BERLIN—Sorafenib (Nexavar) has antiangiogenic and antiproliferative activity and is FDA-approved for advanced renal and hepatocellular cancers. But there is a “profound rationale” for studying the drug in breast cancer because the drug targets both tumor cells and angiogenesis, said Jose Baselga, MD, lead investigator for the SOLTI-0701 trial.
The much-anticipated results from the phase IIb trial indicate that in patients with advanced breast cancer, sorafenib delayed disease progression by 42% (ECCO/ESMO 2009 abstract 3LBA).
According to Dr. Baselga, sorafenib interfered with clinically relevant pathways downstream of tyrosine kinase receptors, including VEGF receptors 1, 2, and 3, as well as prostaglandin-derived growth factor receptor. Also, the drug hindered the pathways of RAF, c-KIT, and FLT3.
SOLTI-0701 is a randomized, double-blind, placebo-controlled study that evaluated the drug’s potential benefit in locally advanced or metastatic breast cancer when used in combination with capecitabine (Xeloda). The study included 220 advanced disease (91% stage IV) patients with HER2-negative tumors who had more than two prior chemotherapy regimens. Patients were randomized to capecitabine (1,000 mg/m2 bid) for 14 of every 21 days plus placebo or the same capecitabine dose plus sorafenib (400 mg/m2 bid) daily.
According to the results, progression-free survival (PFS) was 6.4 months with the capecitabine/sorafenib combination vs 4.1 months with capecitabine alone (HR = .576; P = .0006).
“The benefits were robust across subgroups,” said Dr. Baselga, who is the president of ESMO. A significant PFS advantage was seen with both first-line and second-line treatment. In the first-line setting, median PFS with the combination was 7.6 months vs 4.1 months with capecitabine alone (HR = .498; P = .0022). As a second-line treatment, PFS was 5.7 vs 4.1 months, respectively (HR = .652; P = .0339).
Objective response rates were similar between the arms: 38.3% with the combination and 30.7% with capecitabine alone (P = .1229). Stable disease was observed in 43.5% and 37.7%, respectively, and progressive disease in 10.4% and 23.7%. Overall survival data were too immature to report at this meeting, Dr. Baselga said.
With regard to toxicities, the sorafenib/capecitabine combination was well tolerated, although all grades of hand-foot skin reactions were more frequent (89% vs 63% for capecitabine alone). Less than 5% of the patients in both arms experienced diarrhea, dyspnea, neutropenia, and/or mucositis. The percentage of patients discontinuing treatment due to adverse events was 13.4% with the combination and 8% with capecitabine alone.
“Our findings suggest that sorafenib may be a valuable addition to breast cancer therapy when given in combination with chemotherapy. The fact that this is an oral combination may represent a unique and convenient treatment option,” Dr. Baselga said.
“We believe that further studies are warranted, and they are being performed through the TIES program (Trials to Investigate the Efficacy of Sorafenib in Breast Cancer),” he said.
Clear demonstration of antitumor activity, but toxicity remains a concern
This study clearly demonstrates that sorafenib has considerable antitumor activity in metastatic breast cancer when combined with capecitabine, said Dr. O'Shaughnessy, cochair of the Breast Cancer Research Committee at the Dallas-based US Oncology.
“The hazard ratio of .57 for PFS (P = .0006) is very positive; surprisingly so as bevacizumab (Avastin) did not improve PFS when combined with capecitabine in pretreated metastatic breast cancer patients,” said Dr. O'Shaughnessy who is also codirector of the Breast Cancer Research Program at Baylor-Charles A. Sammons Cancer Center.
“The practical issue will be the increased toxicity of the combination, especially hand-foot syndrome. Capecitabine can be associated with an excellent quality of life and, unless I can offer a patient a survival advantage with a combination, I wouldn't necessarily want to diminish the capecitabine-associated quality-of-life benefits,” Dr. O'Shaughnessy added. “The question for me is: What other agents can I combine sorafenib with and reap the PFS benefits without producing overlapping toxicities?”