26P Pre-clinical modelling and treatment of BRAF mutated colorectal cancer
Mark WhiteTamsin R.M. LannaganLynn McGarryLeo M. CarlinMoyra MillsAyse Seda YazgiliR. L. RidgwayRené JackstadtAndrew D. CampbellR.H. WilsonOwen J. Sansom
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Dabrafenib
Trametinib
Background: Melanoma is the most serious lethal skin cancer, affects the melanin producer cells (melanocytes). Surgery is the most common treatment, whereas for the advance stage the development of a treatment is recommended. BRAF (Dabrafenib and Vemurafenib) inhibitor or MEK inhibitor (Trametinib) is used as the most frequently targeted therapy of melanoma due to more than 80% patient with positive BRAF mutation. In this review, those treatments will be investigated systematically to identify their clinical outcome.Method: This systematic literature review (SLR) was performed from Cochrane, Science Direct, Google Scholar, and Pubmed. Cochrane Risk-of-Bias Tool RoB2 is used to assess RCT studies and New-castle Ottawa Scale Assessment to assess cohort studies by 3 different assessors. Data analysis was carried out by using Review Manager (RevMan 5.4). Heterogenicity test was assessed by I2 Â and Chi2 statisticResult: There are 20 studies used in this article (13 RCT and 7 cohorts). The overall survival (OS) and progression-free survival (PFS) of study that using targeted therapy (vemurafenib, trametinib, or dabrafenib) compare other therapies (chemotherapy, immunotherapy,etc) showed risk ratio (RR) was 1.12 (95%CI 1.07,1.17;Â I2=100%; p<0,00001). The OS and PFS with monotherapy compare of vemurafenib, trametinib, or dabrafenib with combination therapy showed RR was 1.09 (95%CI.06,1.13;I2=99%; p<0,00001). Conclusion: BRAF and MEK targeted therapy has a good prognosis for a patient with a positive BRAF gene mutation and could be combined with other therapy for a better clinical outcome rather than monotherapy.Keyword: melanoma, dabrafenib, vemurafenib, and trametinib
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We report on a patient with an adenocarcinoma of the lung harbouring a BRAF V600E mutation who benefited from combination therapy with dabrafenib-trametinib after developing resistance to vemurafenib. To our knowledge, our report shows, for the first time, that combination therapy with dabrafenib-trametinib can overcome vemurafenib resistance in a BRAF V600E-mutated adenocarcinoma of the lung.
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Since 2011, the treatment options for metastatic malignant melanoma have significantly changed. In that year, ipilimumab, an anti-CTLA4 monoclonal antibody, and vemurafenib, a potent inhibitor of mutated-BRAF (V600E and V600K), were approved by the U.S. Food and Drug Administration (FDA). In 2013, dabrafenib, another inhibitor of mutated-BRAF, and trametinib, a MEK inhibitor, were approved by the FDA. Most recently, combination therapy with dabrafenib and trametinib was approved. This article will describe a patient with metastatic malignant melanoma with BRAFV600E who has responded very well to vemurafenib monotherapy. We will then explore the molecular basis, pharmacologic development and clinical outcomes of inhibition of the mitogen-activated protein (MAP) kinase pathway in patients with metastatic malignant melanoma with oncogenic BRAF (V600E and V600K).
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At present, two selective BRAF inhibitors (dabrafenib and vemurafenib) and one MEK inhibitor (trametinib) are FDA-approved for treating stage IV BRAFV600E -mutated metastatic melanoma. Single-agent dabrafenib but not vemurafenib has been tested against combination dabrafenib/trametinib. Vemurafenib monotherapy is in current use; these investigators studied its efficacy relative to combination dabrafenib/trametinib.
A total of 704 patients were randomized to receive either oral …
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Abstract Efficacy of BRAF V600E targeted therapies in brain tumors harboring the mutation has been shown in several case reports and is currently being studied in larger clinical trials. Monotherapy with vemurafenib has been associated with significant side effects, including rashes, papillomas, and squamous cell carcinomas. Here we describe an adolescent female with anaplastic ganglioglioma and significant skin reaction to vemurafenib with subsequent tumor response and tolerance to the BRAF/MEK inhibitor combination of dabrafenib and trametinib without recurrence of previous reaction.
