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Table of Contents
DRUG REVIEW
Year : 2020  |  Volume : 3  |  Issue : 3  |  Page : 537-544

Dabrafenib: A narrative drug review


Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Submission25-May-2020
Date of Decision10-Jun-2020
Date of Acceptance06-Jul-2020
Date of Web Publication19-Sep-2020

Correspondence Address:
Lakhan Kashyap
Room No. 914, Golden Jubilee Building, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_210_20

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  Abstract 


Activating mutations in the BRAF gene lead to an unregulated downstream signaling of the MAPK/extracellular-signal-regulated kinase pathway. This pathway is implicated in a range of solid tumors, and BRAF inhibitors are an attractive option in the treatment of these cancers. At present, three BRAF inhibitors have received the Food and Drug Administration approval for the treatment of cancer, namely, dabrafenib, vemurafenib, and encorafenib. Dabrafenib is approved for the treatment of advanced melanomas, anaplastic thyroid cancers, non-small cell lung cancers, and for the adjuvant treatment of melanomas harboring the BRAF V600E/K mutation. This review of dabrafenib describes its chemistry, pharmacokinetics, interactions, clinical indications, and safety profile. We identified and included studies from the PubMed database using search terms “dabrafenib”, “trametinib” or “pharmacology” for qualitative synthesis.

Keywords: Anaplastic thyroid cancer, BRAF, dabrafenib, melanoma, non-small cell lung cancer


How to cite this article:
Kashyap L, Saha S, Srikanth A. Dabrafenib: A narrative drug review. Cancer Res Stat Treat 2020;3:537-44

How to cite this URL:
Kashyap L, Saha S, Srikanth A. Dabrafenib: A narrative drug review. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Oct 30];3:537-44. Available from: https://www.crstonline.com/text.asp?2020/3/3/537/295544




  Introduction Top


Activating mutations in the serine threonine kinase BRAF are seen in 7%–15% of human cancers, particularly melanoma, colorectal cancer, non-small cell lung cancer (NSCLC), thyroid cancer, biliary tract cancer, and ovarian cancer. The most common BRAF mutation is V600E that involves the substitution of valine with glutamic acid at 600 amino acid residue in the BRAF protein. This mutation results in the constitutive activation of the RAS–RAF–mitogen-activated protein kinase/ ERK kinase (MEK) pathway, leading to unregulated cell growth and proliferation.[1] Dabrafenib has inhibitory action against the rapidly accelerated fibrosarcoma (RAF) kinases, especially the constitutively active mutant BRAF kinase. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved dabrafenib alone or in combination with the oral MEK inhibitor, trametinib, for the treatment of unresectable or metastatic melanomas and dabrafenib in combination with trametinib for the treatment of resected Stage III melanoma, metastatic NSCLC, and locally advanced or metastatic anaplastic thyroid cancer (ATC) harboring the BRAF V600 mutation.[2],[3] [Table 1] summarizes the key features of dabrafenib. We aim to comprehensively review the literature regarding dabrafenib, including the history, chemistry, drug interactions, indications, toxicity, dosing and modifications in special situations, and ongoing clinical trials.
Table 1: Key features of dabrafenib

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  Materials and Methods Top


We searched in the PubMed database using search terms “dabrafenib”, “trametinib” or “pharmacology”. [Figure 1] depicts the flow chart of the search strategy adopted. All the articles were screened by two authors (L.K. and S.S); case reports, case series and retrospective studies were excluded. Additionally, only full text articles in English were included in the study. Descriptive and relevant data were extracted from each article separately by two authors (L.K. and S.S). These data were included for writing the present review.
Figure 1: The flow diagram depicting the search strategy adopted for the review article on dabrafenib

