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Long press the QR code to receive on May 28, 2021, the FDA announced the accelerated approval of the KRAS inhibitor Lumakras (sotorasib, AMG510) [1] for the treatment of non-small cell lung cancer (NSCLC) patients with KRAS G12C mutations.
So far, Ends the history of no medicine available for KRAS targets.
(Source: Reference 1) KRAS gene carcinogenic mechanism RAS (KRAS, NRAS and HRAS) is the most common mutant gene family in cancer.
KRAS mutations are an important driver of the three deadliest cancers known-lung cancer, colorectal cancer, and pancreatic cancer.
At the same time, KRAS gene mutation is one of the earliest oncogene mutations discovered, and it is also the most common oncogene mutation in human cancer.
KRAS gene mutations exist in 90% of pancreatic cancer, 30% to 40% of colorectal cancer, and 15% to 20% of lung adenocarcinoma [2].
These mutations mainly occur at the 12th codon, that is, the glycine at the 12th position becomes a cysteine, which is KRASG12C.
Approximately 13% of patients with non-small cell lung cancer carry this mutation [3].
The RAS protein itself is a signal protein with GTPase activity.
It is activated when combined with GTP, which can activate a series of downstream pathways.
After the combined GTP is hydrolyzed into GDP, RAS returns to the inactive state.
Oncogenic mutations of RAS proteins, including KRASG12C protein, all show impaired GTPase activity, leading to continuous activation of RAS protein.
The rapid transition of KRAS G12C mutant between the activated state of binding to GTP and the inactive state of binding to GDP (Source: DOI: 10.
1158/2159-8290.
CD-15-1105) Lumakras breaks through the non-drugable target although KRAS The carcinogenic principle of the drug has long been elucidated, but there has been no KRAS targeted drug coming out for more than 30 years before Lumakras.
KRAS was once considered a "non-drugable" target.
In the crystallographic study of the complex that the compound binds to the KRAS G12C mutant, it was discovered that there is a "pocket" on the KRAS G12C mutant protein that can bind to small molecule drugs.
The combination of small molecule compounds with this "pocket" can "lock" the KRAS G12C mutant in an inactive conformation, thereby providing a potential target for inhibiting the activity of the KRAS mutant.
Lumakras is a drug developed based on the carcinogenic mechanism of KRAS.
It and multiple KRAS G12C covalent inhibitors currently in clinical development all target this binding "pocket" [4], by following the inactive state The KRASG12C mutant protein binds to forcibly pull the abnormally activated KRASG12C protein back to an inactive state.
Lumakras has a long half-life to achieve long-lasting and continuous KRAS inhibition and lead to deep and long-lasting anti-tumor activity.
The molecular structure of Lumakras (Source: Wikimedia Commons) The clinical efficacy of Lumakras was approved based on data from a study called CodeBreak 100.
The study included 129 patients with KRASG12C mutant NSCLC patients who had previously received chemotherapy and/or immunotherapy.
Among the 124 patients included in the effectiveness analysis, a total of 46 patients achieved confirmed remission after a median follow-up of 12.
2 months.
, Including 3 cases of complete remission (CR) and 43 cases of partial remission (PR), patients in the Lumakras group achieved an objective response rate (ORR) of 37.
1%.The median time to objective remission was 1.
4 months, and the median duration of remission was 10 months.
43% of patients who responded received continued treatment and the disease did not progress.
The disease control rate (DCR) was 80.
6%, and the median progression-free survival (PFS) was 6.
8 months [5].
A variety of drugs exhibited clinical efficacy, and the once unpreparable targets ushered in a counterattack.
At present, the treatment of targeted KRAS has become the focus of clinical research.
In addition to Lumakras, there are many other drugs that have announced clinical effects.
MRTX849 MRTX849 is a small molecule inhibitor against KRAS G12C mutation.
At the European Lung Cancer Conference 2021 (ELCC 2021), the results of the KRYSTAL-1 study were announced.
The KRYSTAL-1 study is a multi-cohort phase I/II clinical study that included patients with KRAS G12C mutant NSCLC, patients with colorectal cancer (CRC), and patients with other solid tumors.
ELCC 2021 released data on the NSCLC cohort.
Among the 51 evaluable NSCLC patients who had previously received chemotherapy and anti-PD-1/PD-L1 therapy, ORR was 45% and DCR was 96% (49/51).
In patients with STK11 mutation, the ORR is as high as 64% (9/14).
The median duration of response (DoR) was 9.
2 months [6].
VS-6766VS-6766 is a RAF/MEK inhibitor.
