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Introduction On March 27, 2021, Beijing time, "The Lancet Respiratory Medicine" (Impact Factor 25.
094) published the full text online, led by Professor Shi Yuankai from the Cancer Hospital of the Chinese Academy of Medical Sciences, the original third-generation EGFR- TKI vometinib (furmonertinib/AST2818, formerly known as: alflutinib [alflutinib]) in the treatment of patients with EGFR T790M mutation advanced non-small cell lung cancer (NSCLC) Phase IIb clinical study (NCT03452592) results1.
The results of the study showed that the objective response rate (ORR) of vometinib treatment reached 74%, the disease control rate (DCR) reached 94%, the median progression-free survival (PFS) was 9.
6 months, and the median overall survival time ( OS) has not yet reached.
Among subjects with central nervous system (CNS) metastasis, the CNS ORR reached 66%, the CNS DCR reached 100%, and the median CNS PFS was 11.
6 months.
International Standards Reliable Data The Phase IIb study is an open-label, multi-center, single-arm study.
The results of the study were first released at the 2020 American Society of Clinical Oncology (ASCO) annual meeting2.
The study included 220 subjects with locally advanced or metastatic NSCLC who were diagnosed by the central laboratory using tumor tissue testing and carried EGFR T790M mutations, and who had previously received first or second generation EGFR-TKI progression or primary EGFR T790M mutations.
, Received oral treatment of vometinib 80mg once a day.
The study allows subjects with asymptomatic and stable CNS metastasis and an ECOG PS of 0 to 2 to be included in the group.
The primary endpoint is ORR.
Secondary endpoints include DCR, PFS, OS, and safety.
According to the RECIST 1.
1 standard, the blinded independent central evaluation committee (BICR) is used to evaluate the effectiveness of the evaluable effectiveness analysis set.
CTCAE 4.
03 version standard was used to evaluate the safety of the safety analysis set.
At baseline, after 6 weeks, and at the time of disease progression, second-generation gene sequencing (NGS) was used to evaluate ctDNA to explore the efficacy predictors and resistance mechanisms of vomitinib.
From June 4, 2018 to December 8, 2018, a total of 220 subjects received vometinib treatment, and all subjects were included in the efficacy and safety analysis.
As of the data cutoff time on January 29, 2020, 71 (32%) subjects are still receiving treatment.
The median follow-up time was 9.
6 months (range 0.
7-19.
4).
"From the phase I dose ramp up to the phase IIa extended study, and then to the phase IIb Guanjian registered clinical study, the clinical research of vometinib has been steadily and steadily followed by international standards and strictly in accordance with the National Drug Administration's "Quality of Clinical Trials of Drugs" "Management Standards" are carried out.
" Introduction by Professor Shi Yuankai, Chairman of the China Cancer Foundation and Vice President of the Cancer Hospital of the Chinese Academy of Medical Sciences, who led the development of phase I, IIa, and IIb key clinical studies of vometinib.
Reliable efficacy data The IIb study of vometinib included subjects with an ECOG PS score of 2 (4%) and subjects with primary T790M mutation (3%), L858R mutation (38%) and baseline CNS metastasis (48%) The proportion of subjects was relatively high; the subjects who received 1/2/≥3-line system therapy were 74%/17%/6%, respectively.
Professor Yuankai Shi said, “In the case of a relatively high proportion of the L858R population and those who have received line 2 and above, and nearly half (48%) of the subjects have CNS metastasis at baseline, the ORR of vometinib is still 74%.
(163/220, 95% CI 68–80), DCR is as high as 94% (206/220, 95% CI 90–97), and median PFS is 9.
6 months (95% CI 8.
2–9.
7).
The efficacy data is impressive Inspire. "Strongly enters the brain and effectively controls CNS metastasis.
The efficacy and safety data of the phase I dose escalation study and the phase I-II dose expansion study of vormetinib in the treatment of EGFR T790M mutation-positive locally advanced or metastatic NSCLC have been released in June 2020.
It was published in the Journal of Thoracic Oncology (JTO) 3.
The
phase I-II dose expansion study included 116 NSCLC subjects with EGFR T790M mutation-positive and ECOG PS 0-2 points, including asymptomatic and stable Subjects transferred from CNS.
Vometinib (40mg/d, 80mg/d, 160mg/d, 240mg/d) was given in different doses until the disease progressed or intolerable toxicity appeared.
