Dabrafenib for treatment of BRAF-mutant melanoma

Figures & data

Figure 1 Redundancy of the MAPK signaling cascade and targeted inhibitors. Single arrows signify direct pathways. Double arrows reflect a culmination of multiple steps in the signaling cascade.

Note: Adapted from Cancer Discov, copyright 2013, 3(5), 487–490, Girotti MR, Marais R, Déjà vu: EGF receptors drive resistance to BRAF inhibitors, with permission from AACR.⁵⁹
Abbreviations: HGF, human growth factor; IGF-IR, insulin-like growth factor 1 receptor; PDGFR-β, platelet-derived growth factor-β; Pi3K, phosphoinositide 3-kinase; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase.

Table 1 Comparison of endpoints among dabrafenib clinical trials

	# of patients enrolled*	Response rate (confirmed CR and PR)	Stable disease	Progression-free survival
Dabrafenib: Phase I/II^Citation32
All patients	36	19 (53%)	Not reported	5.5 months
V600E	28	16 (57%)		5.5 months
V600K	8	3 (37%)		5.6 months
Dabrafenib vs dacarbazine: Phase III^Citation33
Dabrafenib	187	93 (50%)	78 (42%)	6.9 months^Citation34
Dacarbazine	63	4 (6%)	30 (48%)	2.7 months
Dabrafenib for brain metastasis: Phase II^Citation35
Initial treatment
V600E	74	29 (39%)	31 (42%)	16.1 weeks
V600K	15	1 (7%)	4 (27%)	8.1 weeks
Previously treated
V600E	65	20 (31%)	38 (58%)	16.6 weeks
V600K	18	4 (22%)	5 (28%)	15.9 weeks
Dabrafenib with trametinib: Phase I/II^Citation43
Dabrafenib monotherapy	54	29 (54%)	22 (41%)	5.8 months
Dabrafenib + trametinib	54	41 (76%)	13 (24%)	9.4 months

Note:

* At the recommended Phase II dose.

Abbreviations: CR, complete response: PR, partial response.

Table 2 Active and recruiting clinical trials involving dabrafenib use in patients with melanoma

NCT#	Trial	Status
01677741	The study to determine safety, tolerability, and pharmacokinetics of oral dabrafenib in pediatric subjects	Recruiting
01584648	A Phase III study comparing trametinib and dabrafenib combination therapy to dabrafenib monotherapy in subjects with BRAF-mutant melanoma	Active, not recruiting
01767454	Phase I study of dabrafenib ± trametinib in combination with ipilimumab for V600E/K mutation positive metastatic or unresectable melanoma	Recruiting
01682083	A study of the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib in the adjuvant treatment of high-risk BRAF mutation-positive melanoma after surgical resection	Recruiting
01682213	Adjuvant dabrafenib in patients with surgically resected AJCC stage IIIC melanoma characterized by a BRAFV600E/K mutation	Recruiting
01726738	Open label Phase II trial of dabrafenib and trametinib in unresectable stage III and stage IV BRAF mutant melanoma; correlation of resistance with the kinome and functional mutations	Recruiting
01721603	A Phase II prospective trial of dabrafenib with stereotactic radiosurgery in BRAFV600E melanoma brain metastases	Recruiting
01597908	Dabrafenib plus trametinib vs vemurafenib alone in unresectable or metastatic BRAF V600E/K cutaneous melanoma	Recruiting
01940809	Ipilimumab with and without dabrafenib, and/or trametinib in treating patients with melanoma that is metastatic or cannot be removed by surgery	Recruiting
01701037	Dabrafenib alone and in combination with trametinib before surgery in treating patients with locally or regionally advanced melanoma that can be removed by surgery	Recruiting

Note: Trial information obtained from http://www.clinicaltrials.gov/.⁵⁸

Abbreviation: NCT#, National Clinical Trial number.

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