The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma

Knispel, Sarah; Zimmer, Lisa; Kanaki, Theodora; Ugurel, Selma; Schadendorf, Dirk; Livingstone, Elisabeth

doi:10.1080/14740338.2018.1390562

Cited by 33 publications

(26 citation statements)

References 64 publications

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“…Knispel et al had ever emphasized the significant role of these side effects related to life quality although the effects were moderate, reversible, and can be managed. 40 also demonstrated the same result. 41 Pyrexia was found at a higher risk in our meta-analysis.…”

Section: Discussionsupporting

confidence: 66%

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Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

Xie

et al. 2019

Cancer Medicine

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Background Melanoma is a potentially fatal malignancy with poor prognosis. Several recent studies have demonstrated that combination therapy of BRAF and MEK inhibition achieved better curative effect and appeared less toxic effects. We conducted a meta‐analysis to evaluate the efficacy and safety between BRAF inhibition plus MEK inhibition combination therapy and BRAF inhibition monotherapy in melanoma patients. Methods We performed the search in PubMed, EMBASE, and the Cochrane Library from January 2010 to January 2019. Inclusion and exclusion of studies, assessment of quality, outcome measures, data extraction, and synthesis were independently accomplished by two reviewers. Revman 5.3 software was used for the meta‐analysis. Results Totally, seven randomized controlled trials involving 3146 patients met our inclusion criteria. Comparing the results of combination therapy and monotherapy, combination therapy significantly improved OS (RR = 1.13; 95% CI, 1.08, 1.19; P < 0.00001), ORR (RR = 1.36; 95% CI, 1.28, 1.45; P < 0.00001), PFS (RR = 0.57; 95% CI, 0.52, 0.63; P < 0.00001) and reduced deaths (RR = 0.78; 95% CI, 0.69, 0.88; P < 0.0001). Skin‐related adverse events such as hyperkeratosis, cutaneous squamous‐cell carcinoma were less compared with monotherapy. However, gastrointestinal events like nausea, diarrhea, and vomiting were at a higher frequency. Conclusion Doublet BRAF and MEK inhibition achieved better survival outcomes over single‐agent BRAF inhibition and occurred less skin‐related events, but gastrointestinal events were more in combination therapy.

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Section: Discussionsupporting

confidence: 66%

“…Gastrointestinal events, including nausea, diarrhea, vomiting were found in our meta‐analysis. Knispel et al had ever emphasized the significant role of these side effects related to life quality although the effects were moderate, reversible, and can be managed . Livingstone et al had also demonstrated the same result .…”

Section: Discussionmentioning

confidence: 92%

Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

Xie

et al. 2019

Cancer Medicine

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“…The oral route of DAB and TRA has improved patient's quality of life in comparison with chemotherapy such as dacarbazine. However, patients in "real-life" cohorts exhibit a large interindividual variability (IIV) in clinical outcomes, such as toxicity [5] and efficacy [6], which can result in dose-limiting toxicities (DLT) or early disease progression. As previously reported with vemurafenib (BRAF inhibitor), variability in drug pharmacokinetics can contribute to early progression in BRAF-mutated MM patients [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetics/Pharmacodynamics of Dabrafenib Plus Trametinib in Patients with BRAF-Mutated Metastatic Melanoma

Balakirouchenane

Guégan

Csajka

et al. 2020

Cancers

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Patients treated with dabrafenib/trametinib (DAB/TRA) exhibit a large interindividual variability in clinical outcomes. The aims of this study were to characterize the pharmacokinetics of DAB, hydroxy-dabrafenib (OHD), and TRA in BRAF-mutated patients and to investigate the exposure-response relationship for toxicity and efficacy in metastatic melanoma (MM) patients. Univariate Fisher and Wilcoxon models including drug systemic exposure (area under the plasma concentration curve, AUC) were used to identify prognostic factors for the onset of dose-limiting toxicities (DLT), and Cox models for overall (OS) and progression-free survival (PFS). Seventy-three BRAF-mutated patients were included in pharmacokinetic (n = 424, NONMEM) and 52 in pharmacokinetic/pharmacodynamic analyses. Age and sex were identified as determinants of DAB and OHD clearances (p < 0.01). MM patients experiencing DLT were overexposed to DAB compared to patients without DLT (AUC: 9624 vs. 7485 ng·h/mL, respectively, p < 0.01). Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2 and plasma ratio AUC OHD /AUC DAB ≥ 1 were independently associated with shorter OS (HR: 6.58 (1.29-33.56); p = 0.023 and 10.61 (2.34-48.15), p = 0.022, respectively). A number of metastatic sites ≥3 and cerebral metastases were associated with shorter PFS (HR = 3.25 (1.11-9.50); p = 0.032 and HR = 1.23 (1.35-10.39), p = 0.011; respectively). TRA plasma exposure was neither associated with toxicity nor efficacy. Our results suggest that early drug monitoring could be helpful to prevent the onset of DLT in MM patients, especially in fragile patients such as the elderly. Regarding efficacy, the clinical benefit to monitor plasma ratio AUC OHD /AUC DAB deserves more investigation in a larger cohort of MM patients.

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“…The allosteric binding site is spatially proximal to the ATP binding site. MEK inhibitors, including trametinib (the 2D structure is shown in Figure 1B) [16][17][18], selumetinib [19] and binimetinib, have been used as a rational multitherapy strategy to treat RAS-RAF-MEK-ERK pathway-related cancers. However, the X-ray crystal structure of trametinib bound to MEK1 has not been uncovered to date.…”

Section: Introductionmentioning

confidence: 99%

Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib

Zhu

Yang

et al. 2020

IJMS

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Activation of the mitogen-activated protein kinase (MAPK) signaling pathway regulated by human MAP kinase 1 (MEK1) is associated with the carcinogenesis and progression of numerous cancers. In addition, two active mutations (P124S and E203K) have been reported to enhance the activity of MEK1, thereby eventually leading to the tumorigenesis of cancer. Trametinib is an MEK1 inhibitor for treating EML4-ALK-positive, EGFR-activated, and KRAS-mutant lung cancers. Therefore, in this study, molecular docking and molecular dynamic (MD) simulations were performed to explore the effects of inactive/active mutations (A52V/P124S and E203K) on the conformational changes of MEK1 and the changes in the interaction of MEK1 with trametinib. Moreover, steered molecular dynamic (SMD) simulations were further utilized to compare the dissociation processes of trametinib from the wild-type (WT) MEK1 and two active mutants (P124S and E203K). As a result, trametinib had stronger interactions with the non-active MEK1 (WT and A52V mutant) than the two active mutants (P124S and E203K). Moreover, two active mutants may make the allosteric channel of MEK1 wider and shorter than that of the non-active types (WT and A52V mutant). Hence, trametinib could dissociate from the active mutants (P124S and E203K) more easily compared with the WT MEK1. In summary, our theoretical results demonstrated that the active mutations may attenuate the inhibitory effects of MEK inhibitor (trametinib) on MEK1, which could be crucial clues for future anti-cancer treatment.

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The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma

Cited by 33 publications

References 64 publications

Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

Population Pharmacokinetics/Pharmacodynamics of Dabrafenib Plus Trametinib in Patients with BRAF-Mutated Metastatic Melanoma

Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib

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