Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial

Dummer, Reinhard; Schadendorf, Dirk; Ascierto, Paolo A.; Arance, Ana; Dutriaux, Caroline; Giacomo, Anna Maria Di; Rutkowski, Piotr; Vecchio, Michele Del; Gutzmer, Ralf; Mandalà, Mario; Thomas, Luc; Демидов, Лев В.; Garbe, Claus; Hogg, David; Liszkay, Gabriella; Queirolo, Paola; Wasserman, Ernesto; Ford, James; Weill, Marine; Sirulnik, L. Andres; Jehl, Valentine; Bozón, Viviana; Long, Georgina V.; Flaherty, Keith T.

doi:10.1016/s1470-2045(17)30180-8

Cited by 381 publications

(284 citation statements)

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“…In a recent phase III study (7), the MEKi binimetinib was superior to chemotherapy with dacarbazine but failed to establish an overall survival benefit. However, the demonstrated antitumor activity of binimetinib provides a solid basis for combination treatment strategies in patients with NRAS-mutant metastatic melanoma.…”

Section: Discussionmentioning

confidence: 99%

“…In a phase II trial, the MEK inhibitor binimetinib showed activity in patients with NRAS-mutant melanoma with an overall response rate of 21% and a median progression-free survival of 3.65 months (6). In a recent phase III study, patients with NRAS-mutant metastatic melanoma without previous therapy or after prior immunotherapy were treated with the MEKi binimetinib or chemotherapy (DTIC) (7). Overall response rates were 15% for binimetinib vs. 7% for DTIC.…”

Section: Introductionmentioning

confidence: 99%

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BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

Niessner¹,

Sinnberg²,

Kosnopfel³

et al. 2017

Clinical Cancer Research

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Purpose NRAS mutations in malignant melanoma are associated with aggressive disease requiring rapid antitumor intervention, but there is no approved targeted therapy for this subset of patients. In clinical trials, the MEK inhibitor (MEKi) binimetinib displayed modest antitumor activity, making combinations a requisite. In a previous study, the BRAF inhibitor (BRAFi) vemurafenib was shown to induce endoplasmic reticulum (ER) stress that together with inhibition of the RAF-MEK-ERK (MAPK) pathway amplified its pro-apoptotic activity in BRAF-mutant melanoma. The present study investigated whether this effect might extent to NRAS-mutant melanoma, in which MAPK activation would be expected. Experimental design and results BRAFi increased pERK, but also significantly increased growth inhibition and apoptosis induced by the MEKi in monolayer, spheroids, organotypic and patient-derived tissue slice cultures of NRAS-mutant melanoma. BRAFi such as encorafenib induced an ER stress response via the PERK pathway, as detected by phosphorylation of eIF2α and upregulation of the ER stress-related factors ATF4, CHOP and NUPR1 and the pro-apoptotic protein PUMA. MEKi such as binimetinib induced the expression of the pro-apoptotic protein BIM and activation of the mitochondrial pathway of apoptosis, the latter of which was enhanced by combination with encorafenib. The increased apoptotic rates caused by the combination treatment were significantly reduced through siRNA knockdown of ATF4 and BIM, confirming its critical roles in this process. Conclusion The data presented herein encourage further advanced in vivo and clinical studies to evaluate MEKi in combination with ER stress inducing BRAFi as a strategy to treat rapidly progressing NRAS-mutant melanoma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

Niessner¹,

Sinnberg²,

Kosnopfel³

et al. 2017

Clinical Cancer Research

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“…Human cancers commonly have dysregulation of the mitogen-activated protein kinase (MAPK), and may be amenable to treatment with targeted agents that block this pathway, such as mitogen-activated protein kinase kinase (MEK) inhibitors 1–4 . Targeted agents have a different toxicity profile compared to traditional chemotherapy 5 .…”