At the AACR 2020 annual meeting, the results of a phase I clinical trial of VS-6766 and the FAK inhibitor Defactinib in the treatment of patients with solid tumors with RAS mutations were announced.
In the study, 7 of the 10 KRAS mutant non-small cell lung cancer patients had tumor shrinkage, and one of the G12V mutant patients had tumor shrinkage by more than 30%.
The combination regimen is well tolerated, and the most common adverse reactions are skin rash, elevated creatine kinase, elevated aspartate aminotransferase, hyperbilirubinemia and nausea, all adverse reactions can be reversed [7].
BGB-283BGB-283 is a new type of RAF inhibitor that exists in a unique dimer form and can also inhibit the activity of EGFR.
It has shown anti-tumor activity in pre-clinical models and tumor patients with BRAF V600E mutation, non-V600E BRAF mutation, and KRAS/NRAS mutation.
In 2020, a phase I dose escalation/dose extension study published in the Journal of Clinical Oncology for the first time in humans evaluated BGB-283 in patients with solid tumors with B-RAF or K-RAS/N-RAS mutations The safety, tolerability and efficacy of the product.
The results of the study show that the maximum tolerated dose of BGB-283 is 40 mg/d.
Dose limiting toxicity includes reversible thrombocytopenia and non-hematological toxicity.
Throughout the study, the most common adverse events in ≥3 treatment were hypertension (17.
6%) and fatigue (9.
9%).
Among them, 1 melanoma patient with B-RAF mutation achieved complete remission, 8 patients with B-RAF mutation achieved a confirmed objective remission, and 1 patient with K-RAS G12C mutation NSCLC had partial remission [8].
In summary, whether it is Lumakras, which has been approved, or MRTX849, which has shown very good clinical effects, after many years, the target of unpreparable medicine has finally ushered in a breakthrough, which will bring good news to cancer patients around the world.
It is believed that in the not too distant future, more KRAS inhibitors will surface.
Christina Guo, et al.
, Br J Cancer.
2021 Apr 15.
8.
Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors.
J Clin Oncol.
2020 Mar 17[Online ahead of print].
DOI: 10.
1200/JCO.
19.
02654.
Yaodu APP "Points New Game" company enjoys the database super-value permission dry granulation technology to discuss the ups and downs of 20 years, Kinase Where is the future of inhibitors? Sotrovimab has been authorized by the FDA for emergency use, "broad-spectrum" treatment of mild to moderate COVID-19.
Click "read original" to keep abreast of industry trends
So far, Ends the history of no medicine available for KRAS targets.
(Source: Reference 1) KRAS gene carcinogenic mechanism RAS (KRAS, NRAS and HRAS) is the most common mutant gene family in cancer.
KRAS mutations are an important driver of the three deadliest cancers known-lung cancer, colorectal cancer, and pancreatic cancer.
At the same time, KRAS gene mutation is one of the earliest oncogene mutations discovered, and it is also the most common oncogene mutation in human cancer.
KRAS gene mutations exist in 90% of pancreatic cancer, 30% to 40% of colorectal cancer, and 15% to 20% of lung adenocarcinoma [2].
These mutations mainly occur at the 12th codon, that is, the glycine at the 12th position becomes a cysteine, which is KRASG12C.
Approximately 13% of patients with non-small cell lung cancer carry this mutation [3].
The RAS protein itself is a signal protein with GTPase activity.
It is activated when combined with GTP, which can activate a series of downstream pathways.
After the combined GTP is hydrolyzed into GDP, RAS returns to the inactive state.
Oncogenic mutations of RAS proteins, including KRASG12C protein, all show impaired GTPase activity, leading to continuous activation of RAS protein.
The rapid transition of KRAS G12C mutant between the activated state of binding to GTP and the inactive state of binding to GDP (Source: DOI: 10.
1158/2159-8290.
CD-15-1105) Lumakras breaks through the non-drugable target although KRAS The carcinogenic principle of the drug has long been elucidated, but there has been no KRAS targeted drug coming out for more than 30 years before Lumakras.
KRAS was once considered a "non-drugable" target.
In the crystallographic study of the complex that the compound binds to the KRAS G12C mutant, it was discovered that there is a "pocket" on the KRAS G12C mutant protein that can bind to small molecule drugs.
The combination of small molecule compounds with this "pocket" can "lock" the KRAS G12C mutant in an inactive conformation, thereby providing a potential target for inhibiting the activity of the KRAS mutant.
Lumakras is a drug developed based on the carcinogenic mechanism of KRAS.
It and multiple KRAS G12C covalent inhibitors currently in clinical development all target this binding "pocket" [4], by following the inactive state The KRASG12C mutant protein binds to forcibly pull the abnormally activated KRASG12C protein back to an inactive state.
