective MET inhibitor
.
Returning to the study itself, the study included 70 patients with locally advanced or metastatic MET14 exon skip mutation positive and histological type of PSC or other NSCLC subtypes
.
The patient has previously received at least first-line systemic treatment (or intolerance), and has progressed or cannot tolerate the toxicity of the treatment, and receives treatment with Sevotinib, and the treatment is until the disease has progressed or the toxicity is intolerable
.
The original research design of the study was based on the good efficacy of Syvotinib for PSC patients, and only targeted PSC patients were enrolled
.
Later, due to the small number of patients, the study population was expanded to all NSCLC with skipping mutations in MET14 exon, so up to 1/3 of the patients in this study were PSC patients
.
Studies have shown that the objective response rate (ORR) of Syvotinib in PSC patients reached 40%, the median duration of response (DoR) was 17.
9 months, and the median progression-free survival (PFS) was 5.
5 months
.
For the first time, Syvotinib has brought the possibility of high-efficiency treatment for PSC patients
.
In all populations, the ORR assessed by the Independent Review Committee (IRC) was 42.
9%, the median DoR was 8.
3 months, and 7 patients (10%) sustained remission for 12 months or longer; median overall survival (OS) was 12.
5 months, the median PFS was 6.
8 months, and the 6-month and 12-month PFS rates were 52% and 31.
9%, respectively
.
In terms of safety, the treatment-related adverse reactions (TRAEs) of Syvotinib are mostly grade 1-2, and the most common treatment-related adverse reactions of any grade are peripheral edema (54%), nausea (46%), and elevated ALT ( 39%) and elevated AST (37%), no interstitial lung disease occurred in the enrolled patients, and the patients had good clinical tolerance
.
This study showed that in PSC and other NSCLC patients with skipping mutations in MET14 exon, Saivotinib showed encouraging ORR, with good efficacy and safety
.
This is undoubtedly a new dawn for PSC patients with high malignancy and extremely poor prognosis
.
I hope that more clinical studies will be included in the PSC in the future, bringing more hope to this group of patients with extremely poor prognosis
.
References: [1] Liu Lei, et al.
, Diagnosis and treatment status of pulmonary sarcomatoid carcinoma[J].
Chinese Journal of Lung Cancer, 2018,021(012):902-906.
[2] Yin Limei, et al.
MET14 exon skipping mutation Research progress in non-small cell lung cancer[J].
Chinese Journal of Lung Cancer,2018,21(07):553-559.
[3]Li Y,et al.
,Identification of MET exon14 skipping by targeted DNA-and RNA- based next-generation sequencing in pulmonary sarcomatoid carcinomas[J].
Lung Cancer,2018 Aug;122:113-119.
[4]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[J].
The Lancet Respiratory Medicine,2021.
*This article is only for Scientific information provided by people does not represent the views of this platform
.
Many people are familiar with lung cancer, but when it comes to pulmonary sarcomatoid carcinoma (PSC), you may feel unfamiliar
.
PSC can be said to be the "king" in lung cancer
.
PSC is a general term for a rare type of non-small cell lung cancer (NSCLC), accounting for about 0.
1%-0.
5% of lung malignancies
.
According to the 2015 World Health Organization (WHO) classification standards for lung malignant tumors, PSC belongs to lung malignant epithelial cell tumors, which includes 5 subtypes, namely pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma and Pulmonary blastoma [1]
.
PSC is very "cunning" and has no typical clinical symptoms, but imaging has certain characteristics, and diagnosis requires pathological and immunohistochemical examinations
.
The treatment principle of PSC is similar to that of other NSCLC.
Early patients are treated with a comprehensive treatment model based on surgery
.
Unfortunately, PSC is not sensitive to radiotherapy and chemotherapy, and is prone to recurrence and metastasis, and the prognosis is poor
.
In recent years, with the development of detection technology and the exploration of PSC molecular pathology, mesenchymal-epithelial cell conversion factor (MET) tyrosine kinase inhibitor (TKI) is expected to bring a breakthrough in the treatment of PSC
.
The misdiagnosis rate of PSC is high, and the treatment options are limited.
PSC is more common in elderly, male, and smoking patients.
The average age of the patients is 65-75 years [1].
About 70% of patients have been diagnosed with locally advanced or distant metastases at the time of diagnosis.
To treatment is a clinical difficulty
.
The misdiagnosis rate of PSC is relatively high, and it is difficult to confirm the diagnosis of PSC only by clinical manifestations and imaging examinations, which means that tumor histopathological examination is very important for the differential diagnosis of PSC
.
However, due to the high heterogeneity of PSC, small biopsy or cytology samples cannot provide sufficient evidence for diagnosis
.
In terms of treatment, except for surgery, PSC patients have little benefit from radiotherapy and chemotherapy
.
On the whole, PSC is not only difficult to diagnose, but the greater dilemma lies in the limitations of treatment methods
.
In general, PSC is a type of NSCLC with a high degree of malignancy and a poor prognosis.
Compared with other types of NSCLC, the risk of death is significantly higher, and the treatment needs of patients are far from being met
.
PSC patients with skipping mutations in exon MET14 have a higher risk of recurrence.
With the continuous improvement of detection methods, the exploration of the molecular characteristics of PSC has also been intensified
.
Researchers found that PSC is a type of NSCLC with a high frequency of driving gene mutations, and mutations in EGFR, KRAS, ALK and MET genes are more common
.
