unresectable or metastatic melanoma: summary of the scientific assessment of the Committee
for Medicinal Products for Human Use. Eur J Cancer 49(7):1654–1661
115. Flaherty KT et al (2010) Inhibition of mutated, activated BRAF in metastatic melanoma.
N Engl J Med 363(9):809–819
116. Ravnan MC, Matalka MS (2012) Vemurafenib in patients with BRAF V600E mutationpositive advanced melanoma. Clin Ther 34(7):1474–1486
117. Mattei PL et al (2013) Cutaneous effects of BRAF inhibitor therapy: a case series. Ann Oncol
24(2):530–537
118. Anforth R, Fernandez-Penas P, Long GV (2013) Cutaneous toxicities of RAF inhibitors.
Lancet Oncol 14(1):e11–e18
119. Gibney GT, Zager JS (2013) Clinical development of dabrafenib in BRAF mutant melanoma
and other malignancies. Expert Opin Drug Metab Toxicol 9(7):893–899
120. Hauschild A et al (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre,
open-label, phase 3 randomised controlled trial. Lancet 380(9839):358–365
121. Zhang W (2015) BRAF inhibitors: the current and the future. Curr Opin Pharmacol 23:68–73
122. Barras D (2015) BRAF mutation in colorectal cancer: an update. Biomark Cancer 7(Suppl
1):9–12
123. Witkiewicz AK et al (2015) Whole-exome sequencing of pancreatic cancer defines genetic
diversity and therapeutic targets. Nat Commun 6:6744
124. Poulikakos PI et al (2011) RAF inhibitor resistance is mediated by dimerization of aberrantly
spliced BRAF(V600E). Nature 480(7377):387–390
125. Eisen T et al (2006) Sorafenib in advanced melanoma: a phase II randomised discontinuation
trial analysis. Br J Cancer 95(5):581–586
126. Wilhelm SM et al (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and
targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64(19):7099–7109
127. Rimassa L et al (2013) A phase II randomized dose escalation trial of sorafenib in patients with
advanced hepatocellular carcinoma. Oncologist 18(4):379–380
128. Escudier B et al (2009) Sorafenib for treatment of renal cell carcinoma: final efficacy and
safety results of the phase III treatment approaches in renal cancer global evaluation trial. J
Clin Oncol 27(20):3312–3318
129. Rimassa L, Santoro A (2009) Sorafenib therapy in advanced hepatocellular carcinoma: the
SHARP trial. Expert Rev Anticancer Ther 9(6):739–745
130. Wilhelm S et al (2006) Discovery and development of sorafenib: a multikinase inhibitor for
treating cancer. Nat Rev Drug Discov 5(10):835–844
131. Brose MS et al (2011) Rationale and design of decision: a double-blind, randomized, placebocontrolled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally
advanced or metastatic radioactive iodine (RAI)-refractory, differentiated thyroid cancer.
BMC Cancer 11:349
132. Brose MS et al (2014) Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 384
(9940):319–328
133. Rudalska R et al (2014) In vivo RNAi screening identifies a mechanism of sorafenib resistance
in liver cancer. Nat Med 20(10):1138–1146
134. Janne PA et al (2017) Selumetinib plus docetaxel compared with docetaxel alone and
progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer:
the SELECT-1 randomized clinical trial. JAMA 317(18):1844–1853
135. Kim C, Giaccone G (2018) MEK inhibitors under development for treatment of non-small-cell
lung cancer. Expert Opin Investig Drugs 27(1):17–30
136. Moriceau G et al (2015) Tunable-combinatorial mechanisms of acquired resistance limit the
efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction. Cancer Cell 27
(2):240–256
150
A. Moschopoulou et al.
for Medicinal Products for Human Use. Eur J Cancer 49(7):1654–1661
115. Flaherty KT et al (2010) Inhibition of mutated, activated BRAF in metastatic melanoma.
N Engl J Med 363(9):809–819
116. Ravnan MC, Matalka MS (2012) Vemurafenib in patients with BRAF V600E mutationpositive advanced melanoma. Clin Ther 34(7):1474–1486
117. Mattei PL et al (2013) Cutaneous effects of BRAF inhibitor therapy: a case series. Ann Oncol
24(2):530–537
118. Anforth R, Fernandez-Penas P, Long GV (2013) Cutaneous toxicities of RAF inhibitors.
Lancet Oncol 14(1):e11–e18
119. Gibney GT, Zager JS (2013) Clinical development of dabrafenib in BRAF mutant melanoma
and other malignancies. Expert Opin Drug Metab Toxicol 9(7):893–899
120. Hauschild A et al (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre,
open-label, phase 3 randomised controlled trial. Lancet 380(9839):358–365
121. Zhang W (2015) BRAF inhibitors: the current and the future. Curr Opin Pharmacol 23:68–73
122. Barras D (2015) BRAF mutation in colorectal cancer: an update. Biomark Cancer 7(Suppl
1):9–12
123. Witkiewicz AK et al (2015) Whole-exome sequencing of pancreatic cancer defines genetic
diversity and therapeutic targets. Nat Commun 6:6744
124. Poulikakos PI et al (2011) RAF inhibitor resistance is mediated by dimerization of aberrantly
spliced BRAF(V600E). Nature 480(7377):387–390
125. Eisen T et al (2006) Sorafenib in advanced melanoma: a phase II randomised discontinuation
trial analysis. Br J Cancer 95(5):581–586
126. Wilhelm SM et al (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and
targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64(19):7099–7109
127. Rimassa L et al (2013) A phase II randomized dose escalation trial of sorafenib in patients with
advanced hepatocellular carcinoma. Oncologist 18(4):379–380
128. Escudier B et al (2009) Sorafenib for treatment of renal cell carcinoma: final efficacy and
safety results of the phase III treatment approaches in renal cancer global evaluation trial. J
Clin Oncol 27(20):3312–3318
129. Rimassa L, Santoro A (2009) Sorafenib therapy in advanced hepatocellular carcinoma: the
SHARP trial. Expert Rev Anticancer Ther 9(6):739–745
130. Wilhelm S et al (2006) Discovery and development of sorafenib: a multikinase inhibitor for
treating cancer. Nat Rev Drug Discov 5(10):835–844
131. Brose MS et al (2011) Rationale and design of decision: a double-blind, randomized, placebocontrolled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally
advanced or metastatic radioactive iodine (RAI)-refractory, differentiated thyroid cancer.
BMC Cancer 11:349
132. Brose MS et al (2014) Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 384
(9940):319–328
133. Rudalska R et al (2014) In vivo RNAi screening identifies a mechanism of sorafenib resistance
in liver cancer. Nat Med 20(10):1138–1146
134. Janne PA et al (2017) Selumetinib plus docetaxel compared with docetaxel alone and
progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer:
the SELECT-1 randomized clinical trial. JAMA 317(18):1844–1853
135. Kim C, Giaccone G (2018) MEK inhibitors under development for treatment of non-small-cell
lung cancer. Expert Opin Investig Drugs 27(1):17–30
136. Moriceau G et al (2015) Tunable-combinatorial mechanisms of acquired resistance limit the
efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction. Cancer Cell 27
(2):240–256
150
A. Moschopoulou et al.