Dabrafenib Mesylate (GSK-2118436)

GSK2118436 is a selective BRAF V600E inhibitor. BRAF encodes a proto-oncogene B-Raf also known as serine/threonine protein kinase B-Raf. It is critical in regulating the MAPK/ERK signaling pathway. BRAF mutations frequently occur in many human cancers. [1, 2] BRAF V600E mutant is constitutively active, allowing MAPK/ERK activation independent of upstream cues. [3]

GSK2118436 binds to Raf family kinases and inhibits their activity. It is highly selective against B-Raf V600E with IC50 of 0.8 nM, compared to wild type B-Raf and c-Raf with IC50s of 3.2 nM and 5.0 nM, respectively. [4]

GSK2118436 treatment shows selective inhibition of MAPK/ERK activation, proliferation, transformation and tumorigenicity. FDA approved GSK2118436 as a single agent treatment for advanced melanoma with BRAF V600E mutation on May 30, 2013.

GSK2118436 can be taken orally.

References:
[1]Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S, Rogounovitch TI, Ohtsuru A, Saenko VA, Kanematsu T, Yamashita S. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J. Clin. Endocrinol. Metab. 2003; 88 (9): 4393–7.
[2]Tan YH, Liu Y, Eu KW, Ang PW, Li WQ, Salto-Tellez M, Iacopetta B, Soong R. Detection of BRAF V600E mutation by pyrosequencing. Pathology 2008; 40 (3): 295–8.
[3]Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002; 417: 949-954.
[4]Ma XH, Piao SF, Dey S, McAfee Q, Karakousis G, Villanueva J, Hart LS, Levi S, Hu J, Zhang G, Lazova R, Klump V, Pawelek JM, Xu X, Xu W, Schuchter LM, Davies MA, Herlyn M, Winkler J, Koumenis C, Amaravadi RK. Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Invest. 2014; 124(3): 1406-17.

Cutaneous Toxic Effects of BRAF Inhibitors Alone and in Combination With MEK Inhibitors for Metastatic Melanoma.[Pubmed:26200476]

JAMA Dermatol. 2015 Oct;151(10):1103-9.

IMPORTANCE: The cutaneous adverse effects of the BRAF inhibitors vemurafenib and dabrafenib mesylate in the treatment of metastatic melanoma have been well reported. The addition of a MEK inhibitor to a BRAF inhibitor improves the blockade of the mitogen-activated protein kinase pathway. The combination of dabrafenib with the MEK inhibitor trametinib dimethyl sulfoxide (CombiDT therapy) increases response rate and survival compared with a BRAF inhibitor alone. Clinical trials have suggested that CombiDT therapy induces fewer cutaneous toxic effects than a single-agent BRAF inhibitor. To our knowledge, a direct comparison has not been performed before. OBJECTIVE: To compare the cutaneous toxic effects of BRAF inhibitor monotherapy and CombiDT therapy in a large cohort of patients. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective cohort study from September 1, 2009, through November 30, 2013. The study population included 185 Australian patients with unresectable stages IIIC and IV melanoma referred from Crown Princess Mary Cancer Care Centre who underwent review at the Department of Dermatology, Westmead Hospital. Of these, 119 patients received dabrafenib; 36, vemurafenib; and 30, CombiDT therapy. Data analysis were performed in December 2013. MAIN OUTCOMES AND MEASURES: Multiple cutaneous adverse effects between BRAF inhibitor monotherapy and CombiDT therapy were identified and compared in a cohort of patients who underwent the same dermatologic assessment. RESULTS: The most common cutaneous adverse effects seen in patients receiving the single-agent BRAF inhibitor dabrafenib or vemurafenib included Grover disease (51 patients [42.9%] and 14 [38.9%], respectively [P = .67]), plantar hyperkeratosis (47 [39.5%] and 14 [38.9%], respectively [P = .95]), verrucal keratosis (79 [66.4%] and 26 [72.2%], respectively [P = .51]), and cutaneous squamous cell carcinoma (31 [26.1%] and 13 [36.1%], respectively [P = .54]). Photosensitivity was more common with vemurafenib (14 patients [38.9%]) compared with dabrafenib (1 [0.8%]; P < .001). Compared with dabrafenib, CombiDT therapy showed a higher frequency of folliculitis (12 patients [40.0%] vs. 8 [6.7%]; P < .001) and a significant decrease of cutaneous squamous cell carcinoma (0 vs. 31 [26.1%]; P < .001), verrucal keratosis (0 vs. 79 [66.4%]; P < .001), and Grover disease (0 vs. 51 [42.9%]; P < .001). CONCLUSIONS AND RELEVANCE: This study confirms that the prevalence of cutaneous toxic effects differs among vemurafenib, dabrafenib, and CombiDT therapies. Cutaneous squamous cell carcinoma is the most concerning cutaneous toxic effect related to BRAF inhibitor monotherapy that did not appear with CombiDT therapy. Although CombiDT therapy has an improved profile of cutaneous toxic effects, continuous dermatologic assessments should be provided for all patients when receiving these treatments.