In NSCLC, MET14 exon skip mutation rate is not as common as EGFR, but in PSC, MET14 exon skip mutation rate is very high, reaching 31.
8%
.
PSC is more aggressive than other NSCLC subtypes and has a worse prognosis
.
The protein c-MET encoded by the MET gene is a transmembrane tyrosine kinase receptor.
The MET pathway is involved in the regulation of cell proliferation, migration and angiogenesis
.
Mutations in the MET gene, including the 14th exon skipping and gene amplification, can cause abnormal activation of the MET pathway, thereby driving the proliferation and migration of cancer cells, and promoting tumor development [2]
.
It is understood that advanced PSC has low response to radiotherapy and is resistant to many chemotherapeutic drugs, and the treatment efficiency is low
.
Platinum-based combination chemotherapy is still the current standard treatment for advanced PSC, but the efficacy of first-line chemotherapy is not good
.
A study based on DNA and RNA NGS detected the driver gene mutation profile of 77 Chinese PSC patients, and collected and analyzed the demographic characteristics and clinical results of patients with MET14 exon jumping mutations
.
The results showed that MET14 exon skip mutation is one of the poor prognostic factors for patients with advanced PSC.
The disease recurrence time of MET14 exon skip mutation positive PSC patients was significantly shorter than that of negative patients (P=0.
017) [3]
.
This means that the existence of a jumping mutation in MET14 exon makes the treatment of PSC, which is already highly malignant, more difficult
.
MET inhibitors bring a turning point for MET14 exon skip mutation PSC.
The 2019 American Association for Cancer Research (AACR) annual meeting, a phase II clinical trial on the treatment of MET14 exon skip mutation PSC or other NSCLC subtypes The results of the study were announced for the first time; at the 2020 American Society of Clinical Oncology (ASCO) annual meeting, the study was unveiled again, astounding global experts with a disease control rate (DCR) of 93.
4%
.
This research was led by Professor Lu Shun from the Chest Hospital of Shanghai Jiaotong University
.
The full text was published in The Lancet·Respiratory Medicine in June 2021 [4]
.
The drug used in this study is Syvotinib, a highly selective MET-TKI that inhibits tumor growth and metastasis by blocking the MET signaling pathway
.
Saivotinib has been approved for marketing by the National Medical Products Administration (NMPA) of China in June 2021.
The indications are: disease progression after platinum-containing chemotherapy or intolerance to standard platinum-containing chemotherapy, with MET14 exon skip mutation Of adult patients with locally advanced or metastatic NSCLC
.
The approval of Syvotinib means that China has ushered in the first approved highly selective MET inhibitor
.
Returning to the study itself, the study included 70 patients with locally advanced or metastatic MET14 exon skip mutation positive and histological type of PSC or other NSCLC subtypes
.
The patient has previously received at least first-line systemic treatment (or intolerance), and has progressed or cannot tolerate the toxicity of the treatment, and receives treatment with Sevotinib, and the treatment is until the disease has progressed or the toxicity is intolerable
.
The original research design of the study was based on the good efficacy of Syvotinib for PSC patients, and only targeted PSC patients were enrolled
.
Later, due to the small number of patients, the study population was expanded to all NSCLC with skipping mutations in MET14 exon, so up to 1/3 of the patients in this study were PSC patients
.
Studies have shown that the objective response rate (ORR) of Syvotinib in PSC patients reached 40%, the median duration of response (DoR) was 17.
9 months, and the median progression-free survival (PFS) was 5.
5 months
.
For the first time, Syvotinib has brought the possibility of high-efficiency treatment for PSC patients
.
In all populations, the ORR assessed by the Independent Review Committee (IRC) was 42.
9%, the median DoR was 8.
3 months, and 7 patients (10%) sustained remission for 12 months or longer; median overall survival (OS) was 12.
5 months, the median PFS was 6.
8 months, and the 6-month and 12-month PFS rates were 52% and 31.
9%, respectively
.
In terms of safety, the treatment-related adverse reactions (TRAEs) of Syvotinib are mostly grade 1-2, and the most common treatment-related adverse reactions of any grade are peripheral edema (54%), nausea (46%), and elevated ALT ( 39%) and elevated AST (37%), no interstitial lung disease occurred in the enrolled patients, and the patients had good clinical tolerance
.
This study showed that in PSC and other NSCLC patients with skipping mutations in MET14 exon, Saivotinib showed encouraging ORR, with good efficacy and safety
.
This is undoubtedly a new dawn for PSC patients with high malignancy and extremely poor prognosis
.
I hope that more clinical studies will be included in the PSC in the future, bringing more hope to this group of patients with extremely poor prognosis
.
References: [1] Liu Lei, et al.
, Diagnosis and treatment status of pulmonary sarcomatoid carcinoma[J].
Chinese Journal of Lung Cancer, 2018,021(012):902-906.
[2] Yin Limei, et al.
MET14 exon skipping mutation Research progress in non-small cell lung cancer[J].
Chinese Journal of Lung Cancer,2018,21(07):553-559.
[3]Li Y,et al.
,Identification of MET exon14 skipping by targeted DNA-and RNA- based next-generation sequencing in pulmonary sarcomatoid carcinomas[J].
Lung Cancer,2018 Aug;122:113-119.
[4]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[J].
The Lancet Respiratory Medicine,2021.
*This article is only for Scientific information provided by people does not represent the views of this platform