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  History Top


Early efforts by Rheault etal. from the GlaxoSmithKline RandD laboratory at discovering a potent BRAF inhibitor resulted in the development of the candidate molecule, thiazole 1. This compound showed potentin vitro inhibitory activity against the BRAF kinase in cellular mechanistic and proliferation assays in BRAF V600E mutant melanoma cell lines. However, it showed poor bioavailability and high clearance in nonrodent species. Through a series of detailed and iterative structure activity relationship (SAR) studies, structural changes such as R2 fluorination, sulfonamide head, and tert-butyl thiazole core that led to improved potency of the lead structure were identified, and the nonessential portions were eliminated. The 12th compound in these SAR studies, GSK2118436, retained high potency and demonstrated significant improvement in higher species pharmacokinetics, leading to the discovery of dabrafenib and paving the way for preclinical studies.[4]


  Chemistry and Pharmacokinetics Top


The IUPAC name of dabrafenib mesylate is N-(3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fuorophenyl)-2,6-difuorobenzene sulfonamide. The chemical structure of dabrafenib is depicted in [Figure 2]. It has a molar mass of 615.68 g/mol. Seems to be unnecessary space here. Dabrafenib is a potent, reversible, and selective inhibitor of RAF kinases, especially the mutant BRAF kinase. Inhibition of the BRAF kinase impairs the phosphorylation of the MEK and ERK kinases, leading to the downregulation of the MAPK signaling pathway, which ultimately results in the inhibition of cell proliferation and causes cell death [Figure 3].[4] There is activation of the MAPK pathway in the cells with wild-type BRAF protein by dabrafenib-mediated signaling of CRAF (RAF1), possibly through allosteric mechanisms. This may result in the uncontrolled proliferation of skin cells and development of cutaneous squamous cell carcinoma (CuSCC) and keratoacanthoma.[5]
Figure 2: Chemical structure of dabrafenib mesylate (National Center for Biotechnology Information. PubChem Database. Dabrafenib mesylate, CID = 44516822, https://pubchem.ncbi.nlm.nih.gov/compound/Dabrafenib-mesylate (accessed on May 16, 2020)

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Figure 3: RAS-RAF-MEK-ERK pathway and B-RAF and MEK inhibition by dabrafenib and trametinib. RTK: Receptor tyrosine kinase

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After the oral administration of dabrafenib, the median time for absorption is 2 h and the bioavailability is 95%. Dabrafenib and its metabolites have a high plasma protein-binding affinity, and their apparent volume of distribution in the steady state is 70.3 L.[6] Dabrafenib is a substrate for the breast cancer resistance protein (BCRP) and p-glycoprotein. It can penetrate the blood–brain barrier, and its efficacy in brain metastases can be increased by using it in combination with trametinib. Trametinib enhances the permeability of dabrafenib through the inhibition of BCRP and p-glycoprotein at the blood–brain barrier.[7]

Dabrafenib is primarily eliminated by biliary excretion and oxidative metabolism. The cytochrome P450 enzymes, CYP2C8 and CYP3A4, are involved in the metabolism of dabrafenib. It is metabolized to hydroxy-dabrafenib via oxidation of the t-butyl group. Further metabolic oxidation involves conversion of hydroxy-dabrafenib to carboxy-dabrafenib, which then undergoes pH-dependent decarboxylation to desmethyl-dabrafenib.[8]


  Drug Interactions Top


  1. Strong inhibitors of CYP3A4 (azoles, protease inhibitor, macrolide) or CYP2C8 (gemfibrozil, trimethoprim) lead to increase in dabrafenib's plasma area under the curve (AUC) value
  2. Strong inducers of CYP3A4 (rifampicin, phenytoin) lead to decrease in dabrafenib's plasma AUC value
  3. Dabrafenib is an inducer of CYP3A4 and CYP2B6 and leads to decrease in plasma AUC levels of their substrates (midazolam, warfarin)
  4. Administration of dabrafenib with trametinib leads to a 23% increment in dabrafenib's plasma AUC level.



