Vemurafenib in patients with BRAFV600 mutated metastatic melanoma: an open-label, multicentre, safety study

Larkin, James; Vecchio, Michele Del; Ascierto, Paolo A.; Krajsová, Ivana; Schachter, Jacob; Neyns, Bart; Espinosa, Enrique; Garbe, Claus; Chiarion-Sileni, Vanna; Gogas, Helen; Miller, Wilson H.; Mandalà, Mario; Hospers, Geke A.P.; Arance, Ana; Queirolo, Paola; Hauschild, Axel; Brown, Michael P.; Mitchell, Lada; Véronèse, L.; Blank, Christian U.

doi:10.1016/s1470-2045(14)70051-8

Cited by 255 publications

(272 citation statements)

References 14 publications

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“…Data from patients with metastatic melanoma treated with vemurafenib show QTc prolongations in 3.2% on average and QTc >500 ms in 2.3%, with only 0.06% incidence of arrhythmias 119, 120…”

Section: Resultsmentioning

confidence: 99%

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Porta‐Sánchez

Gilbert

Spears

et al. 2017

JAHA

154

142

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BackgroundThe cardiovascular complications of cancer therapeutics are the focus of the burgeoning field of cardio‐oncology. A common challenge in this field is the impact of cancer drugs on cardiac repolarization (ie, QT prolongation) and the potential risk for the life‐threatening arrhythmia torsades de pointes. Although QT prolongation is not a perfect marker of arrhythmia risk, this has become a primary safety metric among oncologists. Cardiologists caring for patients receiving cancer treatment should become familiar with the drugs associated with QT prolongation, its incidence, and appropriate management strategies to provide meaningful consultation in this complex clinical scenario.Methods and ResultsIn this article, we performed a systematic review (using Preferred Reporting Items of Systematic Reviews and Meta‐Analyses (PRISMA) guidelines) of commonly used cancer drugs to determine the incidence of QT prolongation and clinically relevant arrhythmias. We calculated summary estimates of the incidence of all and clinically relevant QT prolongation as well as arrhythmias and sudden cardiac death. We then describe strategies to prevent, identify, and manage QT prolongation in patients receiving cancer therapy. We identified a total of 173 relevant publications. The weighted incidence of any corrected QT (QTc) prolongation in our systematic review in patients treated with conventional therapies (eg, anthracyclines) ranged from 0% to 22%, although QTc >500 ms, arrhythmias, or sudden cardiac death was extremely rare. The risk of QTc prolongation with targeted therapies (eg, small molecular tyrosine kinase inhibitors) ranged between 0% and 22.7% with severe prolongation (QTc >500 ms) reported in 0% to 5.2% of the patients. Arrhythmias and sudden cardiac death were rare.ConclusionsOur systematic review demonstrates that there is variability in the incidence of QTc prolongation of various cancer drugs; however, the clinical consequence, as defined by arrhythmias or sudden cardiac death, remains rare.

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“…Data from patients with metastatic melanoma treated with vemurafenib show QTc prolongations in 3.2% on average and QTc >500 ms in 2.3%, with only 0.06% incidence of arrhythmias 119, 120…”

Section: Resultsmentioning

confidence: 99%

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Porta‐Sánchez

Gilbert

Spears

et al. 2017

JAHA

154

142

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“…22 Two studies with only univariate analyses, the larger including more than 3000 patients treated with vemurafenib, reported that ECOG, AJCC stage, LDH, and brain metastases were associated with PFS and OS, but followup was limited (median, 11.5 months; maximum, 21 months), and the influence of subsequent active treatments on OS was not taken into account. 16 A pooled analysis of patients from the phase 2 and 3 vemurafenib clinical trials suggested that the only factor influencing the duration of response (12 vs <12 months) and PFS with vemurafenib was LDH, but only a univariate analysis was performed. 23 The serum LDH level is a major factor influencing metastatic survival without treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Consecutive immunotherapy-and MAPK inhibitor-naive patients with V600 BRAF-mutant metastatic melanoma (American Joint Committee on Cancer [AJCC] stage IIIC unresectable melanoma or stage IV melanoma) who were treated with a BRAF inhibitor either as monotherapy or in combination with an MEK inhibitor at 2 centers (Melanoma Institute Australia and Westmead Hospital) during clinical trials between July 2009 and July 2013 were included for analysis. The clinical trials included phase 1 to 3 and phase 2 brain metastasis trials of dabrafenib, 2,11-13 phase 2/3 and phase 2 brain metastasis trials and an expanded access program for vemurafenib, 1,[14][15][16] and phase 1 to 3 trials of combined dabrafenib and trametinib (CombiDT). 3,4,17 Demographics, primary melanoma features, disease characteristics at the time of study commencement, responses to therapy, subsequent systemic therapy responses, and survival data were collected prospectively.…”

Section: Patients and Treatmentmentioning

confidence: 99%

Clinicopathologic features associated with efficacy and long‐term survival in metastatic melanoma patients treated with BRAF or combined BRAF and MEK inhibitors