The 21st meeting this year At the World Conference on Lung Cancer (WCLC 2020), the CNS metastatic population data of the phase I-II dose expansion study of vomitinib for the treatment of EGFR T790M mutation-positive locally advanced or metastatic NSCLC was announced.
The
results show that , The CNS ORR of the 80 mg vomitinib group was 60.
0%, while the CNS ORR of the 160 mg vomitinib group reached 84.
6%, and the CNS DCR was as high as 100%.
The efficacy is clinically significant.
The
efficacy results of subjects with CNS metastasis in different dose groups 4 (Data deadline: 2020-01-29) Abbreviations: CNS, central nervous system; cEFR, CNS assessable efficacy set; cFAS, CNS full analysis set; ORR, objective response rate; DCR, disease control rate; PFS, no progression Survival period; NR, did not reach the results of the phase IIb study of vometinib published in the full text of The Lancet Respiratory Medicine.
The results of the treatment of CNS metastasis NSCLC populations are consistent with the results of the extended phase I-II study.
In 220 cases Among the subjects enrolled in the Phase IIb study, the CNS ORR of subjects (cEFR population, n=29) with baseline measurable CNS metastases treated with 80 mg vormetinib was 66% (95% CI 46-82), CNS The DCR is as high as 100%.
Among subjects with measurable and/or unmeasurable CNS metastases at baseline (cFAS population, n=87), the CNS PFS treated with vormetinib was 11.
6 months (95% CI 8.
3-13.
8).
The results of the Phase Ⅰ-Ⅱ Expansion Study of Vometinib and the Ⅱb study data provide strong support for the use of vometinib in the treatment of NSCLC subjects with CNS metastasis.
The incidence of skin rash and diarrhea is low.
In the phase IIb study, 26% of subjects observed ≥ Grade 3 adverse events (AE), of which 11% were treatment-related, and each single item ≥ Grade 3 treatment-related adverse events was not higher than 1 %.
The incidence of treatment-related diarrhea and skin rash is relatively low, at 5% and 7%, respectively, and both are grade 1 to 2, reflecting the high safety of vometinib.
The most common ≥ grade 3 treatment-related adverse reactions are mainly aspartate aminotransferase (1%), alanine aminotransferase (1%), and gamma glutamyl transpeptidase (1%).
No unexpected events have been found so far.
Special adverse events.
In August 2013, "The Lancet Oncology" published a head-to-head comparison of the first-generation EGFR-TKI imported from China, with Professor Yuankai Shi as the first author and Academician Sun Yan as the corresponding author.
The results of a phase III clinical study of Nissan's second- and third-line treatment of advanced NSCLC5, which was hailed as "creating a new era in the research and development of anticancer drugs in China"6.
After 8 years, the research results of the original third-generation EGFR-TKI in China were listed in The Lancet Respiratory Medicine.
On December 17, 2019, my country National Medical Products Administration officially accepted the marketing application of vometinib and included it in priority review.
On March 3, 2021, Vometinib was officially approved for listing in China.
The approved indications for listing were included in the "China Guidelines for the Treatment of Stage IV Primary Lung Cancer (2021 Edition)" 7 and "Lung Cancer Brain Metastases in China Treatment Guidelines (2021 Edition) 8. References: 1.
Yuankai Shi, Xingsheng Hu, Shucai Zhang, et al.
Efficacy, safety, and genetic analysis of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small-cell lung cancer: a phase 2b, multicentre, single -arm, open-label study.
Lancet Respir Med.
Published on March 26, 2021.
DOI: https://doi.
org/10.
1016/S2213-2600(20)30455-02.
Yuankai Shi, et al.
Presented at ASCO 2020.
Abstract 96023.
Yuankai Shi, et al.
, Safety, Clinical Activity, and Pharmacokinetics of Alflutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation, Journal of Thoracic Oncology, January, 20204.
Y.
Shi et al.
, CNS Efficacy of AST2818 in Patients with T790M-Positive Advanced NSCLC: Data from a Phase I-II Dose-Expansion Study, 2020 WCLC, Abstract 32865.
Shi Y et al.
, Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN):a randomised, double-blind phase 3 non-inferiority trial.
Lancet Oncol.
2013 Sep;14(10):953-61.
doi: 10.
1016/S1470-2045(13)70355-3.
Epub 2013 Aug 13.
6.
Camidge DR.
Icotinib: kick-starting the Chinese anticancer drug industry.
Lancet Oncol.
