RAF Inhibitor Dabrafenib (GSK2118436) is Active in Melanoma Brain Metastases, Multiple BRAF Genotypes and Diverse Cancers
By G. Falchook, Georgina V. Long, Razelle Kurzrock, Kevin B. Kim, T. Arkenau, M. Brown, O. Hamid, J. Infante, Michael Millward, A. Pavlick and 7 more. The Lancet, 2012
870 citations recorded by the source corpus.
Background Dabrafenib (GSK2118436) is a potent ATP-competitive inhibitor of BRAF kinase and was highly selective for mutant BRAF in kinase panel screening, cell lines, and xenografts. Methods A Phase I trial of dabrafenib was conducted to evaluate safety and tolerability in patients with incurable solid tumours. Efficacy at the recommended Phase II dose (RP2D) was studied in patients with BRAF-mutant tumours, including those with non-V600E mutations, in three cohorts: (1) metastatic melanoma, (2) melanoma with untreated brain metastases, and (3) non-melanoma solid tumours. Findings 184 patients enrolled, and 150 mg twice daily was chosen as the RP2D, based on safety, pharmacokinetic, and pharmacodynamic data. At the RP2D in patients with V600 BRAF-mutant melanoma, a response rate of 69% (a confirmed response rate of 50%) was observed overall and a 78% response rate (a confirmed response rate of 56%) in V600E BRAF-mutant melanoma. In V600 BRAF-mutant melanoma, responses were durable, with 17 patients (47%) on treatment for more than 6 months and a median progression-free survival (PFS) of 5·5 months. Responses were observed in patients with non-V600E BRAF mutations, including V600K and V600G. In the RP2D expansion of melanoma with untreated brain metastases, nine of ten patients (90%) showed reduction in brain lesion size and the median PFS was 4.2 months. Among BRAF-mutant non-melanoma solid tumours, antitumour activity was observed in gastrointestinal stromal tumour, papillary thyroid, non-small cell lung, ovarian, and colorectal cancer. Interpretation Dabrafenib is a highly active inhibitor of V600-mutant BRAF with a high response rate in V600E melanoma, and is the first drug of its class to demonstrate activity in melanoma brain metastases. Funding This study was funded and sponsored by GlaxoSmithKline
Subfields: Molecular Biology, Oncology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/db108703793d5d6032877dfc279c53b3ee1f57fc
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Citations in the corpus
- Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer (2015, background): “Our results demonstrate no meaningful differences in pharmacokinetics between patients with CRC and melanoma, with similar adverse event profiles and administered doseintensity.21 Although vemurafenib is a substrate for cellular drug exporters such as P-glycoprotein, which is upregulated in CRC rela”
- Melanoma Staging: Evidence-Based Changes in the American Joint Committee on Cancer Eighth Edition Cancer Staging Manual (2017, methodology): “as well as stratification and analysis, are often based on the presence/absence of CNS disease.(6-20,73,74) Therefore, this additional level of granularity in the M category “maps” bet-”
- Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. (2014, neutral): “(%) 56/210 (27) 61/211 (29) 117/421 (28)”