  Special Situations Top


  1. Pregnancy: Dabrafenib was found to be teratogenic in rats at three times the recommended dose in humans. Therefore, there is a possibility of it causing fetal harm when administered to pregnant women
  2. Lactation: There are no data to suggest that dabrafenib is secreted in breast milk. However, because of the potential adverse reaction in infants, breastfeeding is not recommended during dabrafenib treatment and 2 weeks after the last dose
  3. Fertility: Dabrafenib may impair fertility in females by reducing the number of corpora lutea. There is a risk of irreversible impaired spermatogenesis in males treated with dabrafenib
  4. Pediatric use: There are limited data on the use and safety of dabrafenib in pediatric patients. In juvenile rats, an increased incidence of kidney cysts, tubular deposits, forestomach hyperplasia, and decreased bone length was observed
  5. Geriatric use: Dabrafenib alone or in combination with trametinib is safe and effective in patients with melanoma aged more than 65 years
  6. Hepatic impairment: As dabrafenib is primarily eliminated via biliary excretion, there is a concern of increased exposure in patients with moderate-to-severe hepatic impairment. However, the safe dosing of dabrafenib has not been determined in these patients
  7. Renal impairment: In patients with severe impairment of kidney function, the safe dose of dabrafenib has not been determined. In patients with mild-to-moderate impairment of kidney function, dose modification is not recommended.



  Clinical Indications Top


  1. Melanoma: BRAF activating mutations are identified in around 50% of patients with melanomas.[9] In a Phase III randomized trial evaluating dabrafenib versus dacarbazine in patients with advanced melanomas, a median progression-free survival (PFS) of 5.1 versus 2.7 months (hazard ratio [HR] = 0.30; 95% confidence interval [CI] = 0.18–0.51; P < 0.0001) favoring dabrafenib was observed. There was a trend toward the overall survival (OS) benefit with dabrafenib (18.2 vs. 15.6 months, for dabrafenib and dacarbazine, respectively), but the difference in OS was not statistically significant. Patients in the dacarbazine arm were allowed to switch over to the dabrafenib arm. This trial led to the approval of dabrafenib in patients with unresectable or metastatic melanomas harboring the BRAF V600E mutation[10]


  2. Cutaneous toxicity can occur in patients receiving dabrafenib. This includes the development of CuSCCs secondary to the paradoxical activation of the MAPK pathway by dabrafenib in cells with wild-type BRAF protein.[11] Trametinib reduces the risk of reactivation of the MAPK pathway by downstream MEK inhibition. A Phase III study (COMBI-d) evaluated the combination of dabrafenib and trametinib versus dabrafenib and placebo in patients with advanced melanomas with the BRAF V600E/K mutation. The combination therapy resulted in a median OS of 25.1 months, whereas the OS with dabrafenib alone was 18.7 months (HR, 0.71; 95% CI, 0.55–0.92; P = 0.011), translating into an OS benefit of 6.4 months.[12] In the COMBI-v study, the combination of dabrafenib and trametinib versus vemurafenib alone was evaluated in patients with metastatic melanomas with the BRAF V600E/K mutation. The combination therapy showed a median OS of 25.6 months, whereas the median OS with vemurafenib alone was 18 months (HR, 0.66; 95% CI, 0.53–0.81; P < 0.001).[13] This led to the approval of the combination of dabrafenib and trametinib for the treatment of patients with unresectable or metastatic melanomas harboring the BRAFV600E/K mutation. Another Phase III study, COMBI-AD, evaluated this combination (dabrafenib + trametinib) as adjuvant treatment in patients with completely resected Stage III melanoma having BRAF V600E/K mutation. Patients in the combination therapy arm demonstrated a better 3-year relapse-free survival than those in the placebo arm (58% vs. 39%; HR, 0.47; 95% CI, 0.39–0.58; P < 0.001)[14]

