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Foreword Liver cancer is one of the most common malignant tumors in the world, and China is a major liver cancer country
.
In the past, the prognosis of liver cancer patients in China was very poor, and drug research progressed slowly
.
In recent years, with the rise of various new programs, the systemic treatment of liver cancer has been changing with each passing day, and the survival benefits of patients have been greatly improved
.
At the 2021 CSCO annual meeting, Professor Qin Shukui from Nanjing Jinling Hospital gave an in-depth interpretation of the outcome of the study of advanced hepatocellular carcinoma with poor prognosis in the first-line treatment of Akoladine and the IMbrave150 study of patients in the Chinese population
.
Here, Yimaitong invited Professor Qin Shukui to share the clinical value of these two studies and talk about the prospects of immunotherapy for advanced liver cancer
.
Expert Profile Prof.
Shukui Qin, Chief Physician of Nanjing Jinling Hospital Cancer Center, Ph.
D.
Supervisor, Nanjing University of Traditional Chinese Medicine and Nanjing Medical University Distinguished Professor "Journal of Clinical Oncology" Chief Editor, Chinese Society of Clinical Oncology (CSCO) Vice Chairman, Beijing CSCO Foundation Vice Chairman, China "The King of Cancer", the chairman of the Cancer Rehabilitation and Palliative Care Committee of the Anti-Cancer Association, urgently needs to take off his hat.
Where is the way for a breakthrough in treatment? Professor Qin Shukui: China is a country with a high incidence of liver cancer.
China’s population accounts for only 19% of the world’s population.
However, the incidence and death of liver cancer in China is close to half of the world’s, accounting for 45.
3% and 47.
1%, respectively
.
Since most patients are accompanied by basic liver disease, liver cancer has an insidious onset and rapid progress.
It is mostly in the middle and advanced stages when diagnosed.
Only a small number of patients with liver cancer can undergo surgical resection, liver transplantation or other local treatments
.
However, the risk of recurrence and metastasis in patients receiving local treatment is still high
.
For patients with advanced liver cancer, if they do not receive any anti-tumor treatment, the median overall survival (OS) of the patient is only about 4 months
.
Even after receiving traditional anti-tumor therapy, it can only extend the survival time of more than two months
.
Therefore, liver cancer was once known as the "cancer of the King"
.
In recent years, the diagnosis and treatment of lung cancer, breast cancer, gastrointestinal tumors, etc.
have all made significant progress, while the development of liver cancer lags far behind these cancers
.
The five-year survival rate of breast cancer can exceed 90%, while the five-year survival rate of liver cancer in China is only 12.
1%
.
Therefore, the diagnosis and treatment of liver cancer has attracted great attention from academic circles at home and abroad
.
New first-line treatment options: exploration and harvest of local original innovative drugs Professor Qin Shukui: Akoladine is a small molecule drug extracted, separated, and purified from the natural medicinal plant Epimedium.
It belongs to the national Chinese medicine 1.
2 new drug
.
Basic research data shows that acoraldine has an immunomodulatory effect, which can reduce the concentration of IL-6 in the blood, inhibit the phosphorylation of its downstream signaling pathway JAK2/STAT3, inhibit the expression of PD-L1, etc.
, and affect the release of inflammatory factors, thereby improving Tumor microenvironment
.
Phase II clinical studies have found that indicators such as TMB, PD-L1, AFP, IFN-γ and TNF-α are closely related to the curative effect of Acoladine
.
The multi-center, randomized, double-blind, double-simulation phase III clinical study reported in this report explored the efficacy and safety of first-line treatment of Acoladine or Huachansu tablets for advanced hepatocellular carcinoma with a heavier baseline and a poorer prognosis
.
Based on the results of previous research, and at the same time, drawing on the successful experience of applying the peripheral blood marker AFP in the latest international clinical research-REACH2 research, this research finally adopted a composite biomarker and adaptive enrichment design
.
For the selection of biomarker indicators for the enriched population, researchers have also considered in many ways
.
