Inhibition of Mutated, Activated BRAF in Metastatic Melanoma

TLDR

Somatic BRAF mutations, present in most melanomas, provide a target for oncogene‑directed therapy, prompting a multicenter phase‑1 dose‑escalation study of the orally available BRAF inhibitor PLX4032 (RG7204). Patients received PLX4032 twice daily until progression, with pharmacokinetic and tumor‑response assessments performed in all participants, and tumor biopsies before and during treatment to confirm BRAF inhibition; the study included a dose‑escalation phase followed by an extension phase at the maximum tolerated dose. The recommended phase‑2 dose was 960 mg twice daily, limited by grade 2–3 rash, fatigue, and arthralgia; among 16 V600E‑mutant melanoma patients in the dose‑escalation cohort, 10 achieved partial and 1 complete response, while in the extension cohort of 32 patients, 24 had partial and 2 complete responses, yielding a median progression‑free survival of over 7 months and a majority of patients experiencing tumor regression. Funding was provided by Plexxikon and Roche Pharmaceuticals.

Abstract

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.)