2013 Sep;14(10):913-4.
doi: 10.
1016/S1470-2045(13)70385-1.
Epub 2013 Aug 13.
7.
Chinese Medical Doctor Association Oncologist Branch, Medical Oncology Branch of China Medical Care International Exchange Promotion Association.
Guidelines for the Treatment of Stage IV Primary Lung Cancer in China (2021 Edition)[J].
Chinese Journal of Oncology 2021,43(1):39-59, DOI:10.
3760/cma.
j.
cn112152-20201009-00884.
8.
Chinese Medical Doctor Association Oncologist Branch, Chinese Medical Care International Exchange Promotion Association Medical Oncology Branch.
Chinese treatment guidelines for lung cancer brain metastases (2021 edition)[J].
Chinese Journal of Oncology, 2021, 43(3) :269-281.
Oncologist Branch of Chinese Medical Doctor Association, Medical Oncology Branch of China Medical Care International Exchange Promotion Association.
Guidelines for the Treatment of Stage IV Primary Lung Cancer in China (2021 Edition)[J].
Chinese Journal of Oncology 2021,43(1):39-59, DOI :10.
3760/cma.
j.
cn112152-20201009-00884.
8.
Chinese Medical Doctor Association Oncologist Branch, Chinese Medical Care International Exchange Promotion Association Medical Oncology Branch.
Chinese Treatment Guidelines for Lung Cancer Brain Metastasis (2021 Edition)[J].
Chinese Journal of Oncology, 2021 , 43(3):269-281.
Oncologist Branch of Chinese Medical Doctor Association, Medical Oncology Branch of China Medical Care International Exchange Promotion Association.
Guidelines for the Treatment of Stage IV Primary Lung Cancer in China (2021 Edition)[J].
Chinese Journal of Oncology 2021,43(1):39-59, DOI :10.
3760/cma.
j.
cn112152-20201009-00884.
8.
Chinese Medical Doctor Association Oncologist Branch, Chinese Medical Care International Exchange Promotion Association Medical Oncology Branch.
Chinese Treatment Guidelines for Lung Cancer Brain Metastasis (2021 Edition)[J].
Chinese Journal of Oncology, 2021 , 43(3):269-281. DOI: 10.
3760/cma.
j.
cn112152-20210104-00009.
094) published the full text online, led by Professor Shi Yuankai from the Cancer Hospital of the Chinese Academy of Medical Sciences, the original third-generation EGFR- TKI vometinib (furmonertinib/AST2818, formerly known as: alflutinib [alflutinib]) in the treatment of patients with EGFR T790M mutation advanced non-small cell lung cancer (NSCLC) Phase IIb clinical study (NCT03452592) results1.
The results of the study showed that the objective response rate (ORR) of vometinib treatment reached 74%, the disease control rate (DCR) reached 94%, the median progression-free survival (PFS) was 9.
6 months, and the median overall survival time ( OS) has not yet reached.
Among subjects with central nervous system (CNS) metastasis, the CNS ORR reached 66%, the CNS DCR reached 100%, and the median CNS PFS was 11.
6 months.
International Standards Reliable Data The Phase IIb study is an open-label, multi-center, single-arm study.
The results of the study were first released at the 2020 American Society of Clinical Oncology (ASCO) annual meeting2.
The study included 220 subjects with locally advanced or metastatic NSCLC who were diagnosed by the central laboratory using tumor tissue testing and carried EGFR T790M mutations, and who had previously received first or second generation EGFR-TKI progression or primary EGFR T790M mutations.
, Received oral treatment of vometinib 80mg once a day.
The study allows subjects with asymptomatic and stable CNS metastasis and an ECOG PS of 0 to 2 to be included in the group.
The primary endpoint is ORR.
Secondary endpoints include DCR, PFS, OS, and safety.
According to the RECIST 1.
1 standard, the blinded independent central evaluation committee (BICR) is used to evaluate the effectiveness of the evaluable effectiveness analysis set.
CTCAE 4.
03 version standard was used to evaluate the safety of the safety analysis set.
At baseline, after 6 weeks, and at the time of disease progression, second-generation gene sequencing (NGS) was used to evaluate ctDNA to explore the efficacy predictors and resistance mechanisms of vomitinib.
From June 4, 2018 to December 8, 2018, a total of 220 subjects received vometinib treatment, and all subjects were included in the efficacy and safety analysis.
