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      Cardiovascular adverse events associated with BRAF versus BRAF/MEK inhibitor: Cross‐sectional and longitudinal analysis using two large national registries


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          Cardiovascular adverse events (CVAEs) associated with BRAF inhibitors alone versus combination BRAF/MEK inhibitors are not fully understood.


          This study included all adult patients who received BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) or combinations BRAF/MEK inhibitors (vemurafenib/cobimetinib; dabrafenib/trametinib; encorafenib/binimetinib). We utilized the cross‐sectional FDA’s Adverse Events Reporting System (FAERS) and longitudinal Truven Health Analytics/IBM MarketScan database from 2011 to 2018. Various CVAEs, including arterial hypertension, heart failure (HF), and venous thromboembolism (VTE), were studied using adjusted regression techniques.


          In FAERS, 7752 AEs were reported (40% BRAF and 60% BRAF/MEK). Median age was 60 (IQR 49–69) years with 45% females and 97% with melanoma. Among these, 567 (7.4%) were cardiovascular adverse events (mortality rate 19%). Compared with monotherapy, combination therapy was associated with increased risk for HF (reporting odds ratio [ROR] = 1.62 (CI = 1.14–2.30); p = 0.007), arterial hypertension (ROR = 1.75 (CI = 1.12–2.89); p = 0.02) and VTE (ROR = 1.80 (CI = 1.12–2.89); p = 0.02). Marketscan had 657 patients with median age of 53 years (IQR 46–60), 39.3% female, and 88.7% with melanoma. There were 26.2% CVAEs (CI: 14.8%–36%) within 6 months of medication start in those receiving combination therapy versus 16.7% CVAEs (CI: 13.1%–20.2%) among those receiving monotherapy. Combination therapy was associated with CVAEs compared to monotherapy (adjusted HR: 1.56 (CI: 1.01–2.42); p = 0.045).

          Conclusions and Relevance

          In two independent real‐world cohorts, combination BRAF/MEK inhibitors were associated with increased CVAEs compared to monotherapy, especially HF, and hypertension.


          In two independent real‐world cohorts, combination BRAF/MEK inhibitors were associated with increased cardiovascular adverse events compared to monotherapy, especially HF, and hypertension.

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          Most cited references30

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          Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.

          The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).
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            Improved survival with vemurafenib in melanoma with BRAF V600E mutation.

            Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation. We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths. At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.).
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              Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma

              Patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients remain undefined. To determine 5-year survival rates and clinical characteristics of the patients with durable benefit, we sought to review long-term data from randomized trials of combination therapy with BRAF and MEK inhibitors.

                Author and article information

                Cancer Med
                Cancer Med
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                13 May 2021
                June 2021
                : 10
                : 12 ( doiID: 10.1002/cam4.v10.12 )
                : 3862-3872
                [ 1 ] Harrington Heart and Vascular Institute University Hospitals Case Western Reserve University Cleveland OH USA
                [ 2 ] Division of Hematology and Medical Oncology University Hospitals Cleveland Medical Center Seidman Cancer Center at Case Comprehensive Cancer Center Case Western Reserve University Cleveland OH USA
                [ 3 ] Cardio‐Oncology Program Division of Cardiology University of Pennsylvania Philadelphia PA USA
                [ 4 ] Cardio‐Oncology Center of Excellence Division of Cardiology Washington University in St Louis St. Louis MO USA
                [ 5 ] Layer6 Inc. Toronto Canada
                [ 6 ] Lerner Research Institute Cleveland Clinic Case Comprehensive Cancer Center Cleveland OH USA
                [ 7 ] Department of Population and Quantitative Health Sciences Case Comprehensive Cancer Center Case Western Reserve University School of Medicine Cleveland OH USA
                [ 8 ] Division of Cardiovascular Sciences Cardio‐Oncology Program University of South Florida Tampa General Hospital and Moffitt Cancer Center Tampa FL USA
                Author notes
                [*] [* ] Correspondence

                Avirup Guha, Harrington Heart and Vascular Institute, 1025 Center St, Ashland, OH 44805, USA.

                Email: avirup.guha@ 123456gmail.com

                Prantesh Jain, Division of Hematology and Medical Oncology, University Hospitals, Seidman Cancer Center, Case Comprehensive Cancer Center at Case Western Reserve University, Cleveland, OH, USA.

                Email: prantesh.jain2@ 123456uhhospitals.org

                © 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 5, Tables: 3, Pages: 11, Words: 6261
                Funded by: UHR&E
                Original Research
                Clinical Cancer Research
                Original Research
                Custom metadata
                June 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:17.06.2021

                Oncology & Radiotherapy
                braf inhibitors,braf/mek inhibitors,cardiotoxicity,cardiovascular adverse events,faers,marketscan,pharmacoepidemiology


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