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

ABSTRACT

Introduction: The introduction of BRAF and MEK inhibitors into clinical practice improved the prognosis of metastatic melanoma patients. The combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown its superiority to single agent therapy and is characterized by a tolerable spectrum of adverse events which shows a decrease in incidence over time on treatment.

Areas covered: The current scientific literature on safety and adverse events (AEs) related to BRAF and MEK-inhibition has been investigated with special focus on the large phase 3 studies (COMBI-v, COMBI-d and CoBRIM) as well as recent updates presented at oncology and melanoma meetings. Additionally, published case series/case reports were screened for information on AEs.

Expert opinion: Even though almost every patient (98%) under combination therapy with dabrafenib and trametinib experiences at least one adverse event, these are generally mild to moderate, reversible and can be managed with dose reductions or interruptions. However, due to an increased life expectancy, there is a substantial need to prevent and treat also mild adverse events, as they play a central role for the quality of life of patients. Ongoing clinical trials will have to demonstrate the efficacy as well as safety of triple combination with anti-PD-1/anti-PD-L1 antibodies.

KEYWORDS:

• Adverse events
• BRAF
• dabrafenib
• MEK
• melanoma
• trametinib

Declaration of interest

S Kinspel has received travel support from Bristol Myers Squibb. L Zimmer has served as a consultant and/or received honoraria from Roche, Bristol Myers Squibb, Merck Sharpe & Dohme, GlaxoSmithKline, Novartis, Merck, and travel support from Merck Sharpe & Dohme, Bristol Myers Squibb and Novartis. T Kanaki has received travel support from Amgen, Astra Zeneca and Celgene. S Ugurel has served on advisory boards for Bristol Myers Squibb, Merck Sharpe & Dohme and Roche. Has also received speaker’s honoraria from Bristol Myers Squibb, Merck Sharpe & Dohme, Roche and has received travel support from Bristol Myers Squibb, Merck Sharpe & Dohme, Medac and Roche. E Livingstone has received consultancies and honoraria from Bristol Myers Squibb, GmBH & Co KG, Boehringer Ingelheim, has been a speaker for Amgen, GmBH &Co KG, Boehringer Ingelheim, Grenzach-Wyhlen, Bristol Myers Squibb, GmBH & Co KG, Novartis, Merck Sharpe & Dohme, Merck, has received travel grants from Amgen GmBH, Boehringer Ingleheim, GmBH & Co KG, Merck Sharpe & Dohme and Novartis. D Schadendorf has received personal fees and patients fees from Novartis and GSK and personal fees from Amgen, Boehringer Ingelheim, Roche, Merck, MSD, BMS and LEO PharmaThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Conflict of interest

S.K.: received travel support from Bristol-Myers Squibb.

L.Z.: has served as consultant or/and has received honoraria from Roche, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), GlaxoSmithKline (GSK), Novartis, Merck, and travel support from MSD, BMS, Amgen and Novartis.

T.K.: received travel Support from Amgen, AstraZeneca and Celgene

S.U.: Advisory board: BMS, MSD, Roche. Speaker’s honoraria: BMS, MSD, Roche. Travel support: BMS, MSD, medac, Roche.

D.S.: has received personal fees and patients’ fees from Novartis and GSK, and personal fees from Amgen, Boehringer Ingelheim, Roche, Merck, MSD, BMS and LEO Pharma.

E.L.: Consultancies and Honoraria: Bristol Myers Squibb GmbH & Co KG, Munich; Boehringer-Ingelheim Pharma GmbH & Co KG, Ingelheim; Speakers bureau: Amgen GmbH, Munich; Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim; Roche GmbH, Grenzach-Wyhlen; Bristol-Myers Squibb GmbH & Co KG, Munich; Novartis Pharma GmbH, Nuremberg; MSD SHARP & DOHME GmbH, Haar; Merck KGaA, Darmstadt; Travel Grants: Amgen GmbH, Munich; Boehringer-Ingelheim Pharma GmbH & Co KG, Ingelheim; MSD SHARP & DOHME GmbH, Haar; Novartis Pharma GmbH, Nuremberg.

Additional information

Funding

This paper is not funded.