Menzies

Wilmott

Drummond

et al. 2015

Cancer

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BACKGROUND:The degree of response and the duration of survival of patients treated with mitogen-activated protein kinase (MAPK) inhibitors are highly variable. Whether baseline clinicopathologic factors can predict the clinical course with treatment is largely unknown. METHODS: For 142 consecutive immunotherapy-and MAPK inhibitor-naive patients with BRAF-mutant metastatic melanoma who were treated during clinical trials with BRAF inhibitors (n 5 111) or a combination of dabrafenib and trametinib (n 5 31), clinicopathologic factors were correlated with the response to MAPK inhibitors and survival. RESULTS: The median follow-up was 15.7 months (range, 0.6-60.5 months). The 2-, 3-, and 4-year overall survival (OS) rates were 43%, 24%, and 24%, respectively. A multivariate analysis demonstrated that the only clinicopathologic factors associated with longer progression-free survival (PFS) and OS were female sex and a normal pretreatment serum lactate dehydrogenase (LDH) level. The BRAF V600E genotype and an absence of primary melanoma ulceration were also independently associated with longer PFS but not OS. The median OS was 23.5 months for patients with normal LDH levels and 7.3 months for those with elevated LDH levels (hazard ratio, 0.31; P < .001). Complete responders had the best survival, but disease progression still occurred in 2 of 7 patients. CONCLUSIONS: Long-term survival occurs for a minority of patients receiving MAPK inhibitor treatment alone. Sex, serum LDH, BRAF genotype, and primary melanoma ulceration status are independent factors associated with treatment outcomes. Patients with a complete response to treatment have the best survival, but relapses still occur. Cancer 2015;121:3826-35.

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“…Dacarbazin kezeléssel történő ösz-szehasonlító Fázis III klinikai vizsgálatban a válaszadási ráta 50% volt a dabrafenibbel kezelt betegeknél, míg 6% volt a kemoterápiával kezelt csoportban, a PFSm 5,1 hónap volt BRAF inhibitor kezelés mellett, 2,7 hónap dacarbazin kezelés mellett (18). BRAF-gátló terápia mellett a betegek legalább 2/3 ré-szénél (67-90%) jelentkezik valamilyen mellékhatás, mely többnyire tolerálható, azonban az esetek egyharmadában dó-zismódosításra van szükség (19,20). Leggyakrabban bőr-gyógyászati mellékhatásokkal kell számolnunk, melyek az összes mellékhatás több mint 90%-át teszik ki.…”

Section: Braf Inhibitor Kezelés (Hatékonyság Mellékhatás)unclassified

Targeted therapy for BRAF-mutation positive metastatic melanoma

Szabó¹,

Ócsai²,

Kiss³

et al. 2017

BVSZ

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ÖSSZEFOGLALÁS A BRAFV600E/K génmutáció a melanoma kialakulásá-ban és progressziójában is fontos pathogenetikai tényező. Az esetek felében kimutatható a tumor metasztázisban és hatásának ellensúlyozására kifejlesztett célzott molekulá- Kulcsszavak: áttétes melanoma -BRAF inhibitor -MEK inhibitor -gyógyszer mellékhatás SUMMARY An important pathogenic factor in both the development and progression of melanoma is the V600E/K mutation of BRAF, which can be found in half of metastatic tumors. It is unsurprising therefore that molecular inhibitors targeting its effect are able to offer significantly higher progression free and overall survival as compared to conventional chemotherapy in the majority of patients diagnosed with metastatic melanoma. Moreover, the combination of BRAF-and MEK inhibitor therapy has greatly improved the prognosis of patients with confirmed mutations in distant metastases, showing that optimal use of new therapeutic agents by broadening clinical expertise is an effective way of expanding the inventory of anti-melanoma agents. The management of potential adverse events related to new treatments is also improved by their widespread use and the consequent enhancement of practical knowledge related to the new agents, ultimately leading to the improvement of quality of life of patients. Key words: metastatic melanoma -BRAF inhibitor -MEK inhibitor -drug adverse eventA melanoma pathofiziológiájáról szerzett, az elmúlt év-tizedben robbanásszerűen felhalmozódott ismereteink és a modern biotechnológia lehetővé tették új típusú onkoterá-piák megjelenését, mint amilyenek a célzott molekuláris inhibitorok vagy a biológiai terápiák, és ezzel megváltoztatták a metasztatikus betegek túlélési esélyeit és átírták a korábbi kezelési irányvonalakat (1-3). A melanoma kialakulásában és progressziójában kulcsszerepet játszó génmutációk komplex módon, az intracelluláris jelátviteli folyamatok kö-zötti egyensúly megbomlását okozva vezetnek megnöve-kedett sejttúléléséhez, kórosan fokozott sejtproliferációhoz. Az egyik legfontosabb pathogenetikai lépés a MAPK (Mitogén Aktivált Protein-Kináz)-útvonal aktivitásának fokozódása (4), ami igen gyakran, a melanomás eseteknek a 160 Levelező szerző: Dr. Szabó Imre Lőrinc

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Vemurafenib in patients with BRAFV600 mutated metastatic melanoma: an open-label, multicentre, safety study

Cited by 255 publications

References 14 publications

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Clinicopathologic features associated with efficacy and long‐term survival in metastatic melanoma patients treated with BRAF or combined BRAF and MEK inhibitors

Targeted therapy for BRAF-mutation positive metastatic melanoma

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