  3. NSCLC: BRAF V600E mutation has been reported in 2%–4% of lung adenocarcinomas. In a Phase II trial, Planchard etal. demonstrated an objective response rate (complete and partial response) of 66% and a median PFS of 9.7 months with the combination of dabrafenib and trametinib in 59 previously treated patients with metastatic NSCLC having the BRAF V600E mutation.[15] In another Phase II trial evaluating the combination of dabrafenib and trametinib in 36 untreated metastatic NSCLC patients harboring the BRAF V600E mutation, an objective response rate of 64% and median PFS and OS of 10.9 months and 24.6 months, respectively, were observed.[16] This led to the approval of dabrafenib in combination with trametinib by the FDA and EMA for patients with metastatic NSCLC harboring the BRAF V600E mutation
  4. ATC: BRAF V600E mutation is found in 20%–50% of patients with ATC. A Phase II basket trial (NCT02034110) evaluated the safety and efficacy of dabrafenib in combination with trametinib in 100 patients with BRAF V600E-mutated rare cancers, including the 16 previously treated patients with ATC. The overall response rate was 69%, which was superior to the response rate in the historical controls of 15%. The median duration of response, PFS, and OS were not reached, however, the estimated 12-month duration of response, PFS, and OS were 90%, 79%, and 80%, respectively.[17] Wang etal. reported a case series of six patients with BRAF V600E-mutated ATC who underwent complete surgical resection after neoadjuvant dabrafenib and trametinib. There was 100% locoregional control and 83% OS at 12 months[18]
  5. Other solid tumors: BRAF mutations are found in 7%–10% of metastatic colorectal cancers (mCRC). In BRAF-mutated mCRC, reactivation of the EGFR (epidermal growth factor receptor) signaling bypasses BRAF inhibition and leads to therapeutic resistance to BRAF inhibitors.[19] As MEK plays a key role in EGFR-mediated resistance to BRAF inhibition, the combination of BRAF, EGFR, and MEK inhibitors has been studied in clinical trials. A Phase I/II study showed promising activity of the combination of dabrafenib, trametinib, and panitumumab in patients with mCRC. The triplet combination resulted in an objective response rate of 21% compared to the 10% achieved with the combination of dabrafenib and panitumumab.[20] BRAF mutation has been reported in approximately 5% of high-grade gliomas (HGGs) and 15%–20% of low-grade gliomas (LGGs). Phase I/II studies evaluating the combination of dabrafenib and trametinib have shown an objective response rate of 45% and 72% in relapsed or refractory HGG and LGG, respectively.[21],[22]


[Table 2] summarizes the key trials of dabrafenib which led to its approval for the treatment of melanomas, NSCLC, and ATC.
Table 2: Summary of the key trials for dabrafenib in solid tumors with BRAF V600 mutation

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  Safety Profile Top


  1. Across the clinical trials following adverse events have been observed with dabrafenib.[2]Cutaneous and noncutaneous malignancies: Dabrafenib may induce cell proliferation in cells with wild-type BRAF protein via the paradoxical activation of the MAP kinase pathway. Across clinical trials, the incidence of CuSCC with dabrafenib monotherapy was 11%. In the COMBI-d trial among patients receiving dabrafenib with trametinib, the incidence of CuSCC and basal cell carcinoma was 3% and 3.3%, respectively. The incidence of noncutaneous malignancies in patients receiving dabrafenib with trametinib in the COMBI-d and COMBI-AD trials was 1.4% and 1%, respectively
  2. Hemorrhage, including symptomatic major hemorrhage, can occur with the combination of dabrafenib and trametinib. In the COMBI-d study, hemorrhagic events occurred in 19% of the patients. Gastrointestinal hemorrhage occurred in 6% and fatal intracranial hemorrhage occurred in 1.4% of the patients
  3. Cardiomyopathy: In the COMBI-d trial, the incidence of cardiomyopathy in patients receiving dabrafenib with trametinib and dabrafenib alone was 6% and 2.9%, respectively. Cardiomyopathy was defined as ≥10% reduction in the left ventricular ejection fraction from baseline and below the institutional lower limit of normal. In the COMBI-AD trial, cardiomyopathy occurred in 3% of the patients receiving the combination. Cardiomyopathy resolved in the majority of the patients after dose interruption, reduction, or discontinuation
  4. Serious febrile reaction and fever of any severity can occur with dabrafenib. The incidence is higher when it is combined with trametinib. Fever occurred in 54% of the patients who received dabrafenib with trametinib in the COMBI-v and COMBI-d trials. The incidence of serious febrile reaction or fever associated with hypotension, syncope, dehydration, renal dysfunction, or severe chills/rigors was 17%
  5. Dabrafenib alone or in combination with trametinib can cause deranged glycemic control in patients with diabetes mellitus, thus making more intensive hypoglycemic therapy necessary. In the COMBI-d trial, the incidence of Grade 3 and Grade 4 hyperglycemia in patients receiving dabrafenib with trametinib was 5% and 0.5%, respectively
  6. Across clinical trials, the incidence of uveitis in patients receiving dabrafenib alone and dabrafenib with trametinib was 1% and 2%, respectively
  7. Dabrafenib can cause hyperkeratosis, rashes, alopecia, and palmo-plantar erythrodysesthesia. However, Grade 3 or 4 skin and subcutaneous adverse events have been reported in <2% of the patients
  8. Musculoskeletal adverse events such as arthralgia, back pain, or myalgia can occur in patients receiving dabrafenib.


