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*For medical professionals to read and reference JAMA Oncology's latest research first! Recently, the top oncology journal Lancet Oncology published a single-arm, phase II study (CodeBreak100) titled "Sotorasib in previously treated colorectal cancer with KRASG12C mutation"
.
"Medical Tumor Channel" specially invited Professor Wang Xicheng from Peking University Cancer Hospital to analyze this research and interpret the research results from a prospective perspective, so as to bring you in-depth academic sharing on colorectal cancer
.
Colorectal cancer is the third most common cancer in the world and the second highest in mortality
.
About 40% of colorectal cancer cells have KRAS mutations, of which about 3% are KRASG12C mutations
.
Although the current standard anti-vascular targeted therapy and chemotherapy drugs have a certain effect on KRAS mutant patients, if the disease progresses, such patients urgently need new treatment options
.
Sotorasib (AMG-510) is a specific, irreversible KRASG12C mutein inhibitor
.
The previous Phase I study of CodeBreaK100 preliminarily verified the clinical efficacy of sotorasib monotherapy in KRASG12C mutant solid tumors (including colorectal cancer).
Efficacy and Safety
.
Q: What is the significance of the CodeBreaK100 research? Professor Wang Xicheng: More than half of colorectal cancer patients have KRAS and NRAS gene mutations, but there is still a lack of targeted drugs for this target.
For a long time, only chemotherapy and anti-angiogenesis drugs can be used for treatment, with limited efficacy
.
The CodeBreaK100 study is an important step toward further addressing clinical needs
.
The previous CodeBreaK100 Phase I study partially confirmed the safety of sotorasib.
This CodeBreaK100 Phase II trial enrolled 62 patients, and further clarified the drug activity and patient prognosis
.
The results showed that 9.
7% (95%CI 3.
6%-19.
9%) of colorectal cancer patients achieved objective response, and 82.
3% (95%CI 70.
5%-90.
8%) patients achieved disease control (complete response, partial response, stable disease) ), the disease control rate is acceptable
.
Although the objective response rate (ORR) of sotorasib did not meet expectations, its preliminary efficacy has been proved, and it has taken the first step of oral targeted drugs for patients with KRAS mutations in colorectal cancer, which is the basis for further combined drug research in the future
.
The positive results of the CodeBreaK100 study are inseparable from the druggable advantage of the KRASG12C target
.
NGS (high-throughput next-generation sequencing) detection can find more mutation types in KRAS and NRAS
.
However, it is currently believed that only the KRASG12C target can be used as a drug, because when the glycine (G) of codon 12 of the KRAS gene is mutated to a cysteine (C) with a polar sulfhydryl group, it can be covalently bound to the target drug.
Make the drug work
.
Q: What are the points worth thinking about the CodeBreaK100 research? ▎Further improvement of ORR through combination therapy At present, in addition to Amgen's Sotorasib (ORR is 9.
7%), a variety of KRASG12C inhibitors have entered the clinical research stage, some of which have a single-agent ORR of up to 20%, and in combination with EGFR It can even increase to 47% after the antibody
.
In addition, basic research has found that KRAS inhibitors can regulate the immune microenvironment around tumor cells, which may improve the tumor-killing effect of CD8(+) T cells.
Therefore, the combination of KRAS inhibitors and immunotherapy is also a direction worthy of attention and exploration in the future
.
It is worth noting that in terms of adverse reactions, Sotorasib may cause severe diarrhea, and medical oncologists should pay extra attention to the related adverse reactions in the future when combining drugs
.
▎The problem of drug resistance needs to be overcome.
The CodeBreaK100 study has confirmed the effectiveness of KRASG12C inhibitors, but the duration of remission (DoR) of monotherapy is not long, and patients will develop drug resistance 3-4 months after treatment.
disease progression
.
The current combination therapy (combined with EGFR-Ab) can improve ORR, but whether it can prolong PFS needs more mature data verification
.
▎The benefit population can be expanded In the KRASG12C mutation, the sulfhydryl group of cysteine provides a good site for the binding of targeted drugs, so whether Sotorasib can also play a role in KRASG13C, NRASG12C, which also have cysteine mutations It is also worth exploring further
.
Expert Profile Associate Professor Wang Xicheng Chief Physician, Department of Gastroenterology, Peking University Cancer Hospital, CSCO Youth Expert Committee Member "Chinese version editorial board reference: [1] Marwan G, et al.
Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial.
