Clinical Cancer Research
Phase II Trial of Temozolomide and Sorafenib in Advanced Melanoma Patients with or without Brain Metastases
Ravi Amaravadi, Lynn M Schuchter, David F. McDermott, Amy Kramer, Lydia Giles, Kristi Gramlich, Mary Carberry, Andrea B. Troxel, Richard Letrero, Katherine L. Nathanson, Michal B. Atkins, Peter J.Odwyer and Keith Flaherty.
Purpose: The combination of the oral alkylating agent temozolomide and the oral multikinase inhibitor sorefenib was evaluated in advanced melanoma patients.
Experimental Design: Patient with metastatic melanoma (n = 167) were treated on four arms. All patients received sorafenib at 400 mg p.o. twice daily without interruption. Patient without brain metases or prior temozolomide were randomized between arm A: extended dosing of temozolomide (75 mg/m2 temozolomide daily for 6 of every 8 weeks) and arm B: standard dosing (150 mg/m2 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 ams 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)