Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma.

PURPOSE The primary objective of this study was to determine whether carboplatin, paclitaxel, and sorafenib (CPS) improve overall survival (OS) compared with carboplatin and paclitaxel (CP) in chemotherapy-naive patients with metastatic melanoma. PATIENTS AND METHODS In this double-blind, randomized, placebo-controlled phase III study, all patients received carboplatin at area under the [concentration-time] curve 6 and paclitaxel 225 mg/m(2) intravenously once every 21 days with random assignment to sorafenib 400 mg orally twice per day on days 2 through 19 every 21 days or placebo. The primary end point was OS, and secondary end points included progression-free survival, objective tumor response, and toxicity. RESULTS In all, 823 patients were enrolled over 34 months. At final analysis, the median OS was 11.3 months (95% CI, 9.8 to 12.2 months) for CP and 11.1 months (95% CI, 10.3 to 12.3 months) for CPS; the difference in the OS distribution was not statistically significant by the stratified log-rank test, stratified on American Joint Committee on Cancer (AJCC) stage, Eastern Cooperative Oncology Group (ECOG) performance status, and prior therapy (P = .878). Median progression-free survival was 4.9 months for CPS and 4.2 months for CP (P = .092, stratified log-rank test). Response rate was 20% for CPS and 18% for CP (P = .427). More patients on the CPS arm had grade 3 or higher toxicities (84% v 78%; P = .027), with increased rash, hand-foot syndrome, and thrombocytopenia accounting for most of the difference. CONCLUSION Sorafenib does not improve OS when given in combination with CP for chemotherapy-naive patients with metastatic melanoma. This study establishes benchmark end points for the CP regimen in first-line therapy of metastatic melanoma.

[1]  C. Maley,et al.  Alteration of the epigenome during carcinogenesis of intestinal-type gastric cancer. , 2012 .

[2]  D. McDermott,et al.  Multicenter, Phase II Study of Axitinib, a Selective Second-Generation Inhibitor of Vascular Endothelial Growth Factor Receptors 1, 2, and 3, in Patients with Metastatic Melanoma , 2011, Clinical Cancer Research.

[3]  A. Hauschild,et al.  Improved survival with vemurafenib in melanoma with BRAF V600E mutation. , 2011, The New England journal of medicine.

[4]  A. Harris,et al.  Prognostic and Predictive Role of Lactate Dehydrogenase 5 Expression in Colorectal Cancer Patients Treated with PTK787/ZK 222584 (Vatalanib) Antiangiogenic Therapy , 2011, Clinical Cancer Research.

[5]  J. Nemunaitis,et al.  Assessment of clinical activity of E7080, a multitargeted kinase inhibitor, in patients with advanced melanoma treated in two phase I trials. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  D. Polsky,et al.  A Phase II Trial of Sorafenib in Metastatic Melanoma with Tissue Correlates , 2010, PloS one.

[7]  D. Schadendorf,et al.  Improved survival with ipilimumab in patients with metastatic melanoma. , 2010, The New England journal of medicine.

[8]  T. Mikkelsen,et al.  Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  E. Merkle,et al.  Phase I Trial of Pazopanib in Patients with Advanced Cancer , 2009, Clinical Cancer Research.

[10]  A. Hauschild,et al.  Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  J. Llovet,et al.  Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling , 2008, Molecular Cancer Therapeutics.

[12]  D. Elder,et al.  A Phase I Trial of the Oral, Multikinase Inhibitor Sorafenib in Combination with Carboplatin and Paclitaxel , 2008, Clinical Cancer Research.

[13]  P. Bycott,et al.  Axitinib (AG-013736) in patients with metastatic melanoma: A phase II study , 2008 .

[14]  G. Linette,et al.  Double-blind randomized phase II study of the combination of sorafenib and dacarbazine in patients with advanced melanoma: a report from the 11715 Study Group. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  K. Flaherty,et al.  Pilot study of DCE-MRI to predict progression-free survival with sorafenib therapy in renal cell carcinoma , 2008, Cancer biology & therapy.

[16]  Donna Niedzwiecki,et al.  Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  E. Perez,et al.  Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. , 2007, The New England journal of medicine.

[18]  Bohuslav Melichar,et al.  Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial , 2007, The Lancet.

[19]  S. Wilhelm,et al.  Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. , 2006, Cancer research.

[20]  Robert Gray,et al.  Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. , 2006, The New England journal of medicine.

[21]  H. Pehamberger,et al.  Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  M. Ratain,et al.  Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis , 2006, British Journal of Cancer.

[23]  R. Motzer,et al.  Sunitinib in patients with metastatic renal cell carcinoma. , 2006, JAMA.

[24]  J. Berlin,et al.  Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. , 2004, The New England journal of medicine.

[25]  L. Kanter,et al.  Screening of N-ras codon 61 mutations in paired primary and metastatic cutaneous melanomas: mutations occur early and persist throughout tumor progression. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[26]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[27]  C. Begg,et al.  Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  G. Linette,et al.  BEAM: a randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  D. Schadendorf,et al.  Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.