This ought to make us think more about when to go forward with phase III trials. The bar has to be higher, or we have to have a very strong scientific hypothesis.
—José Baselga, MD, PhD
In patients with locally advanced or metastatic breast cancer, the addition of sorafenib (Nexavar), a broad-spectrum tyrosine kinase inhibitor, to capecitabine did not improve progression-free or overall survival in the phase III RESILIENCE trial. The findings were presented at the European Society for Medical Oncology (ESMO) 2014 Congress by José Baselga, MD, PhD, who is Physician-in-Chief at Memorial Sloan Kettering Cancer Center, New York.1
The combination of sorafenib and capecitabine led to a median progression-free survival of 5.5 months vs 5.4 months for capecitabine plus placebo (hazard ratio [HR] = 0.973, P = .406). Median overall survival was 18.9 months with capecitabine/sorafenib and 20.3 months with capecitabine/placebo (HR = 1.195, P = .93).
“The trial did not meet its primary endpoint [progression-free survival],” Dr. Baselga announced. No subgroup was identified that derived benefit from the addition of this targeted agent.
The results were in contrast to those from previous preclinical and selected clinical studies. In a phase IIb trial,2 the combination of sorafenib and capecitabine improved progression-free survival in patients with advanced HER2-negative breast cancer (HR = 0.58, P = .001), and the drug has conferred a survival benefit in several other tumors, including advanced renal cell and hepatocellular carcinoma, Dr. Baselga indicated.
Although the sorafenib/capecitabine phase II trial was clearly positive, other phase II trials were either negative or demonstrated borderline superiority, including a combination study with paclitaxel or gemcitabine/capecitabine. Dr. Baselga noted that the results of the RESILIENCE trial, in light of the combined phase II trials, should make us think more about when to go forward with phase III trials. The bar has to be higher, or we have to have a very strong scientific hypothesis.”
The randomized phase III RESILIENCE trial enrolled 537 women with locally advanced or metastatic HER2-negative breast cancer who had received no more than one prior regimen. The trial excluded women previously treated with a vascular endothelial growth factor (VEGF) receptor inhibitor. Patients received capecitabine at 1,000 mg/m2 twice daily plus sorafenib or placebo 600 mg/d. Of note, the dose of sorafenib was reduced for the phase III trial to manage toxicity observed in the phase II trial. The impact of dose reduction on efficacy is unknown.
In addition to the lack of benefit with sorafenib for the primary endpoint, the overall response rate was numerically higher in the capecitabine/placebo arm (15.5% vs 13.5%). The disease-control rate was numerically higher in the sorafenib arm (60.5% vs 58.3%).
Adverse events were consistent with known safety profiles of sorafenib and capecitabine. Sorafenib was associated with more treatment-emergent adverse events of grade 3 (58.5% vs 39.3%), grade 4 (5.8% vs 4.5%), and grade 5 (6.2% vs 4.5%). This arm also had more serious adverse events, adverse events leading to dose reductions, and adverse events leading to treatment discontinuation.
However, Dr. Baselga indicated, “The trend for lower median overall survival in patients treated with sorafenib plus capecitabine was not readily explainable by study treatment-related toxicity.” ■
Disclosure: Dr. Baselga reported no potential conflicts of interest. For full disclosures of the study authors visit www.esmo.org.
1. Baselga J, et al: ESMO Congress. Abstract LBA8. Presented September 28, 2014.
2. Baselga J, et al: J Clin Oncol 30:1484-1491, 2012.
Hope S. Rugo, MD, Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, discussed the results of the RESILIENCE trial presented at the European Society for Medical Oncology ...