KRAS mutation treatment, trimetinib
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Author HK HIS Date19-09-16 18:19 View701 Comment0관련링크
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The KRAS gene mutation is currently the most difficult genetic mutation in the world. Trimetinib is a MEK1 / 2 inhibitor that affects the MAPK pathway and primarily inhibits cell proliferation through the action of the MEK protein. Since MEK is a downstream signaling protein of RAS and RAF, trimetinib may also be effective against carcinomas with RAS or RAF mutations. FDA co-approved the treatment of BRAFV600E or V600K incapacitating or metastatic melanoma and metastatic non-small cell lung cancer (NSCLC) and cialis of the gene mutation for the treatment of the Nepal BRAFV600E mutation.
trametinib (trametinib)
Trimetinib is a MEK1 / 2 inhibitor that affects the MAPK pathway and primarily inhibits cell proliferation through the action of the MEK protein. Since MEK is a downstream signaling protein of RAS and RAF, trimetinib may also be effective against carcinomas with RAS or RAF mutations.
US Medicines Name: Mekinist
Vendor: Novartis / Glaxo
Here is the molecular formula of trimetinib:
The FDA, trimetinib, was approved on June 22, 2017 and was administered concomitantly with darafini to patients with BRAF V600E mutation-positive metastatic non-small cell lung cancer (NSCLC). This is the first FDA specifically approved for the treatment of patients with BRAF V600E mutation-positive metastatic non-small cell lung cancer.
On January 10, 2014, trametinib in combination with darafene in the treatment of patients with BRAF V600E mutation-positive melanoma is benign, which can not be resected or metastasized.
May 29, 2013 BRAF V600E or V600K mutation to treat unresectable or metastatic melanoma patients.
What is the clinical effect of trimetinib?
1. BRF113928 (NCT01336634)
On June 22, 2017, the FDA approved trimetinib and darafini for BRAF V600E mutation-positive metastatic non-small cell lung cancer (NSCLC) patients. Approval is based on data from Phase II clinical trial BRF113928.
Experimental design:
93 patients received trimethadine - elotinib (2 mg oral), initial therapy (36 patients), and 57 patients received combined chemotherapy combined drug (150 mg oral).
Experiment result :
The overall response rate for newly diagnosed patients was 61%, and the overall response rate for patients receiving chemotherapy was 63% and the median duration of mitigation was 12.6 months.
It is a common malignant tumor that threatens human health. In the world, about 18 million people are diagnosed with lung cancer every year. More than 80% of them are non-small cell lung cancer, and 1 to 3% of all non-small cell lung cancer patients have BRAF V600 mutation There is. Moreover, in the past, the main treatment for this type of patient group was chemotherapy, with several other options! The emergence of combination therapy with dabrafenib and trametinib and approval by the European Commission and the US FDA has been an important milestone in lung cancer therapy!
Side Effect :
Fever, diarrhea, nausea, vomiting, fatigue, rash, anorexia, edema, cough and other symptoms, no serious side effects, safety control possible.
2 Melanoma I / II study
In 2014, the US Food and Drug Administration approved the combination of MEK inhibitor trimetinib and BRAF inhibitor dalafinib for the treatment of BRAF V600E or V600K mutations for nonoperable or metastatic melanoma. Approvals are based on public I / II surveys.
Experimental design:
A total of 162 patients with advanced melanoma were enrolled and treated with trimetinib and dalafini.
Results :
When compared to dalafini monotherapy, the combination of trimetinib and dalafini can effectively increase the overall response rate (ORR). The mean time for tumor contraction or disappearance in 76% of patients was 10.5 months. In contrast, researchers found that 54% of patients treated with darapenib alone had a mean tumor shrinkage or 5.6 months of disappearance.
Side Effect :
Swelling of the hands and feet, coughing, headache, joint pain, night sweats, loss of appetite, constipation and muscle aches. Serious side effects include bleeding, thrombosis, heart failure, skin and eye problems, and kidney damage.
The FDA emphasized that women of childbearing age, trimetinib and dalafini, should advise infants of congenital anomalies and treatment with trimetinib and dalafini should be indicated as causing infertility.
3 A randomized double-blind study of melanoma
In May 2013, the FDA approved TREMATINIP (GlaxoSmithKline) to treat metastatic melanoma with a BRAF V600E or V600K mutation.
Experimental design:
Multiple, international, randomized, double-blind study of 322 patients receiving ≤1 chemotherapy
Results :
A 4.8-month PFS comparison of the Trametinib therapy group was performed: 8%: 1.5 months (P <0.0001), and the objective response rate was 22%. The recommended doses are: Progression of the disease or tolerance to toxicity Trametinib 2 mg po or QD (1 hour before or 2 hours after meals). Common side effects include rash, diarrhea and lymphatic edema. A single agent for the treatment of BRAF V600E mutation carries a MEK inhibitor, oral tablet, which is either a surgical or non-metastatic melanoma melanoma adenocarcinoma patient with a V600K to Mekinist (trametinib).
Side Effect :
Rash, diarrhea and lymphadenopathy.
Serious side effects in patients taking tramadinib include cardiomyopathy, retinal pigment epithelial detachment, retinal vein occlusion, interstitial lung disease and severe skin toxicity.
How to get this medicine?
Prior to treatment with MEKINIST, we identified BRAF V600E and V600K mutations in tumor samples.