Given that the detection of TMB and PD-L1 expression requires liver puncture, the acceptance of patients and family members is low, and dynamic observation is not possible, and IL-6 detection has certain clinical problems.
The study finally selected three composite biomarker indicators (three At least any two of the indicators are positive for enriched population): AFP>400ng/ml, IFN-γ>7.
0pg/ml, TNF-α<2.
5pg/ml
.
At present, the detection technologies for these three indicators are relatively mature, which can be detected by collecting peripheral blood, and will be convenient for clinical use in the future
.
The study included more than 280 patients, of which 71 were enriched
.
The results showed that, compared with the Huachansu tablets control group, the first-line treatment of acoradine can significantly improve the survival benefit of the enriched population.
The median OS of the two groups was 13.
54 months and 6.
87 months (HR=0.
43, p=0.
0092)
.
In the overall population, there was no significant difference in survival outcomes between Acoladine and Huachansu tablets
.
However, it is worth noting that the curative effect of Huachansu tablets has been greatly improved after the addition of the analog agent, and the OS has increased from more than 7 months to about 12 months, but the OS results of the acoradine group are still comparable.
Affirmed the curative effect of Akoladine
.
More importantly, if you continue to take acocladine after the disease progresses, the median OS will also be significantly prolonged compared to the cinocabine tablets group, and you can continue to benefit.
This is also complementary to the immune regulation mechanism of acocladine
.
In terms of safety, compared with the Huachansu tablets group, the incidence and severity of adverse events in the acoradine group were lower, especially those of the digestive tract
.
In addition, although there is no head-to-head study, from the data point of view, the safety of Akoladine is also more advantageous than that of chemotherapeutics, targeted drugs and immune checkpoint inhibitors already on the market.
.
Figure: Median OS in enriched population and Median OS in disease progression The success of Akoladine not only has good clinical value, but also has important scientific research significance
.
On the one hand, Akoladine provides a new treatment option for liver cancer patients with complex baseline disease and poor prognosis
.
On the other hand, Akoladine also provides a good reference for the modernization of other traditional Chinese medicines
.
"Ice-breaking" move: IMbrave150 research creates a "post-era" of sorafenib Professor Qin Shukui: In the exploration of the treatment of advanced liver cancer, the IMbrave150 research has also attracted attention
.
IMbrave150 is a global multicenter study designed to evaluate the efficacy and safety of atelizumab + bevacizumab versus sorafenib in the first-line treatment of patients with unresectable hepatocellular carcinoma
.
Bevacizumab can improve the tumor microenvironment, inhibit Treg cells, stimulate T cells to respond to tumor antigens, and work in concert with the PD-L1 inhibitor atelizumab
.
A total of 501 patients were included in the study, including 194 Chinese patients
.
The results of the IMbrave150 study showed that in the global population, the median OS of atelizumab + bevacizumab versus sorafenib was 19.
2 months and 13.
4 months (HR=0.
66), respectively; in the Chinese subgroup Among them, the median OS of the two groups was 24.
0 months and 11.
4 months (HR=0.
53)
.
The so-called "it is easy to send charcoal in the snow, but it is difficult to add flowers to the cake.
" The curative effect of the Chinese population is better than the overall population of the trial.
The first reason is that patients with advanced liver cancer in Europe and the United States have a longer survival period.
It is relatively more difficult to extend it on this basis, but China The patient's survival period is relatively short, so the survival benefit of atelizumab + bevacizumab treatment is more obvious; the second reason is that Chinese experts and scholars, sponsors, and CRO companies have worked together during the entire trial process.
A good grasp of the quality control of clinical trials
.
In terms of safety, the performance of the Chinese population is basically the same as that of the global population.
The combination therapy has the same known safety characteristics as the previous single medication, and no new safety signals have been found
.
Figure: IMbrave150 study Chinese subgroup median OS After sorafenib was launched in 2007, until IMbrave150 data was released, there has been no breakthrough in the treatment of advanced liver cancer
.
Atelizumab+bevacizumab broke through the curative effect bottleneck of sorafenib for the first time, making the first-line treatment of liver cancer entered the "post-age" of sorafenib
.