JAMA Oncol.
2021 Dec 14.
doi: 10.
1016/S1470-2045(21)00605-7.
https://
.
"Medical Tumor Channel" specially invited Professor Wang Xicheng from Peking University Cancer Hospital to analyze this research and interpret the research results from a prospective perspective, so as to bring you in-depth academic sharing on colorectal cancer
.
Colorectal cancer is the third most common cancer in the world and the second highest in mortality
.
About 40% of colorectal cancer cells have KRAS mutations, of which about 3% are KRASG12C mutations
.
Although the current standard anti-vascular targeted therapy and chemotherapy drugs have a certain effect on KRAS mutant patients, if the disease progresses, such patients urgently need new treatment options
.
Sotorasib (AMG-510) is a specific, irreversible KRASG12C mutein inhibitor
.
The previous Phase I study of CodeBreaK100 preliminarily verified the clinical efficacy of sotorasib monotherapy in KRASG12C mutant solid tumors (including colorectal cancer).
Efficacy and Safety
.
Q: What is the significance of the CodeBreaK100 research? Professor Wang Xicheng: More than half of colorectal cancer patients have KRAS and NRAS gene mutations, but there is still a lack of targeted drugs for this target.
For a long time, only chemotherapy and anti-angiogenesis drugs can be used for treatment, with limited efficacy
.
The CodeBreaK100 study is an important step toward further addressing clinical needs
.
The previous CodeBreaK100 Phase I study partially confirmed the safety of sotorasib.
This CodeBreaK100 Phase II trial enrolled 62 patients, and further clarified the drug activity and patient prognosis
.
The results showed that 9.
7% (95%CI 3.
6%-19.
9%) of colorectal cancer patients achieved objective response, and 82.
3% (95%CI 70.
5%-90.
8%) patients achieved disease control (complete response, partial response, stable disease) ), the disease control rate is acceptable
.
Although the objective response rate (ORR) of sotorasib did not meet expectations, its preliminary efficacy has been proved, and it has taken the first step of oral targeted drugs for patients with KRAS mutations in colorectal cancer, which is the basis for further combined drug research in the future
.
The positive results of the CodeBreaK100 study are inseparable from the druggable advantage of the KRASG12C target
.
NGS (high-throughput next-generation sequencing) detection can find more mutation types in KRAS and NRAS
.
However, it is currently believed that only the KRASG12C target can be used as a drug, because when the glycine (G) of codon 12 of the KRAS gene is mutated to a cysteine (C) with a polar sulfhydryl group, it can be covalently bound to the target drug.
Make the drug work
.
Q: What are the points worth thinking about the CodeBreaK100 research? ▎Further improvement of ORR through combination therapy At present, in addition to Amgen's Sotorasib (ORR is 9.
7%), a variety of KRASG12C inhibitors have entered the clinical research stage, some of which have a single-agent ORR of up to 20%, and in combination with EGFR It can even increase to 47% after the antibody
.
In addition, basic research has found that KRAS inhibitors can regulate the immune microenvironment around tumor cells, which may improve the tumor-killing effect of CD8(+) T cells.
Therefore, the combination of KRAS inhibitors and immunotherapy is also a direction worthy of attention and exploration in the future
.
It is worth noting that in terms of adverse reactions, Sotorasib may cause severe diarrhea, and medical oncologists should pay extra attention to the related adverse reactions in the future when combining drugs
.
▎The problem of drug resistance needs to be overcome.
The CodeBreaK100 study has confirmed the effectiveness of KRASG12C inhibitors, but the duration of remission (DoR) of monotherapy is not long, and patients will develop drug resistance 3-4 months after treatment.
disease progression
.
The current combination therapy (combined with EGFR-Ab) can improve ORR, but whether it can prolong PFS needs more mature data verification
.
▎The benefit population can be expanded In the KRASG12C mutation, the sulfhydryl group of cysteine provides a good site for the binding of targeted drugs, so whether Sotorasib can also play a role in KRASG13C, NRASG12C, which also have cysteine mutations It is also worth exploring further
.
Expert Profile Associate Professor Wang Xicheng Chief Physician, Department of Gastroenterology, Peking University Cancer Hospital, CSCO Youth Expert Committee Member "Chinese version editorial board reference: [1] Marwan G, et al.
Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial.
JAMA Oncol.
2021 Dec 14.
doi: 10.
1016/S1470-2045(21)00605-7.
https://
