Inhibition of Mutated, Activated BRAF in Metastatic Melanoma

Abstract

Background 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. 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. 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. Conclusions 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.)

Phase II Efficacy and Pharmacogenomic Study of Selumetinib (AZD6244; ARRY-142886) in Iodine-131 Refractory Papillary Thyroid Carcinoma with or without Follicular Elements

“…In a recent phase II study of selumetinib in advanced melanoma, a mutated BRAF status conferred a more favorable outcome. More strikingly, a recently completed phase I trial of the BRAF inhibitor PLX4032 in metastatic melanoma resulted in complete or partial tumor regression in the majority of patients carrying the BRAF V600E mutation (40). Unfortunately, the objective responses in PTC have not been as striking and may be explained by involvement of additional mutations of cell signaling pathways.…”

Frequency and Spectrum of BRAF Mutations in a Retrospective, Single-Institution Study of 1112 Cases of Melanoma

“…In recently published phase 1 and phase 2 clinical trials, vemurafenib therapy showed unprecedented response rates in patients with advanced-stage, BRAF-mutated melanoma. 3,4 Moreover, in a phase 3 trial, vemurafenib therapy resulted in improved overall and progression-free survival, compared with dacarbazine, in patients with previously untreated metastatic melanoma with BRAF mutation. 5 In 2011, vemurafenib was approved by the US Food and Drug Administration (FDA) to treat patients with advanced stage melanoma who harbor the BRAF p.V600E mutation; also approved was a companion diagnostic test, the cobas 4800 BRAF V600 mutation test (Roche Molecular Diagnostics, Branchburg, NJ), designed to detect the BRAF c.1799T>A (p.V600E) mutation from formalin-fixed, paraffin-embedded tissue samples in a qualitative manner (http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm268241.htm, last accessed January 2, 2013).…”

BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma

“…For metastatic melanoma, small-molecule inhibitors of BRAF V600E protein have demonstrated clinical activity and have rapidly changed standard treatment of BRAFmutated melanoma patients. [7][8][9] Similarly, these targeted therapies might also have antitumor activity in various other BRAF-mutated neoplasias. [10][11][12][13][14] Accurate and rapid detection of BRAF mutations in metastatic melanoma is therefore essential for optimal patient care and may possibly be also required in other tumor entities in the near future.…”