Future of combination therapy with dabrafenib and trametinib in metastatic melanoma.
BACKGROUND
Combination therapy with BRAF and MEK inhibitors is a recommended treatment strategy for metastatic melanoma patients with BRAF(V600) mutations. This treatment provides significant response rates and little added toxicity, with relatively improved survival outcomes compared to RAF/MEK inhibitor monotherapy and chemotherapy.


METHODS
This review covers the pharmacology, efficacy, and toxicity data derived from clinical studies of dabrafenib, trametinib , and the combination thereof. The major downfall of combiDT is the limited durability of response, which is largely due to acquired resistance in the MAPK pathway.


CONCLUSIONS
Future directions of combiDT concentrate on further combinations with immunotherapy or other targeted inhibitors, referred to triple-agent therapy, which may be essential to improving durability of responses and overcoming resistance.
a 1 UCSF Helen Diller Comprehensive Cancer Center , 1600 Divisadero Street, Room B708, San Francisco, CA 94115, USA +1 20 24 89 19 86 ; +1 41 55 14 69 69 ; yaszia@gmail.com.
Yasaman
Y
Zia
b 2 UCSF Helen Diller Comprehensive Cancer Center , 1600 Divisadero Street, Room B708, San Francisco, CA 94115, USA.
Lawrence
L
Chen
c 3 UCSF Helen Diller Comprehensive Cancer Center , 1600 Divisadero Street, Room B708, San Francisco, CA 94115, USA.
Adil
A
Daud
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary; D009154:Mutation; D010091:Oximes / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D011728:Pyridones / Q000008:administration & dosage; D011744:Pyrimidinones / Q000008:administration & dosage; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology
D007093:Imidazoles; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C561627:dabrafenib
BRAF; MAPK; MEK; combination therapy; dabrafenib; melanoma; targeted inhibition; trametinib