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Author: Cornflower This article is published by Yimaitong authorized by the author, please do not reprint without authorization.
Cholangiocarcinoma (cholangiocarcinoma) is a malignant tumor that originates from bile duct epithelial cells.
It can be divided into two categories: intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.
The incidence of intrahepatic cholangiocarcinoma ICC (intrahepatic cholangiocarcinoma ICC) accounts for about 15-20% of primary liver malignancies, and it is on the rise1.
Most of the ICC patients are often accompanied by local invasion or distant metastasis at the first visit and lose the chance of radical surgery.
The chemotherapy regimen of gemcitabine combined with platinum is recommended as the first-line regimen for the treatment of advanced cholangiocarcinoma, with an objective response rate (ORR) of 15~26%, and drug resistance often occurs.
There is an urgent need for other effective therapeutic drugs and programs in clinical practice.
Fibroblast growth factor receptors (Fibroblast growth factor receptors, FGFR) targeted drugs turned out to solve the urgent needs of patients with cholangiocarcinoma.
Following the approval of pemigatinib last year as the first targeted drug for cholangiocarcinoma approved by the U.
S.
Food and Drug Administration (FDA), on May 29 this year, the FDA again approved a new drug, infigratinib, for the treatment of patients with cholangiocarcinoma2.
Both drugs are FGFR2 inhibitors.
In addition, at the upcoming 2021 ASCO conference, there will be a number of treatment advances.
So far, the treatment of cholangiocarcinoma has finally ushered in a harvest period.
At the beginning, when the star target FGFR refers to the treatment plan for cholangiocarcinoma, the star target FGFR has to be mentioned.
It is a typical target of receptor tyrosine kinases, and its family includes four receptors: FGFR1, FGFR2, FGFR3 and FGFR4.
FGFR plays an important role in many physiological processes, such as embryo formation, angiogenesis, damage repair and so on.
In the human body, abnormal activation of the FGF/FGFR pathway can enable tumor cells to maintain growth in a "self-sufficient" way of growth signals, promote cell proliferation, epithelial-mesenchymal transition and angiogenesis, and promote tumor cell invasion, metastasis and treatment Tolerance.
These findings make FGFRs an increasingly attractive new target for cancer treatment.
In cholangiocarcinoma, the cause of abnormal activation of FGF/FGFR signaling pathway is more FGFR fusion mutation.
In intrahepatic cholangiocarcinoma, there is a higher proportion of FGFR2 fusion with a mutation frequency of about 11%, while extrahepatic cholangiocarcinoma is rare.
Infigratinib was approved based on Infigratinib is an innovative, oral, selective and potent FGFR1-3 inhibitor.
The approval of infigratinib is based on the results of a phase II clinical trial cohort 1 study3.
As of March 31, 2020, a total of 108 patients were enrolled.
Among these patients, 107 had previously received gemcitabine treatment, 88 had FGFR2 fusion, and 20 had FGFR2 gene rearrangement.
The median follow-up time was 10.
6 months (1.
1-55.
9 months).
The results of the study showed that the ORR was 23.
1% (95% CI: 16, 32), including 1 complete remission (CR) and 24 partial remission (PR); the best objective response (BOR) was 34.
3%, and the disease control rate ( DCR) reached 84.
3%, and the median duration of response (DOR) was 5.
0 months.
Among the responders, 8 patients (32.
0%) had a DOR of 6 months.
The median progression-free survival (PFS) of all patients was 7.
3 months, and the 4-month PFS rate was 75.
2%.
The median overall survival (OS) was 12.
2 months. The ORR of patients with second-line treatment was 34%, and the ORR of patients with third-line/post-line treatment was 13.
8%.
2021 Progress in ASCO Cholangiocarcinoma Targeted Therapy 01 Pemigatinib (Abstr: 4086) The pemigatinib mentioned above is a potent, selective, and oral FGFR1-3 inhibitor, which has been shown to rearrange FGFR2 in the FIGHT-202 study The efficacy and safety of fusion of cholangiocarcinoma in patients, and therefore approved for the second-line treatment of intrahepatic cholangiocarcinoma.
