Inhibition of Mutated, Activated BRAF in Metastatic Melanoma

Abramson Cancer Center of the University of Pennsylvania, Philadelphia, USA.
New England Journal of Medicine (Impact Factor: 55.87). 08/2010; 363(9):809-19. DOI: 10.1056/NEJMoa1002011
Source: PubMed


The identification of somatic mutations in the gene encoding the serine-threonine protein kinase B-RAF (BRAF) in the majority of melanomas offers an opportunity to test oncogene-targeted therapy for this disease.
We conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition.
A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months.
Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.)

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    • "Frequent BRAF mutations led to the development of mutated BRAF inhibitors for the treatment of melanomas [2] [3]. However, the emergence of acquired resistance to BRAF inhibitors limited their effectiveness in the treatment of melanoma [4]. Our findings showed that gossypol retained its efficacy even after long-term treatment. "
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    • "dabrafenib. These anti-BRAF V600E therapies have led to improvements in the survival of patients with melanomas harboring the BRAF V600E mutation (Flaherty et al., 2010). However, most patients treated with BRAF inhibitors (BRAFi) develop resistance to these therapies after only several months (Flaherty et al., 2012; Franco et al., 2011; Sullivan and Flaherty, 2013). "
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