We clearly haven’t figured out how to use oral tyrosine kinase inhibitors in breast cancer.
—Hope S. Rugo, MD
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 (ESMO) 2014 Congress in Madrid.
“With sorafenib [Nexavar] we had a glimmer of hope from phase II studies,” she said. With other small-molecule kinase inhibitors (sunitinib [Sutent], axitinib [Inlyta], motesanib), multiple trials had been negative and toxicity was a concern, she said. “But in the development of sorafenib, we started with an interesting approach: large randomized phase II trials designed to power a better phase III trial with a higher chance of success.”
The phase II studies of sorafenib in combination with various chemotherapy agents returned mixed results, and toxicity was still concerning for the combination of sorafenib plus capecitabine (despite improved progression-free survival). The decision was made to reduce the dose of sorafenib from 800 mg to 600 mg for the phase III trial.
Even with this dose reduction, the combination arm received a lower dose intensity of capecitabine, had a shorter duration of treatment, and had a markedly higher number of dose interruptions or reductions of both agents, compared with the placebo arm. The combination arm also suffered a 20% increase in grade ≥ 3 adverse events, including hand-foot syndrome, hypertension, mucositis, and diarrhea, she noted.
Dr. Rugo suggested that the toxicity and the dose reductions “potentially limited the combined efficacy” of this regimen. Nevertheless, she added, “It’s hard to believe that a difference of 200 mg is the cause [of the negative results], but it may have contributed.”
She continued, “What we thought initially to be an advantage in the treatment of cancer [multiple targeting], may, for breast cancer, turn out to be a significant disadvantage: off-target toxicities that limit the dose of the targeted agent and also its accompanying chemotherapy. We clearly haven’t figured out how to use oral tyrosine kinase inhibitors in breast cancer.” ■
Disclosure: Dr. Rugo has received research funding from Genentech/Roche.
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 ...