The results of second-line treatment were announced again at this ASCO meeting.
147 patients were enrolled (group A: FGFR2 fusion/rearrangement, n=108; group B: other FGF/FGFR mutations, n = 20; group C: no FGF/FGFR mutation, n = 17).
The results of the study showed that the ORR of patients in group A was 37%, the median OS was 17.
5 months, and the median OS of responders vs.
non-responders was 30.
1 vs 13.
7 months, respectively.
The most common adverse event (TEAE) was hyperphosphatemia (58.
5%; grade ≥3, 0%).
The updated OS data is longer than the historical data, and the OS of respondents is more than twice that of non-responders.
02ICP-192 (Abstr: 4092) ICP-192 (gunagratinib) is a new pan-FGFR inhibitor that can effectively and selectively inhibit FGFR activity through covalent binding.
The study to be announced at this ASCO meeting included a total of 30 patients with solid tumors receiving ICP-192 treatment.
In the dose escalation phase, for patients with advanced solid tumors with or without FGF/FGFR changes, use increasing doses of ICP-192 (2, 4, 8, 10, 12, 14, 16 mg, etc.
) once a day for 21 days One cycle until disease progression or unacceptable toxicity; during the dose expansion phase, patients with cholangiocarcinoma with FGFR2 gene fusion/translocation received 12 mg of ICP-192 per day for continuous treatment. Among the 12 patients with FGF/FGFR gene mutations who completed at least one tumor evaluation, the ORR was 33.
3%, of which 1 case (8.
3%) was CR, 3 cases (25%) were PR, and DCR was 91.
7%.
In patients with advanced solid tumors, ICP-192 is safe and well tolerated.
It has shown anti-tumor activity in a variety of tumor types with FGF/FGFR gene alterations, including cholangiocarcinoma.
As the treatment time is extended, a better response is expected.
The most common TRAE (> 20%) includes hyperphosphatemia, hypercalcemia and so on.
03 Pembrolizumab + lenvatinib (Abstr: 4080) Pembrolizumab is an anti-PD-1 therapy, by blocking PD-1 mediated immunosuppressive signal, increase the body's immune system to detect and fight The ability of tumor cells.
Lenvatinib is a kinase inhibitor that can inhibit the activity of vascular endothelial growth factor protein receptors VEGFR1, VEGFR2 and VEGFR3.
It can also inhibit the activity of other kinases related to pathogenic angiogenesis, tumor growth and cancer progression.
Pembrolizumab + lenvatinib is an important immune combination therapy.
In the non-randomized, open-label Phase II study to be announced at the ASCO meeting, 31 patients with advanced (metastatic and/or unresectable) cholangiocarcinoma who had previously received disease progression after one treatment were included.
The patient received lenvatinib 20 mg once a day + pembrolizumab 200 mg once every 3 weeks for 35 cycles (about 2 years).
The results showed that the ORR was 10%, 3 cases achieved PR, 18 cases were stable disease (SD), DCR was 68%, median DOR was 5.
3 months, median PFS was 6.
1 months, and median OS was 8.
6 months.
TRAE occurred in 30 patients (97%), of which 15 patients (48%) had grade 3 TRAE, and there was no grade 4 or 5 TRAE.
Although the existing targeted therapies and immunotherapy have prolonged the survival time of many types of cancer patients, patients diagnosed with cholangiocarcinoma faced extremely limited treatment options before, and survival statistics were very low.
For patients with cholangiocarcinoma, this year can be described as a rewarding year.
Whether it is targeted therapy or immune combination therapy, multiple clinical research results will promote the progress of the field of cholangiocarcinoma treatment, increase more treatment options for cancer patients, and bring more hope.
References: 1.
Zhang Wenjie, Sun Beicheng.
Progress in the treatment of cholangiocarcinoma[J].
Journal of Hepatobiliary and Pancreatic Surgery, 2020, 32(6): 326-330.
2.
https:// approves-infigratinib-for-cholangiocarcinoma.