Approved indications and dose

Dabrafenib is administered at a dose of 150 mg twice daily in the approved indications. Dabrafenib doses are taken either 1 h before or 2 h after a meal and 12 h apart.[2]

  1. Unresectable or metastatic melanoma: Dabrafenib is given as a single agent in patients with tumor harboring the BRAF V600E mutation, and it is given in combination with trametinib in patients with tumors harboring the BRAF V600E/K mutation. It is continued until progression or unacceptable toxicity
  2. Resected Stage III melanoma: Dabrafenib is given in combination with trametinib for adjuvant treatment in patients with tumors harboring the BRAF V600E/K mutation for 12 months in the absence of recurrence of disease or until unacceptable toxicity
  3. Metastatic NSCLC: Dabrafenib is given in combination with trametinib in patients with tumors harboring the BRAF V600E mutation until progression or unacceptable toxicity
  4. Unresectable or metastatic ATC: Dabrafenib is given in combination with trametinib in patients with tumors harboring the BRAF V600E mutation until progression or unacceptable toxicity.


Dose modification

Dabrafenib is permanently discontinued if patients develop RAS mutation-positive, noncutaneous malignancies or recurrent Grade 4 adverse reactions. Dose reduction in dabrafenib is done sequentially at 100, 75, and 50 mg levels. Dabrafenib should be withheld if patients develop a temperature of ≥101.3°F, and trametinib should be withheld if the temperature is ≥104°F. It can be resumed at the same or reduced dose after the resolution of the febrile episode. If fever is complicated by dehydration, renal failure, rigors or chills, or hypotension, dabrafenib should be resumed at a lower dose. Corticosteroids (prednisolone 10 mg orally once daily for 5 days) should be given for the second and subsequent episodes of fever if it does not subside in 3 days or is associated with complications in the previous episode. If the patient is unable to tolerate dabrafenib at a 50-mg dose, it is discontinued permanently. The dose modification for adverse reactions is outlined in [Table 3].[2],[3]
Table 3: Recommended dose modification of dabrafenib

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Monitoring

  1. Left ventricular systolic function should be assessed by two-dimensional echocardiography or multigated acquisition scan before starting dabrafenib. It should be monitored at 1 month and thereafter at 2–3-month intervals while receiving dabrafenib
  2. Monitor the serum glucose levels upon initiation of treatment with dabrafenib and as clinically indicated in patients with preexisting deranged blood sugar
  3. Monitor for new or worsening skin lesions, including the development of CuSCC
  4. Monitor for febrile reaction. If fever persists for ≥3 days or fever is associated with complications, corticosteroids such as prednisolone (10 mg) for 5 days can be considered for the second and subsequent episodes of fever
  5. Monitor for ophthalmic symptoms or signs such as change in vision, eye pain, or photophobia suggestive of uveitis.