The IMbrave150 study has changed the treatment pattern of liver cancer and provided a combination treatment plan with excellent efficacy, safety and accessibility for the clinic.
At the same time, this combined treatment model has also changed the treatment concept and brought useful inspiration for the development of other studies.
.
The diagnosis and treatment of liver cancer is changing day by day, and combined immunotherapy is the hope and direction.
Professor Qin Shukui: The diagnosis and treatment of primary liver cancer has made great progress in recent years, and the treatment progress in the last 3 years has exceeded the sum of the past 30 years
.
At present, liver cancer has got rid of the "king of cancer" hat.
In the IMbrave150 study, the median OS of the first-line treatment of the Chinese subgroup was 24.
0 months; in the CheckMate-040 study, the median OS of the first-line treatment was 28.
6 In the second-line treatment, the median OS is still more than 15 months
.
The treatment of advanced liver cancer has moved from single-agent therapy to combined therapy
.
In the first-line treatment, IMbrave150 studies atilizumab combined with bevacizumab, ORIENT-32 studies sintilizumab combined with dabevacizumab, and RESCUE studies carrelizumab combined with apatinib The success of other programs suggests that clinical combination therapy based on PD-1/PD-L1 inhibitors is a new treatment model for liver cancer
.
However, it must be pointed out that combination therapy requires sufficient research data to prove that it can synergize or reduce toxicity before it can be used.
The Drug Evaluation Center of the State Drug Administration has also shown the guiding principles for combination therapy, which should be studied and followed
.
In general, the future treatment of liver cancer will be a combination therapy led by immunotherapy, including a combination of different drugs, as well as a combination of drugs and surgery, radiotherapy, interventional therapy and even ablation, which is expected to change the survival outcome of liver cancer patients.
.
October Breast Cancer Prevention Month Free Clinic Lecture Scan the QR code below, add the assistant WeChat, you can participate in the breast cancer lecture on-site interaction, and you will have the opportunity to receive a copy of the exquisite boutique!
.
In the past, the prognosis of liver cancer patients in China was very poor, and drug research progressed slowly
.
In recent years, with the rise of various new programs, the systemic treatment of liver cancer has been changing with each passing day, and the survival benefits of patients have been greatly improved
.
At the 2021 CSCO annual meeting, Professor Qin Shukui from Nanjing Jinling Hospital gave an in-depth interpretation of the outcome of the study of advanced hepatocellular carcinoma with poor prognosis in the first-line treatment of Akoladine and the IMbrave150 study of patients in the Chinese population
.
Here, Yimaitong invited Professor Qin Shukui to share the clinical value of these two studies and talk about the prospects of immunotherapy for advanced liver cancer
.
Expert Profile Prof.
Shukui Qin, Chief Physician of Nanjing Jinling Hospital Cancer Center, Ph.
D.
Supervisor, Nanjing University of Traditional Chinese Medicine and Nanjing Medical University Distinguished Professor "Journal of Clinical Oncology" Chief Editor, Chinese Society of Clinical Oncology (CSCO) Vice Chairman, Beijing CSCO Foundation Vice Chairman, China "The King of Cancer", the chairman of the Cancer Rehabilitation and Palliative Care Committee of the Anti-Cancer Association, urgently needs to take off his hat.
Where is the way for a breakthrough in treatment? Professor Qin Shukui: China is a country with a high incidence of liver cancer.
China’s population accounts for only 19% of the world’s population.
However, the incidence and death of liver cancer in China is close to half of the world’s, accounting for 45.
3% and 47.
1%, respectively
.
Since most patients are accompanied by basic liver disease, liver cancer has an insidious onset and rapid progress.
It is mostly in the middle and advanced stages when diagnosed.
Only a small number of patients with liver cancer can undergo surgical resection, liver transplantation or other local treatments
.
However, the risk of recurrence and metastasis in patients receiving local treatment is still high
.