3.
https://
Cholangiocarcinoma (cholangiocarcinoma) is a malignant tumor that originates from bile duct epithelial cells.
It can be divided into two categories: intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.
The incidence of intrahepatic cholangiocarcinoma ICC (intrahepatic cholangiocarcinoma ICC) accounts for about 15-20% of primary liver malignancies, and it is on the rise1.
Most of the ICC patients are often accompanied by local invasion or distant metastasis at the first visit and lose the chance of radical surgery.
The chemotherapy regimen of gemcitabine combined with platinum is recommended as the first-line regimen for the treatment of advanced cholangiocarcinoma, with an objective response rate (ORR) of 15~26%, and drug resistance often occurs.
There is an urgent need for other effective therapeutic drugs and programs in clinical practice.
Fibroblast growth factor receptors (Fibroblast growth factor receptors, FGFR) targeted drugs turned out to solve the urgent needs of patients with cholangiocarcinoma.
Following the approval of pemigatinib last year as the first targeted drug for cholangiocarcinoma approved by the U.
S.
Food and Drug Administration (FDA), on May 29 this year, the FDA again approved a new drug, infigratinib, for the treatment of patients with cholangiocarcinoma2.
Both drugs are FGFR2 inhibitors.
In addition, at the upcoming 2021 ASCO conference, there will be a number of treatment advances.
So far, the treatment of cholangiocarcinoma has finally ushered in a harvest period.
At the beginning, when the star target FGFR refers to the treatment plan for cholangiocarcinoma, the star target FGFR has to be mentioned.
It is a typical target of receptor tyrosine kinases, and its family includes four receptors: FGFR1, FGFR2, FGFR3 and FGFR4.
FGFR plays an important role in many physiological processes, such as embryo formation, angiogenesis, damage repair and so on.
In the human body, abnormal activation of the FGF/FGFR pathway can enable tumor cells to maintain growth in a "self-sufficient" way of growth signals, promote cell proliferation, epithelial-mesenchymal transition and angiogenesis, and promote tumor cell invasion, metastasis and treatment Tolerance.
These findings make FGFRs an increasingly attractive new target for cancer treatment.
In cholangiocarcinoma, the cause of abnormal activation of FGF/FGFR signaling pathway is more FGFR fusion mutation.
In intrahepatic cholangiocarcinoma, there is a higher proportion of FGFR2 fusion with a mutation frequency of about 11%, while extrahepatic cholangiocarcinoma is rare.
Infigratinib was approved based on Infigratinib is an innovative, oral, selective and potent FGFR1-3 inhibitor.
The approval of infigratinib is based on the results of a phase II clinical trial cohort 1 study3.
As of March 31, 2020, a total of 108 patients were enrolled.
Among these patients, 107 had previously received gemcitabine treatment, 88 had FGFR2 fusion, and 20 had FGFR2 gene rearrangement.
The median follow-up time was 10.
6 months (1.
1-55.
9 months).
The results of the study showed that the ORR was 23.
1% (95% CI: 16, 32), including 1 complete remission (CR) and 24 partial remission (PR); the best objective response (BOR) was 34.
3%, and the disease control rate ( DCR) reached 84.
3%, and the median duration of response (DOR) was 5.
0 months.
Among the responders, 8 patients (32.
0%) had a DOR of 6 months.
The median progression-free survival (PFS) of all patients was 7.
3 months, and the 4-month PFS rate was 75.
2%.
The median overall survival (OS) was 12.
2 months. The ORR of patients with second-line treatment was 34%, and the ORR of patients with third-line/post-line treatment was 13.
8%.
2021 Progress in ASCO Cholangiocarcinoma Targeted Therapy 01 Pemigatinib (Abstr: 4086) The pemigatinib mentioned above is a potent, selective, and oral FGFR1-3 inhibitor, which has been shown to rearrange FGFR2 in the FIGHT-202 study The efficacy and safety of fusion of cholangiocarcinoma in patients, and therefore approved for the second-line treatment of intrahepatic cholangiocarcinoma.
