Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF -mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial

Dummer, Reinhard; Ascierto, Paolo A.; Gogas, Helen; Arance, Ana; Mandalà, Mario; Liszkay, Gabriella; Garbe, Claus; Schadendorf, Dirk; Krajsová, Ivana; Gutzmer, Ralf; Chiarion-Sileni, Vanna; Dutriaux, Caroline; Groot, Jan Willem B. de; Yamazaki, Naoya; Loquai, Carmen; Parseval, Laure A Moutouh-de; Pickard, Michael D.; Sandor, Victor; Robert, Caroline; Flaherty, Keith T.

doi:10.1016/s1470-2045(18)30142-6

Cited by 813 publications

(780 citation statements)

References 27 publications

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“…Seven randomized controlled trials were selected in total . Our initial literature search found a total of 549 relevant citations.…”

Section: Resultsmentioning

confidence: 99%

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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“…Seven randomized controlled trials were selected in total . Our initial literature search found a total of 549 relevant citations.…”

Section: Resultsmentioning

confidence: 99%

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 recently conducted phase III study for applying ENC plus the accordingly applied MEK1/2 inhibitor Binimetinib versus VEM or ENC administered alone showed improved progression-free survival and improved overall response of Encorafenib/Binimetinib treated patients. Treatment with ENC exerted less adverse events such as rash compared to VEM, although the frequency of grade 3 rash was slightly increased [274]. …”

Section: Anti-cancer Agents Induce Il-1βmentioning

confidence: 99%

Interleukin-1 Beta—A Friend or Foe in Malignancies?

Bent

Moll

Grabbe

et al. 2018

IJMS

300

221

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Interleukin-1 beta (IL-1β) is induced by inflammatory signals in a broad number of immune cell types. IL-1β (and IL-18) are the only cytokines which are processed by caspase-1 after inflammasome-mediated activation. This review aims to summarize current knowledge about parameters of regulation of IL-1β expression and its multi-facetted role in pathophysiological conditions. IL-1 signaling activates innate immune cells including antigen presenting cells, and drives polarization of CD4+ T cells towards T helper type (Th) 1 and Th17 cells. Therefore, IL-1β has been attributed a largely beneficial role in resolving acute inflammations, and by initiating adaptive anti-tumor responses. However, IL-1β generated in the course of chronic inflammation supports tumor development. Furthermore, IL-1β generated within the tumor microenvironment predominantly by tumor-infiltrating macrophages promotes tumor growth and metastasis via different mechanisms. These include the expression of IL-1 targets which promote neoangiogenesis and of soluble mediators in cancer-associated fibroblasts that evoke antiapoptotic signaling in tumor cells. Moreover, IL-1 promotes the propagation of myeloid-derived suppressor cells. Using genetic mouse models as well as agents for pharmacological inhibition of IL-1 signaling therapeutically applied for treatment of IL-1 associated autoimmune diseases indicate that IL-1β is a driver of tumor induction and development.

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“…1 An ongoing trial of vemurafenib, cobimetinib, and atezolizumab modified the original dosing schedule due to pyrexia and rash to allow a 4-week run-in of targeted therapy before therapy with programmed death-ligand 1 (PD-L1) was initiated. [1][2][3] More recently, case reports 14-17 and a small series 18 have described severe reactions to BRAF-MEK inhibition after PD-1 blockade, including systemic inflammatory response syndrome, hemophagocytic lymphohistiocytosis, and cutaneous toxicities. [1][2][3] More recently, case reports 14-17 and a small series 18 have described severe reactions to BRAF-MEK inhibition after PD-1 blockade, including systemic inflammatory response syndrome, hemophagocytic lymphohistiocytosis, and cutaneous toxicities.…”

Section: Introductionmentioning

confidence: 99%

Tolerance and efficacy of BRAF plus MEK inhibition in patients with melanoma who previously have received programmed cell death protein 1‐based therapy

Saab

Mooradian

Wang

et al. 2018

Cancer

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BACKGROUND: Combined BRAF and MEK inhibition (BRAF-MEK) is a standard therapy for patients with BRAF V600-mutant melanoma, but to the authors' knowledge, the tolerance, adverse event (AE) profile, and efficacy have not been well defined in the postprogrammed cell death protein 1 (PD-1) setting. METHODS: Patients with BRAF V600-mutant melanoma who received combined BRAF-MEK after prior PD-1-based therapy were assembled from 4 tertiary care centers in the United States and Australia. Dose modification was defined as a treatment break, dose reduction, or intermittent dosing. Rates of hospitalization and discontinuation due to AEs were collected, and overall survival (OS) was calculated using Kaplan-Meier methods from the time of the initiation of BRAF-MEK therapy. RESULTS: A total of 78 patients were identified as having received a BRAF-MEK regimen at a median of 34 days after the last dose of PD-1-based therapy. The majority of patients (86%) received the combination of dabrafenib and trametinib. Approximately 80% of patients had American Joint Committee on Cancer M1c or M1d disease. Sixty-five regimens (83%) had ≥1 dose modification. The median time to the first dose modification was 14 days; 86% occurred within 90 days and 71% involved pyrexia. Dose modifications were more common in patients receiving BRAF-MEK <90 days after the last dose of PD-1 and who were not receiving steroids. Of the dose modifications, 25 (31%) led to an AE-related hospitalization. Among 55 BRAF-naive patients, the median time receiving BRAF-MEK therapy was 5.8 months and the median OS was 15.6 months. CONCLUSIONS: The majority of patients receiving BRAF-MEK inhibition after PD-1 therapy require dose interruptions, and a significant minority require hospitalization for AEs. In this higher risk population, the median time receiving therapy and OS may be inferior to those presented in published phase 3 trials. Cancer 2019;125:884-891.

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Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF -mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial

Abstract: Array BioPharma, Novartis.

Cited by 813 publications

References 27 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

Interleukin-1 Beta—A Friend or Foe in Malignancies?

Tolerance and efficacy of BRAF plus MEK inhibition in patients with melanoma who previously have received programmed cell death protein 1‐based therapy

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