Pharmaceutical approval update.[Pubmed:24391391]

P T. 2013 Nov;38(11):705-7.

Vortioxetine (Brintellix) for major depressive disorder; ustekinumab (stelara) for psoriatic arthritis; and dabrafenib mesylate (Tafinlar) for metastatic melanoma.

The GIST of targeted therapy for malignant melanoma.[Pubmed:24531699]

Ann Surg Oncol. 2014 Jun;21(6):2059-67.

The high response rates to the tyrosine kinase inhibitor imatinib in KIT-mutated gastrointestinal stromal tumors (GIST) has led to a paradigm shift in cancer treatment. In a parallel fashion, the field of melanoma is shifting with the utilization of targeted therapy to treat BRAF-mutated melanoma. We reviewed published literature in PubMed on GIST and melanoma, with a focus on both past and current clinical trials. The data presented centers on imatinib, vemurafenib, and most recently dabrafenib, targeting KIT and BRAF mutations and their outcomes in GIST and melanoma. The BRAF(V600E) melanoma mutation, like the KIT exon 11 mutation in GIST, has the highest response to therapy. High response rates with inhibition of KIT in GIST have not been recapitulated in KIT-mutated melanoma. Median time to resistance to targeted agents occurs in ~7 months with BRAF inhibitors and 2 years for imatinib in GIST. In GIST, the development of secondary mutations leads to resistance; however, there have been no similar gatekeeper mutations found in melanoma. Although surgery remains an important component of the treatment of early GIST and melanoma, surgeons will need to continue to define the thresholds and timing for operation in the setting of metastatic disease with improved targeted therapies. Combination treatment strategies may result in more successful clinical outcomes in the management of melanoma in the future.

Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma.[Pubmed:25502142]

Nat Commun. 2014 Dec 15;5:5712.

Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas.

[Melanoma: from molecular studies to the treatment breakthrough].[Pubmed:24341237]

Arkh Patol. 2013 Sep-Oct;75(5):63-72.

Melanoma holds a leading position in the mortality from skin tumors. Standard treatment of metastatic melanoma allows tumor remission to be achieved only in a small subset of patients. Studies on melanoma molecular pathogenesis led to the identification of several causative genetic events and, consequently, to the development of novel targeted drugs. More than a half of melanomas contain amine acid substitutions in serine-threonine kinase BRAF. Clinical trials involving specific BRAF inhibitors--vemurafenib and dabrafenib--demonstrated high efficacy of these agents towards BRAF-mutated melanoma. MEK inhibitors may show activity against both BRAF--and NRAS-driven tumors. Mucosal and acral melanomas frequently contain mutation in KIT receptor and can be successfully treated by imatinib. There are novel therapeutic monoclonal antibodies targeted against immunosuppressive molecules CTLA4, PD-1 and PD-L1. In some instances these drugs allow to obtain exceptionally prolonged responses. Whole genome sequencing led to the identification of new melanoma genes, e.g. GRIN2A, TRRAP, PREX2, RAC1, STK19, PPP6C, etc. Molecular testing, especially BRAF mutation analysis, has become a mandatory part of melanoma diagnosis. Nevertheless, despite the revolution in melanoma treatment, the prevention of excessive ultraviolet exposure, cancer awareness and early diagnosis remain the main tools for the management of this disease.