As of the data cutoff time on January 29, 2020, 71 (32%) subjects are still receiving treatment.
The median follow-up time was 9.
6 months (range 0.
7-19.
4).
"From the phase I dose ramp up to the phase IIa extended study, and then to the phase IIb Guanjian registered clinical study, the clinical research of vometinib has been steadily and steadily followed by international standards and strictly in accordance with the National Drug Administration's "Quality of Clinical Trials of Drugs" "Management Standards" are carried out.
" Introduction by Professor Shi Yuankai, Chairman of the China Cancer Foundation and Vice President of the Cancer Hospital of the Chinese Academy of Medical Sciences, who led the development of phase I, IIa, and IIb key clinical studies of vometinib.
Reliable efficacy data The IIb study of vometinib included subjects with an ECOG PS score of 2 (4%) and subjects with primary T790M mutation (3%), L858R mutation (38%) and baseline CNS metastasis (48%) The proportion of subjects was relatively high; the subjects who received 1/2/≥3-line system therapy were 74%/17%/6%, respectively.
Professor Yuankai Shi said, “In the case of a relatively high proportion of the L858R population and those who have received line 2 and above, and nearly half (48%) of the subjects have CNS metastasis at baseline, the ORR of vometinib is still 74%.
(163/220, 95% CI 68–80), DCR is as high as 94% (206/220, 95% CI 90–97), and median PFS is 9.
6 months (95% CI 8.
2–9.
7).
The efficacy data is impressive Inspire. "Strongly enters the brain and effectively controls CNS metastasis.
The efficacy and safety data of the phase I dose escalation study and the phase I-II dose expansion study of vormetinib in the treatment of EGFR T790M mutation-positive locally advanced or metastatic NSCLC have been released in June 2020.
It was published in the Journal of Thoracic Oncology (JTO) 3.
The
phase I-II dose expansion study included 116 NSCLC subjects with EGFR T790M mutation-positive and ECOG PS 0-2 points, including asymptomatic and stable Subjects transferred from CNS.
Vometinib (40mg/d, 80mg/d, 160mg/d, 240mg/d) was given in different doses until the disease progressed or intolerable toxicity appeared.
The 21st meeting this year At the World Conference on Lung Cancer (WCLC 2020), the CNS metastatic population data of the phase I-II dose expansion study of vomitinib for the treatment of EGFR T790M mutation-positive locally advanced or metastatic NSCLC was announced.
The
results show that , The CNS ORR of the 80 mg vomitinib group was 60.
0%, while the CNS ORR of the 160 mg vomitinib group reached 84.
6%, and the CNS DCR was as high as 100%.
The efficacy is clinically significant.
The
efficacy results of subjects with CNS metastasis in different dose groups 4 (Data deadline: 2020-01-29) Abbreviations: CNS, central nervous system; cEFR, CNS assessable efficacy set; cFAS, CNS full analysis set; ORR, objective response rate; DCR, disease control rate; PFS, no progression Survival period; NR, did not reach the results of the phase IIb study of vometinib published in the full text of The Lancet Respiratory Medicine.
The results of the treatment of CNS metastasis NSCLC populations are consistent with the results of the extended phase I-II study.
In 220 cases Among the subjects enrolled in the Phase IIb study, the CNS ORR of subjects (cEFR population, n=29) with baseline measurable CNS metastases treated with 80 mg vormetinib was 66% (95% CI 46-82), CNS The DCR is as high as 100%.
Among subjects with measurable and/or unmeasurable CNS metastases at baseline (cFAS population, n=87), the CNS PFS treated with vormetinib was 11.
6 months (95% CI 8.
3-13.
8).
The results of the Phase Ⅰ-Ⅱ Expansion Study of Vometinib and the Ⅱb study data provide strong support for the use of vometinib in the treatment of NSCLC subjects with CNS metastasis.
The incidence of skin rash and diarrhea is low.
In the phase IIb study, 26% of subjects observed ≥ Grade 3 adverse events (AE), of which 11% were treatment-related, and each single item ≥ Grade 3 treatment-related adverse events was not higher than 1 %.
The incidence of treatment-related diarrhea and skin rash is relatively low, at 5% and 7%, respectively, and both are grade 1 to 2, reflecting the high safety of vometinib.
The most common ≥ grade 3 treatment-related adverse reactions are mainly aspartate aminotransferase (1%), alanine aminotransferase (1%), and gamma glutamyl transpeptidase (1%).
No unexpected events have been found so far.
