Phase II Trial of Temozolomide and Sorafenib in Advanced Melanoma Patients with or without Brain Metastases

Abstract

PURPOSE: The combination of the oral alkylating agent temozolomide and the oral multikinase inhibitor sorafenib was evaluated in advanced melanoma patients. EXPERIMENTAL DESIGN: Patients with metastatic melanoma (n = 167) were treated on four arms. All patients received sorafenib at 400 mg p.o. twice daily without interruption. Patients without brain metastases or prior temozolomide were randomized between arm A: extended dosing of temozolomide (75 mg/m(2) temozolomide daily for 6 of every 8 weeks) and arm B: standard dosing (150 mg/m(2) temozolomide daily for 5 of every 28 days). Patients previously treated with temozolomide were enrolled on arm C: extended dosing of temozolomide. Patients with brain metastases and no prior temozolomide were assigned to arm D: standard dosing. The primary end point was 6-month progression-free survival (PFS) rate. Secondary end points included response rate, toxicity rates, and the rates of BRAF or NRAS mutations. RESULTS: The 6-month PFS rate for arms A, B, C, and D were 50%, 40%, 11%, and 23%. The median PFS for patients on arm A, B, C, and D was 5.9, 4.2, 2.2, and 3.5 months, respectively. No significant differences were observed between arms A and B in 6-month PFS rate, median PFS, or response rates. Treatment was well tolerated in all arms. No significant differences in toxicity were observed between arms A and B except for more grade 3 to 4 lymphopenia in arm A. CONCLUSION: Temozolomide plus sorafenib was well tolerated and showed activity in melanoma patients without prior history of temozolomide. The activity of this combination regimen warrants further investigation. (Clin Cancer Res 2009;15(24):7711-8).

Fig 1

Progression-free survival (PFS) and overall survival (OS) in melanoma patients treated with temozolomide and sorafenib. (A–B): Kaplan-Meier curves for (A) PFS and (B) OS; Arm A (Blue):patients without brain metastases or prior temozolomide, treated with extended dosing temozolomide (EDT) Arm B (orange); patients without brain metastases or prior temozolomide treated with standard dosing temozolomide (STD), Arm C (red) Patients with prior temozolomide, EDT Arm D (green) patients with brain metastases,,without prior temozolomide, SDT: Dots: censored patients.

Fig 2

Kaplan-Meier curves for progression-free survival (PFS) for patients with tumor genotypes wild-type BRAF/mutant NRAS (WT/MuNRAS; red), mutant BRAF/wild-type NRAS (MuBRAF/WT; blue), wild-type BRAF/wild-type NRAS (WT/WT; green)