Section: Introductionmentioning

confidence: 99%

Clinical and Morphologic Characteristics of MEK Inhibitor–Associated Retinopathy

et al. 2017

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Purpose To investigate the clinical and morphologic characteristics of serous retinal disturbances in patients taking Mitogen-activated protein kinase kinase (MEK)-inhibitors. Participants 313 fluid foci in 50 eyes of 25 patients receiving MEK-inhibitors for treatment of their metastatic cancer, whom had evidence of serous retinal detachments confirmed by optical coherence tomography(OCT). Design Single center, retrospective, cohort study Methods Clinical exam and OCT were used to evaluate MEK-inhibitor associated subretinal fluid. The morphology, distribution and location of fluid foci were serially evaluated for each eye. Choroidal thickness was measured at each time point (baseline, fluid accumulation and fluid resolution). Two independent observers performed all measurements. Statistical analysis was used to correlate inter-observer findings, compare choroidal thickness and visual acuity at each time point. Main Outcom1e Measures Comparison of OCT characteristcs of retinal abnormalities at baseline to fluid accumulation. Results The majority of patients had fluid foci that were bilateral (92%), multifocal (77%) and at least one focus involving the fovea (83.3%). All fluid foci occurred between the interdigitation zone and an intact retinal pigment epithelium. The 313 fluid foci were classified into four morphologies as follows: 231 (73.8%) dome, 36 (11.5%) caterpillar, 31 (9.9%) wavy and 15 (4.8%) splitting. Best-corrected visual acuity at fluid resolution was not statistically different from baseline; and no eye lost more than two Snellen lines from baseline at the time of fluid accumulation. There was no statistical difference in the choroidal thickness between the different time points (baseline, fluid accumulation and fluid resolution). A strong positive inter-observer correlation was obtained for choroidal thickness measurements (r=0.97, p<0.0001) and grading of foci morphology (r=0.97, p<0.0001). Conclusion The subretinal fluid foci associated with MEK-inhibitors have unique clinical and morphologic characteristics, which can be distinguished from the findings of central serous chorioretinopathy. In this series, MEK-inhibitors did not cause irreversible loss of vision or serious eye damage.

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“…These class-specific side effects have also been described at a similar frequency with other MEK inhibitors [38]. However, certain AEs, in particular an increase of blood CPK, occur at a higher frequency with binimetinib and contribute to the markedly elevated rate of dose reductions and treatment discontinuations reported in the NEMO trial in comparison with Phase III data for trametinib in the METRIC study [26,38].…”

Section: Discussionmentioning

confidence: 71%

A review of binimetinib for the treatment of mutant cutaneous melanoma

2017

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UTUREAlthough significant progress has been made in the treatment of unresectable or metastatic melanoma, at least half of all advanced melanoma patients eventually progress and pass away due to their disease. Especially patients with NRAS-mutated melanoma still face limited therapeutic options, with immunotherapy being the current treatment type of choice. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway. The results of a recent Phase III trial rendered binimetinib the first targeted therapy agent to significantly improve progression-free survival in NRAS-mutated melanoma. This review will summarize the development and clinical data of binimetinib in melanoma in general and also explore the potential future role of this substance as single agent or combination therapy. Recently, the advent of targeted therapies and immunotherapy in metastatic melanoma has significantly changed the therapeutic landscape of this devastating disease with impressive tumor responses seen after kinase inhibitor treatment along with a small proportion of patients even achieving long-term survival of 10 years or more after immunotherapy with CTLA-4 antibodies [1][2][3][4][5][6][7]. Despite the availability and effectiveness of these novel treatments, the majority of patients with advanced melanoma still eventually face fatal progression of their disease, thus maintaining an unmet need for the development of further therapeutic agents.While immunotherapy with anti-CTLA-4 or anti-PD1-antibodies in melanoma utilizes a rather universal approach harnessing the patients' own immune system, in other words, T cells to attack and kill aberrant melanocytic tumor cells, targeted therapies, such as BRAF-or MEK-inhibitors aim to reverse the effects of distinct oncogenic mutations that confer proliferation and survival of melanoma cells. Increasing insight into the mutational landscape of cutaneous melanoma by large-scale genomic studies -published by The Cancer Genome Atlas Network and others -has led to the definition of four distinct mutational profiles based on genetic alterations impacting the MAPK pathway in cutaneous melanoma [8,9]. Being the most frequent, BRAF-mutations (predominantly the V600E hotspot mutation) occur in 40-50% of all melanomas, while NRAS-and NF1 mutations are less common, found in approximately 20 and 15% of melanomas, respectively [8][9][10][11]. Of note, BRAF and NRAS mutations are considered to be mutually exclusive despite the recent demonstration of their co-occurrence in melanoma cells, whereas loss-of-function mutations in the tumor suppressor gene NF1 can infrequently be detected both in BRAF-and NRAS-mutated melanomas, albeit being most common in BRAF Wt /NRAS Wt tumors [9,12]. Last, melanomas belonging to the so-called triple

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Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial

Cited by 381 publications

References 30 publications

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

Clinical and Morphologic Characteristics of MEK Inhibitor–Associated Retinopathy

A review of binimetinib for the treatment of mutant cutaneous melanoma

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