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.)

Figure 1. Mean PLX4032 Concentrations over a 24-Hour Period

Data are shown for the microprecipitated-bulk-powder formulation. Panel A shows the mean area under the plasma concentration–time curve (AUC_0–24), according to the twice-daily dose. Panel B shows the mean concentration after the administration of a single dose, on day 1, or multiple doses at the steady state, on day 15, at the recommended phase 2 dose of 960 mg twice daily. I bars indicate standard deviations.

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 immunohisto-chemical 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.

Figure 3. Antitumor Response in Each of the 32 Patients in the Extension Cohort

All 32 patients had melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF). All were treated at the recommended phase 2 dose of 960 mg twice daily. Panel A shows the best overall response for each of the 32 patients, measured as the change from baseline in the sum of the largest diameter of each target lesion. Negative values indicate tumor shrinkage, and the dashed line indicates the threshold for a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) (i.e., shrinkage by 30%). Two patients had a complete response. Panel B shows the duration and characteristics of the responses in each patient.