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Background and importance
Dabrafenib/trametinib and vemurafenib/cobimetinib significantly increased progression free survival (PFS) and overall survival (OS) in patients with advanced or metastatic melanoma with BRAF mutations, in phase III clinical trials (CT).Aim and objectives
To assess the effectiveness and safety of vemurafenib/cobimetinib and dabrafenib/trametinib in patients with locally advanced or metastatic melanoma in real life.Material and methods
We performed a retrospective, multicentre, observational study of patients with BRAF mutated melanoma treated with vemurafenib/cobimetinib or dabrafenib/trametinib until 30 September 2020. Variables collected were: sex, age, stage, performance status (PS), previous treatments, duration of treatment and response, dose received and dose adjustments. Variables evaluated were: PFS, OS, adverse events (AE), withdrawal rate and reason for withdrawal.Results
We included 42 patients (27 men, mean age 62.4±15.2 years). 81% had metastatic melanoma and 19% had locally advanced melanoma. 20 patients received vemurafenib/cobimetinib, 13 dabrafenib/trametinib, 1 dabrafenib and 8 received both drugs. 14 patients presented PS=0, 24 PS=1 and 13 PS≥2. 71.4% and 14.3% of patients treated with vemurafenib/cobimetinib and dabrafenib/trametinib, respectively, received the drug as firstline treatment. Effectiveness and safety variables were evaluated in 38 patients (n=4 loss to follow-up): median PFS was 9.71 (95% CI 5.77 to NA) and median OS was 18.5 (95% CI 11.9 to NA) in vemurafenib/trametinib treated patients, while in those who received dabrafenib/cobimetinib, median PFS was 10.1 (95% CI 7.7 to NA) and OS was not reached. median duration of treatment with vemurafenib/cobimetinib and dabrafenib/trametinib was 99 (IR 20–243) and 198 (IR 73–632) days, respectively. 14.8% and 26.3% of patients treated with vemurafenib/cobimetinib and dabrafenib/trametinib, respectively, showed complete response, 33.3% and 26.3% partial response, 11.1% and 15.8% progressed and 33.3% and 15.8% were not assessable (early toxicity or recent onset). All patients treated with vemurafenib/cobimetinib presented with AE during treatment (85.2% dermatological and 74.1% gastrointestinal) and in 26% treatment was withdrawn. In patients treated with dabrafenib/trametinib, 94.7% showed AE (52.6% dermatological, 68.4% gastrointestinal and 57.9% low grade fever/discomfort), and in 15.8% treatment was withdrawn due to toxicity.Conclusion and relevance
The effectiveness observed in our patients was slightly lower than that seen in the pivotal CT (COBRIM-b) in vemurafenib/cobimetinib patients. In contrast, it was similar to that seen in other pivotal CTs (COMBI-v and COMBI-d) in patients treated with dabrafenib/trametinib. The toxicity profile of both drugs was similar to the pivotal CTs. Dabrafenib/trametinib was better tolerated than vemurafenib/cobimetinib.References and/or acknowledgements
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Background
In recent years, new drugs have been approved for metastatic melanoma. The BRAF gene is the most common mutation in cutaneous melanomas and is present in 50% of melanomas. Vemurafenib and dabrafenib are used for the treatment of adult patients with unresectable or metastatic melanoma who are BRAF V600 mutation positive.Purpose
To analyse the use of the targeted anti-BRAF therapies, vemurafenib or dabrafenib, alone or combined with the MEK inhibitor trametinib or cobimetinib in a tertiary hospital in patients diagnosed with metastatic melanoma.Material and methods
A retrospective observational study was conducted in all patients treated with vemurafenib or dabrafenib, alone or with trametinib or cobimetinib, from May 2014 to April 2016. SAP software was used for medical history, nursing and dispensation records.Results
6 patients, 50% men, were evaluated, with an average age of 63 years (84–46). 1 received vemurafenib alone, 3 patients received vemurafenib associated with cobimetinib and the other 2 received trametinib with dabrafenib. 1 of the patients who received dabrafenib and trametinib (2 cycles, ECOG 2) and the patient who received vemurafenib alone (3 cycles, not reflected ECOG) died. The remaining patients continued on treatment: 17 cycles for the patient who received dabrafenib-trametinib, 5 cycles for 2 patients who received vemurafenib-cobimetinib and 4 cycles for the other, with ECOG 0. 1 patient had lung, lymph nodes and liver metastases, 1 lung metastases, 1 mediastinal metastases, 1 skin and peritoneal metastases and 2 patients had lymph node progression when they started anti-BRAF therapy. LDH levels were increased in 50% of patients. Adverse reactions included fever in the patient who received dabrafenib-trametinib and acne, mild abdominal pain and asthenia in 1 patient who received dabrafenib-trametinib. In the case of vemurafenib, eritrodermia required discontinuation of treatment. In the cases of vemurafenib-cobimetinib, skin toxicity (sores) associated with vemurafenib reached grade III, forcing halving of the dose to both drugs, and the likely drug induced fever caused hospitalisation of this patient.Conclusion
It seems that the number and location of metastases, LDH values, ECOG 0 and combination of anti-BRAF drugs with the MEK inhibitor determines survival and tolerance to the drug, but further follow-up is needed to determine the evolution of patients.References and/or acknowledgements
https://www.aemps.gob.es/medicamentosUsoHumano/informesPublicos/docs/IPT-zelboraf-melanoma.pdfhttps://www.aemps.gob.es/medicamentosUsoHumano/informesPublicos/docs/IPT-dabrafenib-tafinlar.pdf No conflict of interestDabrafenib
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