For patients with advanced liver cancer, if they do not receive any anti-tumor treatment, the median overall survival (OS) of the patient is only about 4 months
.
Even after receiving traditional anti-tumor therapy, it can only extend the survival time of more than two months
.
Therefore, liver cancer was once known as the "cancer of the King"
.
In recent years, the diagnosis and treatment of lung cancer, breast cancer, gastrointestinal tumors, etc.
have all made significant progress, while the development of liver cancer lags far behind these cancers
.
The five-year survival rate of breast cancer can exceed 90%, while the five-year survival rate of liver cancer in China is only 12.
1%
.
Therefore, the diagnosis and treatment of liver cancer has attracted great attention from academic circles at home and abroad
.
New first-line treatment options: exploration and harvest of local original innovative drugs Professor Qin Shukui: Akoladine is a small molecule drug extracted, separated, and purified from the natural medicinal plant Epimedium.
It belongs to the national Chinese medicine 1.
2 new drug
.
Basic research data shows that acoraldine has an immunomodulatory effect, which can reduce the concentration of IL-6 in the blood, inhibit the phosphorylation of its downstream signaling pathway JAK2/STAT3, inhibit the expression of PD-L1, etc.
, and affect the release of inflammatory factors, thereby improving Tumor microenvironment
.
Phase II clinical studies have found that indicators such as TMB, PD-L1, AFP, IFN-γ and TNF-α are closely related to the curative effect of Acoladine
.
The multi-center, randomized, double-blind, double-simulation phase III clinical study reported in this report explored the efficacy and safety of first-line treatment of Acoladine or Huachansu tablets for advanced hepatocellular carcinoma with a heavier baseline and a poorer prognosis
.
Based on the results of previous research, and at the same time, drawing on the successful experience of applying the peripheral blood marker AFP in the latest international clinical research-REACH2 research, this research finally adopted a composite biomarker and adaptive enrichment design
.
For the selection of biomarker indicators for the enriched population, researchers have also considered in many ways
.
Given that the detection of TMB and PD-L1 expression requires liver puncture, the acceptance of patients and family members is low, and dynamic observation is not possible, and IL-6 detection has certain clinical problems.
The study finally selected three composite biomarker indicators (three At least any two of the indicators are positive for enriched population): AFP>400ng/ml, IFN-γ>7.
0pg/ml, TNF-α<2.
5pg/ml
.
At present, the detection technologies for these three indicators are relatively mature, which can be detected by collecting peripheral blood, and will be convenient for clinical use in the future
.
The study included more than 280 patients, of which 71 were enriched
.
The results showed that, compared with the Huachansu tablets control group, the first-line treatment of acoradine can significantly improve the survival benefit of the enriched population.
The median OS of the two groups was 13.
54 months and 6.
87 months (HR=0.
43, p=0.
0092)
.
In the overall population, there was no significant difference in survival outcomes between Acoladine and Huachansu tablets
.
However, it is worth noting that the curative effect of Huachansu tablets has been greatly improved after the addition of the analog agent, and the OS has increased from more than 7 months to about 12 months, but the OS results of the acoradine group are still comparable.
Affirmed the curative effect of Akoladine
.
More importantly, if you continue to take acocladine after the disease progresses, the median OS will also be significantly prolonged compared to the cinocabine tablets group, and you can continue to benefit.
This is also complementary to the immune regulation mechanism of acocladine
.
In terms of safety, compared with the Huachansu tablets group, the incidence and severity of adverse events in the acoradine group were lower, especially those of the digestive tract
.
In addition, although there is no head-to-head study, from the data point of view, the safety of Akoladine is also more advantageous than that of chemotherapeutics, targeted drugs and immune checkpoint inhibitors already on the market.
.
Figure: Median OS in enriched population and Median OS in disease progression The success of Akoladine not only has good clinical value, but also has important scientific research significance
.
On the one hand, Akoladine provides a new treatment option for liver cancer patients with complex baseline disease and poor prognosis
.
On the other hand, Akoladine also provides a good reference for the modernization of other traditional Chinese medicines
.