Ongoing clinical trials

The BRAF V600 mutation is identified in a range of malignancies apart from melanomas, NSCLC, and ATC. There are ongoing clinical trials evaluating the safety and efficacy of dabrafenib in these malignancies. Concurrent or sequential immunotherapy in combination with BRAF inhibitors may lead to incremental response and better outcomes in patients with tumors harboring the BRAF V600 mutation, particularly melanomas. [Table 4] summarizes some of the selected ongoing trials evaluating dabrafenib. Noeparast et al. in their study have demonstrated thein vitro activity of the combination of dabrafenib and trametinib in non-BRAF V600E mutant cell lines.[23] However, further clinical studies are required to demonstrate the efficacy of the combination in this scenario.
Table 4: Ongoing trials for dabrafenib

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  Conclusion Top


Dabrafenib in combination with trametinib in patients with advanced melanoma, NSCLC, and ATC and as adjuvant therapy in resectable Stage III melanoma is an effective and well-tolerated first-line treatment. Presence of BRAF V600E/K mutation should be confirmed prior to the initiation of treatment. Further studies are needed to evaluate the role of dabrafenib in other solid tumors with a BRAF-activating mutation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Rheault TR, Stellwagen JC, Adjabeng GM, Hornberger KR, Petrov KG, Waterson AG, et al. Discovery of dabrafenib: A selective inhibitor of raf kinases with antitumor activity against B-Raf-driven tumors. ACS Med Chem Lett 2013;4:358-62.  Back to cited text no. 4
    
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Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010;464:427-30.  Back to cited text no. 5
    
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Ouellet D, Gibiansky E, Leonowens C, O'Hagan A, Haney P, Switzky J, et al. Population pharmacokinetics of dabrafenib, a BRAF inhibitor: Effect of dose, time, covariates, and relationship with its metabolites. J Clin Pharmacol 2014;54:696-706.  Back to cited text no. 6
    
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Davies MA, Saiag P, Robert C, Grob JJ, Flaherty KT, Arance A, et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): A multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 2017;18:863-73.  Back to cited text no. 7
    
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Bershas DA, Ouellet D, Mamaril-Fishman DB, Nebot N, Carson SW, Blackman SC, et al. Metabolism and disposition of oral dabrafenib in cancer patients: proposed participation of aryl nitrogen in carbon-carbon bond cleavage via decarboxylation following enzymatic oxidation. Drug Metab Dispos 2013;41:2215-24.  Back to cited text no. 8
    
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Menzies AM, Long GV, Murali R. Dabrafenib and its potential for the treatment of metastatic melanoma. Drug Des Devel Ther 2012;6:391-405.  Back to cited text no. 9
    
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Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: A multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012;380:358-65.  Back to cited text no. 10
    
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Menzies AM, Kefford RF, Long GV. Paradoxical oncogenesis: are all BRAF inhibitors equal? Pigment Cell Melanoma Res 2013;26:611-5.  Back to cited text no. 11
    
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Grob JJ, Amonkar MM, Karaszewska B, Schachter J, Dummer R, Mackiewicz A, et al. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): Results of a phase 3, open-label, randomised trial. Lancet Oncol 2015;16:1389-98.  Back to cited text no. 13
    
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Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med 2017;377:1813-23.  Back to cited text no. 14
    
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Planchard D, Besse B, Groen HJM, Souquet PJ, Quoix E, Baik CS, et al. Dabrafenib plus trametinib in patients with previously treated BRAF (V600E)-mutant metastatic non-small cell lung cancer: An open-label, multicentre phase 2 trial. Lancet Oncol 2016;17:984-93.  Back to cited text no. 15
    
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23.
Noeparast A, Teugels E, Giron P, Verschelden G, De Brakeleer S, Decoster L, et al. Non-V600 BRAF mutations recurrently found in lung cancer predict sensitivity to the combination of Trametinib and Dabrafenib. Oncotarget 2017;8:60094-108.  Back to cited text no. 23
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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