Lumakras has a long half-life to achieve long-lasting and continuous KRAS inhibition and lead to deep and long-lasting anti-tumor activity.
The molecular structure of Lumakras (Source: Wikimedia Commons) The clinical efficacy of Lumakras was approved based on data from a study called CodeBreak 100.
The study included 129 patients with KRASG12C mutant NSCLC patients who had previously received chemotherapy and/or immunotherapy.
Among the 124 patients included in the effectiveness analysis, a total of 46 patients achieved confirmed remission after a median follow-up of 12.
2 months.
, Including 3 cases of complete remission (CR) and 43 cases of partial remission (PR), patients in the Lumakras group achieved an objective response rate (ORR) of 37.
1%.The median time to objective remission was 1.
4 months, and the median duration of remission was 10 months.
43% of patients who responded received continued treatment and the disease did not progress.
The disease control rate (DCR) was 80.
6%, and the median progression-free survival (PFS) was 6.
8 months [5].
A variety of drugs exhibited clinical efficacy, and the once unpreparable targets ushered in a counterattack.
At present, the treatment of targeted KRAS has become the focus of clinical research.
In addition to Lumakras, there are many other drugs that have announced clinical effects.
MRTX849 MRTX849 is a small molecule inhibitor against KRAS G12C mutation.
At the European Lung Cancer Conference 2021 (ELCC 2021), the results of the KRYSTAL-1 study were announced.
The KRYSTAL-1 study is a multi-cohort phase I/II clinical study that included patients with KRAS G12C mutant NSCLC, patients with colorectal cancer (CRC), and patients with other solid tumors.
ELCC 2021 released data on the NSCLC cohort.
Among the 51 evaluable NSCLC patients who had previously received chemotherapy and anti-PD-1/PD-L1 therapy, ORR was 45% and DCR was 96% (49/51).
In patients with STK11 mutation, the ORR is as high as 64% (9/14).
The median duration of response (DoR) was 9.
2 months [6].
VS-6766VS-6766 is a RAF/MEK inhibitor.
At the AACR 2020 annual meeting, the results of a phase I clinical trial of VS-6766 and the FAK inhibitor Defactinib in the treatment of patients with solid tumors with RAS mutations were announced.
In the study, 7 of the 10 KRAS mutant non-small cell lung cancer patients had tumor shrinkage, and one of the G12V mutant patients had tumor shrinkage by more than 30%.
The combination regimen is well tolerated, and the most common adverse reactions are skin rash, elevated creatine kinase, elevated aspartate aminotransferase, hyperbilirubinemia and nausea, all adverse reactions can be reversed [7].
BGB-283BGB-283 is a new type of RAF inhibitor that exists in a unique dimer form and can also inhibit the activity of EGFR.
It has shown anti-tumor activity in pre-clinical models and tumor patients with BRAF V600E mutation, non-V600E BRAF mutation, and KRAS/NRAS mutation.
In 2020, a phase I dose escalation/dose extension study published in the Journal of Clinical Oncology for the first time in humans evaluated BGB-283 in patients with solid tumors with B-RAF or K-RAS/N-RAS mutations The safety, tolerability and efficacy of the product.
The results of the study show that the maximum tolerated dose of BGB-283 is 40 mg/d.
Dose limiting toxicity includes reversible thrombocytopenia and non-hematological toxicity.
Throughout the study, the most common adverse events in ≥3 treatment were hypertension (17.
6%) and fatigue (9.
9%).
Among them, 1 melanoma patient with B-RAF mutation achieved complete remission, 8 patients with B-RAF mutation achieved a confirmed objective remission, and 1 patient with K-RAS G12C mutation NSCLC had partial remission [8].
In summary, whether it is Lumakras, which has been approved, or MRTX849, which has shown very good clinical effects, after many years, the target of unpreparable medicine has finally ushered in a breakthrough, which will bring good news to cancer patients around the world.
It is believed that in the not too distant future, more KRAS inhibitors will surface.
Christina Guo, et al.
, Br J Cancer.
2021 Apr 15.
8.
Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors.
J Clin Oncol.
2020 Mar 17[Online ahead of print].
DOI: 10.
1200/JCO.
19.
02654.
Yaodu APP "Points New Game" company enjoys the database super-value permission dry granulation technology to discuss the ups and downs of 20 years, Kinase Where is the future of inhibitors? Sotrovimab has been authorized by the FDA for emergency use, "broad-spectrum" treatment of mild to moderate COVID-19.
Click "read original" to keep abreast of industry trends