The results of second-line treatment were announced again at this ASCO meeting.
147 patients were enrolled (group A: FGFR2 fusion/rearrangement, n=108; group B: other FGF/FGFR mutations, n = 20; group C: no FGF/FGFR mutation, n = 17).
The results of the study showed that the ORR of patients in group A was 37%, the median OS was 17.
5 months, and the median OS of responders vs.
non-responders was 30.
1 vs 13.
7 months, respectively.
The most common adverse event (TEAE) was hyperphosphatemia (58.
5%; grade ≥3, 0%).
The updated OS data is longer than the historical data, and the OS of respondents is more than twice that of non-responders.
02ICP-192 (Abstr: 4092) ICP-192 (gunagratinib) is a new pan-FGFR inhibitor that can effectively and selectively inhibit FGFR activity through covalent binding.
The study to be announced at this ASCO meeting included a total of 30 patients with solid tumors receiving ICP-192 treatment.
In the dose escalation phase, for patients with advanced solid tumors with or without FGF/FGFR changes, use increasing doses of ICP-192 (2, 4, 8, 10, 12, 14, 16 mg, etc.
) once a day for 21 days One cycle until disease progression or unacceptable toxicity; during the dose expansion phase, patients with cholangiocarcinoma with FGFR2 gene fusion/translocation received 12 mg of ICP-192 per day for continuous treatment. Among the 12 patients with FGF/FGFR gene mutations who completed at least one tumor evaluation, the ORR was 33.
3%, of which 1 case (8.
3%) was CR, 3 cases (25%) were PR, and DCR was 91.
7%.
In patients with advanced solid tumors, ICP-192 is safe and well tolerated.
It has shown anti-tumor activity in a variety of tumor types with FGF/FGFR gene alterations, including cholangiocarcinoma.
As the treatment time is extended, a better response is expected.
The most common TRAE (> 20%) includes hyperphosphatemia, hypercalcemia and so on.
03 Pembrolizumab + lenvatinib (Abstr: 4080) Pembrolizumab is an anti-PD-1 therapy, by blocking PD-1 mediated immunosuppressive signal, increase the body's immune system to detect and fight The ability of tumor cells.
Lenvatinib is a kinase inhibitor that can inhibit the activity of vascular endothelial growth factor protein receptors VEGFR1, VEGFR2 and VEGFR3.
It can also inhibit the activity of other kinases related to pathogenic angiogenesis, tumor growth and cancer progression.
Pembrolizumab + lenvatinib is an important immune combination therapy.
In the non-randomized, open-label Phase II study to be announced at the ASCO meeting, 31 patients with advanced (metastatic and/or unresectable) cholangiocarcinoma who had previously received disease progression after one treatment were included.
The patient received lenvatinib 20 mg once a day + pembrolizumab 200 mg once every 3 weeks for 35 cycles (about 2 years).
The results showed that the ORR was 10%, 3 cases achieved PR, 18 cases were stable disease (SD), DCR was 68%, median DOR was 5.
3 months, median PFS was 6.
1 months, and median OS was 8.
6 months.
TRAE occurred in 30 patients (97%), of which 15 patients (48%) had grade 3 TRAE, and there was no grade 4 or 5 TRAE.
Although the existing targeted therapies and immunotherapy have prolonged the survival time of many types of cancer patients, patients diagnosed with cholangiocarcinoma faced extremely limited treatment options before, and survival statistics were very low.
For patients with cholangiocarcinoma, this year can be described as a rewarding year.
Whether it is targeted therapy or immune combination therapy, multiple clinical research results will promote the progress of the field of cholangiocarcinoma treatment, increase more treatment options for cancer patients, and bring more hope.
References: 1.
Zhang Wenjie, Sun Beicheng.
Progress in the treatment of cholangiocarcinoma[J].
Journal of Hepatobiliary and Pancreatic Surgery, 2020, 32(6): 326-330.
2.
https:// approves-infigratinib-for-cholangiocarcinoma.
3.
https://