"Ice-breaking" move: IMbrave150 research creates a "post-era" of sorafenib Professor Qin Shukui: In the exploration of the treatment of advanced liver cancer, the IMbrave150 research has also attracted attention
.
IMbrave150 is a global multicenter study designed to evaluate the efficacy and safety of atelizumab + bevacizumab versus sorafenib in the first-line treatment of patients with unresectable hepatocellular carcinoma
.
Bevacizumab can improve the tumor microenvironment, inhibit Treg cells, stimulate T cells to respond to tumor antigens, and work in concert with the PD-L1 inhibitor atelizumab
.
A total of 501 patients were included in the study, including 194 Chinese patients
.
The results of the IMbrave150 study showed that in the global population, the median OS of atelizumab + bevacizumab versus sorafenib was 19.
2 months and 13.
4 months (HR=0.
66), respectively; in the Chinese subgroup Among them, the median OS of the two groups was 24.
0 months and 11.
4 months (HR=0.
53)
.
The so-called "it is easy to send charcoal in the snow, but it is difficult to add flowers to the cake.
" The curative effect of the Chinese population is better than the overall population of the trial.
The first reason is that patients with advanced liver cancer in Europe and the United States have a longer survival period.
It is relatively more difficult to extend it on this basis, but China The patient's survival period is relatively short, so the survival benefit of atelizumab + bevacizumab treatment is more obvious; the second reason is that Chinese experts and scholars, sponsors, and CRO companies have worked together during the entire trial process.
A good grasp of the quality control of clinical trials
.
In terms of safety, the performance of the Chinese population is basically the same as that of the global population.
The combination therapy has the same known safety characteristics as the previous single medication, and no new safety signals have been found
.
Figure: IMbrave150 study Chinese subgroup median OS After sorafenib was launched in 2007, until IMbrave150 data was released, there has been no breakthrough in the treatment of advanced liver cancer
.
Atelizumab+bevacizumab broke through the curative effect bottleneck of sorafenib for the first time, making the first-line treatment of liver cancer entered the "post-age" of sorafenib
.
The IMbrave150 study has changed the treatment pattern of liver cancer and provided a combination treatment plan with excellent efficacy, safety and accessibility for the clinic.
At the same time, this combined treatment model has also changed the treatment concept and brought useful inspiration for the development of other studies.
.
The diagnosis and treatment of liver cancer is changing day by day, and combined immunotherapy is the hope and direction.
Professor Qin Shukui: The diagnosis and treatment of primary liver cancer has made great progress in recent years, and the treatment progress in the last 3 years has exceeded the sum of the past 30 years
.
At present, liver cancer has got rid of the "king of cancer" hat.
In the IMbrave150 study, the median OS of the first-line treatment of the Chinese subgroup was 24.
0 months; in the CheckMate-040 study, the median OS of the first-line treatment was 28.
6 In the second-line treatment, the median OS is still more than 15 months
.
The treatment of advanced liver cancer has moved from single-agent therapy to combined therapy
.
In the first-line treatment, IMbrave150 studies atilizumab combined with bevacizumab, ORIENT-32 studies sintilizumab combined with dabevacizumab, and RESCUE studies carrelizumab combined with apatinib The success of other programs suggests that clinical combination therapy based on PD-1/PD-L1 inhibitors is a new treatment model for liver cancer
.
However, it must be pointed out that combination therapy requires sufficient research data to prove that it can synergize or reduce toxicity before it can be used.
The Drug Evaluation Center of the State Drug Administration has also shown the guiding principles for combination therapy, which should be studied and followed
.
In general, the future treatment of liver cancer will be a combination therapy led by immunotherapy, including a combination of different drugs, as well as a combination of drugs and surgery, radiotherapy, interventional therapy and even ablation, which is expected to change the survival outcome of liver cancer patients.
.
October Breast Cancer Prevention Month Free Clinic Lecture Scan the QR code below, add the assistant WeChat, you can participate in the breast cancer lecture on-site interaction, and you will have the opportunity to receive a copy of the exquisite boutique!