The recommended dose regimen for MEKINIST is dabrafenib, which takes 150 mg / day twice a day orally twice daily with a single drug. MEKINIST should take at least one hour before meals and at least two hours after meals.
Usage form and specification
Tablets: 0.5 mg, 1 mg and 2 mg.
What should I pay attention to when using?
New primary malignant tumors, skin and non-skin: May occur when MEKINIST is combined with dabrafenib. Before, after, and after the combination therapy, new malignant diseases were observed.
Bleeding: A major bleeding event may occur in patients receiving MEKINIST with dabrafenib. Monitor bleeding symptoms and symptoms.
Venous thromboembolism: Deep vein thrombosis and pulmonary embolism may occur in patients receiving MEKINIST with dabrafenib.
Cardiomyopathy: LVEF was assessed every month, two to three months after treatment.
Ocular toxicity: Ophthalmic evaluation of visual impairment. For retinal vein occlusion (RVO), terminate MEKINIST permanently
Interstitial lung disease (ILD): MEKINIST does not cause lung symptoms that can not be described as new and progressive. MEKINIST is permanently terminated by treatment-associated ILD and pneumonia.
Severe exothermic reaction: May occur when MEKINIST is combined with dabrafenib.
Severe Skin Toxicity: Monitor skin toxicity and secondary infection. In the unbearable 2nd, 3rd, and 4th graders, medication was not improved within 3 weeks of stopping MEKINIST.
Hyperglycemia: Monitor serum glucose levels in patients with existing diabetes and hyperglycemia.
Embryo Fetal Toxicity: Causes harm to the fetus Advise women who have potential for reproductive harm to the fetus.
What are the common side effects?
MEKINIST is a common side effect (more than 20%) including rash, diarrhea and lymphadenopathy.
Meierrothinib hides in the dabrafenib with the most common adverse reactions (≥20%) and fever, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, joint pain, Includes loss, constipation and muscle pain.
About MEK:
MEK is one of the earliest discovered and well-studied targets of scientists. The RAS-RAF-MEK-ERK pathway, which can be divided into MEK (mitogen-activated protein kinase) and MEK2 MEK1, is an important signaling molecule that plays an important role in cell proliferation, apoptosis, and cell differentiation.
It has been reported that in clinical trials of MEK, in the treatment of advanced colorectal cancer, for example, oral MEK inhibitor CI-1040 is targeted for the clinical trial phase II of non-small cell lung cancer, breast cancer or pancreatic cancer patients. AZD6244 (also known as sterminib) inhibits tumor cell proliferation with Q56P and K57N mutations.
Many types of cancer are associated with MEK, and the suppression of MEK has become one of the tools to control a variety of cancers. To date, there has been a particular inhibition of MEK, in addition to multiple targets including MEK and target Nexavar hydroentangles, including Trametinib (Qumei's Placenta / Mekinist), Selumetinib (AZD6244 / selumetinib), and also the aforementioned CI-1040 There is.
Of course, MEK inhibitors are used and the presence of the MEK gene must be detected.
Recommended Clinical Trials (Patients may apply):
1. Recurrent or stage IV TRASMATIN, coupled with methacellin in the treatment of KRAS mutation-positive non-small cell lung cancer. (NCT02642042)
This phase 2 study examined how trametinib and docetaxel contribute to the treatment of patients with non-small cell lung cancer or relapsed cancer with KRAS mutation. Trametinib blocks the growth of tumor cells by blocking some enzymes necessary for cell growth. Drugs used in chemotherapy, such as docetaxel, block the growth of tumor cells in many ways, kill cells, prevent division, or prevent spread. Administration of trametinib and docetaxel can be a better treatment for non-small cell lung cancer.
Experiment location:
1. University of California, Davis General Cancer Center
2. Los Angeles Cancer Center
Patients may be concerned about global oncology microchannel public network number Follow the instructions to submit medical records to participate in clinical trials, the medical department will assess the suitability of the preliminary, and contact you as soon as possible, Please call us at 400-666-7998.
2. Efficacy and Safety of dalafini and Trametinib in BRAF V600E-Mutant (Rare Tumor) Patients (NCT02034110)
This is a multi-center study of non-randomized, open-label Phase II Dabrafenib co-Trametinib for rare cancer patients, including this undifferentiated thyroid cancer, biliary cancer, gastrointestinal stromal tumor, original spermatogenesis non-germ cell tumor non-malignant germ cell tumor, hair cell Leukemia, glioma 1 or 2, 3 or 4 (advanced) glioma, multiple myeloma and small bowel cancer, BRAF V600E positive -mutations. This study was designed to determine the oral Dallas Phoenix with the ORA of the patient's Oral Trametinib treatment with rare BRAF V600E mutation total validity (ORR). The subject must provide fresh or frozen tumor tissue samples to confirm the BRAF V600E mutation status. Only those subjects who are diagnosed with advanced disease and do not have standard therapies can register for histology. Subjects will undergo eye examinations (eye examinations, echocardiography) within 14 days to determine eligibility to be included in the study prior to initiation of treatment.
Experiment location:
1. UCLA / Johnson Total Cancer Center
2. MD Anderson Cancer Center
3. National Institute of Health Clinical Trials Center
4. Massachusetts General Hospital
5. Bregen and Women's Hospital
