Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats. Original Article Inhibition of Mutated, Activated BRAF in Metastatic Melanoma Keith T. Flaherty, M.D., Igor Puzanov, M.D., Kevin B. Kim, M.D., Antoni Ribas, M.D., Grant A. McArthur, M.B., B.S., Ph.D., Jeffrey A.
Sosman, M.D., Peter J. O'Dwyer, M.D., Richard J. Lee, M.D., Ph.D., Joseph F. Grippo, Ph.D., Keith Nolop, M.D., and Paul B. Chapman, M.D. N Engl J Med 2010; 363:809-819 DOI: 10.1056/NEJMoa1002011.
Methods 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. Results 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.
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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. Figure 2 Representative Findings of the Effect of PLX4032 at the Recommended Phase 2 Dose in Study Patients with Melanoma That Carried the V600E Mutation. The recommended phase 2 dose was 960 mg twice daily.
Panel A (hematoxylin and eosin) shows immunohistochemical analyses of the expression of phosphorylated extracellular signal-regulated kinase (ERK), cyclin D1, and Ki-67 in tumor-biopsy specimens obtained at baseline and on day 15 of treatment. Panel B shows the uptake of 18F-fluorodeoxyglucose (FDG) at baseline and on day 15 of treatment, as assessed by means of positron-emission tomography (PET). Panel C shows computed tomographic images of lesions (arrows) in lung, liver, and bone (with each pair of images shown for a different patient) at baseline and at 8 weeks. Metastatic melanoma is an aggressive disease for which there are few effective therapies. The two therapies approved by the Food and Drug Administration, high-dose interleukin-2 and dacarbazine, are each associated with response rates of only 10 to 20% and a small percentage of complete responses; neither is thought to improve overall survival.