Special adverse events.
In August 2013, "The Lancet Oncology" published a head-to-head comparison of the first-generation EGFR-TKI imported from China, with Professor Yuankai Shi as the first author and Academician Sun Yan as the corresponding author.
The results of a phase III clinical study of Nissan's second- and third-line treatment of advanced NSCLC5, which was hailed as "creating a new era in the research and development of anticancer drugs in China"6.
After 8 years, the research results of the original third-generation EGFR-TKI in China were listed in The Lancet Respiratory Medicine.
On December 17, 2019, my country National Medical Products Administration officially accepted the marketing application of vometinib and included it in priority review.
On March 3, 2021, Vometinib was officially approved for listing in China.
The approved indications for listing were included in the "China Guidelines for the Treatment of Stage IV Primary Lung Cancer (2021 Edition)" 7 and "Lung Cancer Brain Metastases in China Treatment Guidelines (2021 Edition) 8. References: 1.
Yuankai Shi, Xingsheng Hu, Shucai Zhang, et al.
Efficacy, safety, and genetic analysis of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small-cell lung cancer: a phase 2b, multicentre, single -arm, open-label study.
Lancet Respir Med.
Published on March 26, 2021.
DOI: https://doi.
org/10.
1016/S2213-2600(20)30455-02.
Yuankai Shi, et al.
Presented at ASCO 2020.
Abstract 96023.
Yuankai Shi, et al.
, Safety, Clinical Activity, and Pharmacokinetics of Alflutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation, Journal of Thoracic Oncology, January, 20204.
Y.
Shi et al.
, CNS Efficacy of AST2818 in Patients with T790M-Positive Advanced NSCLC: Data from a Phase I-II Dose-Expansion Study, 2020 WCLC, Abstract 32865.
Shi Y et al.
, Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN):a randomised, double-blind phase 3 non-inferiority trial.
Lancet Oncol.
2013 Sep;14(10):953-61.
doi: 10.
1016/S1470-2045(13)70355-3.
Epub 2013 Aug 13.
6.
Camidge DR.
Icotinib: kick-starting the Chinese anticancer drug industry.
Lancet Oncol.
2013 Sep;14(10):913-4.
doi: 10.
1016/S1470-2045(13)70385-1.
Epub 2013 Aug 13.
7.
Chinese Medical Doctor Association Oncologist Branch, Medical Oncology Branch of China Medical Care International Exchange Promotion Association.
Guidelines for the Treatment of Stage IV Primary Lung Cancer in China (2021 Edition)[J].
Chinese Journal of Oncology 2021,43(1):39-59, DOI:10.
3760/cma.
j.
cn112152-20201009-00884.
8.
Chinese Medical Doctor Association Oncologist Branch, Chinese Medical Care International Exchange Promotion Association Medical Oncology Branch.
Chinese treatment guidelines for lung cancer brain metastases (2021 edition)[J].
Chinese Journal of Oncology, 2021, 43(3) :269-281.
Oncologist Branch of Chinese Medical Doctor Association, Medical Oncology Branch of China Medical Care International Exchange Promotion Association.
Guidelines for the Treatment of Stage IV Primary Lung Cancer in China (2021 Edition)[J].
Chinese Journal of Oncology 2021,43(1):39-59, DOI :10.
3760/cma.
j.
cn112152-20201009-00884.
8.
Chinese Medical Doctor Association Oncologist Branch, Chinese Medical Care International Exchange Promotion Association Medical Oncology Branch.
Chinese Treatment Guidelines for Lung Cancer Brain Metastasis (2021 Edition)[J].
Chinese Journal of Oncology, 2021 , 43(3):269-281.
Oncologist Branch of Chinese Medical Doctor Association, Medical Oncology Branch of China Medical Care International Exchange Promotion Association.
Guidelines for the Treatment of Stage IV Primary Lung Cancer in China (2021 Edition)[J].
Chinese Journal of Oncology 2021,43(1):39-59, DOI :10.
3760/cma.
j.
cn112152-20201009-00884.
8.
Chinese Medical Doctor Association Oncologist Branch, Chinese Medical Care International Exchange Promotion Association Medical Oncology Branch.
Chinese Treatment Guidelines for Lung Cancer Brain Metastasis (2021 Edition)[J].
Chinese Journal of Oncology, 2021 , 43(3):269-281. DOI: 10.
3760/cma.
j.
cn112152-20210104-00009.
