BERLIN—The first of a series of trials to investigate the use of sorafenib for the treatment of advanced breast cancer has found that adding the targeted drug to capecitabine significantly extends progression-free survival times.
In the study of 229 patients, those given sorafenib plus capecitabine lived 2.3 months longer before their disease progressed than those given capecitabine alone.
The findings were presented here at a Presidential Session at the joint Congress of the European CanCer Organisation and European Society for Medical Oncology (ECCO15-ESMO34).
“The magnitude of the benefit is such that it suggests that this agent will be an important addition to our therapeutic armory in breast cancer,” said ESMO's President and the study's chief investigator, José Baselga, MD, Head of Oncology at Vall d'Hebron University Hospital in Barcelona. In addition, because it's administered orally, sorafenib “is a unique and convenient treatment option.”
The study was funded by Bayer and Onyx, which make and distribute sorafenib.
A targeted therapy, sorafenib is an oral multi-kinase inhibitor with anti-proliferative and anti-angiogenic activity. It is currently approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma.
Previous research has shown that sorafenib is safe in combination with commonly used chemotherapy drugs such as capecitabine in breast cancer, Dr. Baselga noted.
The TIES (Trials to Investigate the Efficacy of Sorafenib in Breast Cancer) Program involves the current and three other Phase IIB randomized controlled trials in advanced breast cancer patients.
William J. Gradishar, MD, Director of Breast Medical Oncology at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, is heading a trial looking at sorafenib and paclitaxel; a group led by Clifford A. Hudis, MD, Chief of the Breast Cancer Medicine Service at Memorial-Sloan Kettering Cancer Center, is investigating a combination of sorafenib and chemotherapy in patients whose disease has progressed on bevacizumab; and Edith A. Perez, MD, Professor of Medicine at the Mayo Clinic, is heading a trial looking at sorafenib and an aromatase inhibitor, Dr. Baselga said. “We're the first to report results.”
In the study, 229 women with locally advanced or metastatic breast cancer were randomly assigned in a one-to-one fashion to receive capecitabine (1,000 mg/m2, orally, twice daily, for 14 of every 21 days) with either placebo or sorafenib (400 mg orally twice a day continuously). Randomization was stratified by visceral vs nonvisceral metastatic disease.
Eligibility criteria included having HER-2 negative tumors and fewer than two prior chemotherapy regimens for locally advanced or metastatic breast cancer. Patients with active brain metastasis were excluded.
The primary endpoint was progression-free survival times; secondary endpoints were overall survival times, time to progression, response rate, response duration, and safety.
Patients were examined every six weeks for 24 weeks, and then every nine weeks thereafter.
The treatment arms were balanced for age (median 55 years); Eastern Cooperative Oncology Group performance status (status 0, 68%); Stage (IV, 91%); visceral disease (75%); and hormone-positive tumors (73%). Eighty-nine percent of patients had received prior anthracycline therapy, and 60% had been on taxanes.
PFS Longer in Sorafenib Arm
By investigator assessment, the median progression-free survival time was 6.4 months for the sorafenib group vs 4.1 months for the capecitabine-placebo group, translating into a 42% significant reduction in risk of disease progression in the sorafenib arm, Dr. Baselga reported.
“Statistically significant benefit was seen when sorafenib was given as both first- and second-line treatments.”
As first line-treatment, sorafenib was associated with a 50% reduction in risk of disease progression; as second-line therapy, the risk reduction was 35%.
The overall response rate was 38% for the sorafenib arm, compared with 31% for the chemotherapy-placebo arm, a difference that did not reach statistical significance. Two patients in the sorafenib arm and one patient in the control arm had complete responses.
There was one treatment-related death in the control group and none in the sorafenib group. The main increased toxicity in the sorafenib group was hand-foot skin reaction, which occurred in 45% of patients, compared with 13% in the control group.
Fifteen percent of patients in the sorafenib group discontinued therapy due to adverse effects, compared with 7% in the placebo group. The most common reasons for discontinuation were hand-foot syndrome and diarrhea.
Asked if clinicians should be concerned about the 45% rate of hand-foot skin reaction in sorafenib-treated patients, Chris Twelves, MD, Cochairman of the ECCO15-ESMO34 Program Committee, said that hand-foot syndrome can usually be reversed if patients take “a drug holiday”—“Hand-foot syndrome is not something that develops overnight. You need to explain to patients that if their hands or feet start getting red or sore or cracked, they need to come in so we can modify the dose.”
OS vs PFS
It was too early to evaluate overall survival rates, but both Dr. Baselga and Dr. Twelves said that sorafenib has a role in the treatment of patients with locally advanced or metastatic breast cancer.
“Based on what we have seen with other angiogenesis inhibitors in breast cancer, such as Avastin [bevacizumab], this is a very important study,” said Dr. Twelves, Professor of Clinical Cancer Pharmacology at the Leeds Institute of Molecular Medicine in England.
“They both target angiogenesis and we know that in broad terms, Avastin makes chemotherapy work better in breast cancer. Now we are seeing for the first time that sorafenib seems to make breast cancer chemotherapy work more effectively as well,” he said.
Dr. Baselga noted that unlike the situation in many other cancers, progression-free survival time is increasingly being used as the primary endpoint in breast cancer trials.
“In breast cancer, we have multiple treatment options that interfere with overall survival. If you're testing only one agent, progression-free survival correlates with overall survival. But if you are looking at multiple lines of therapy, as is typical, overall survival can be influenced by the study agent or any of the other agents. As a result, we're shifting toward the idea of using progression-free survival as an endpoint.”
That said, though, Dr. Baselga continued, “Progression-free survival is loaded with issues. Clinical trials have to be well controlled.”
Dr. Twelves noted that bevacizumab was granted FDA approval for use in metastatic breast cancer based on data showing that it improved progression-free survival rates—although it had failed to extend overall survival times (Miller K et al: NEJM; 2007;357:2666–2676).
“In breast cancer, there are so many treatments that there is no one simple route for all patients. We don't know yet exactly where sorafenib will fit in, but I believe it will play an important role in treating our patients,” he said.
FDA Approval for Arzerra for CLL
The FDA has approved the use of the monoclonal antibody ofatumumab (Arzerra) for patients with chronic lymphocytic leukemia (CLL) that is no longer being controlled by other forms of chemotherapy. The drug, which binds to a protein found on the surface of both normal and malignant B cells, was approved under the FDA's accelerated approval process, which allows earlier approval of drugs that meet unmet medical needs. Products may receive accelerated approval based on a surrogate endpoint, such as a reduction in the size of the tumor or decrease in the number of cancerous white cells or in an enlarged spleen or lymph nodes.
“The approval of Arzerra illustrates FDA's commitment to using the accelerated approval process to approve drugs for patients who have limited therapeutic options,” said Richard Pazdur, MD, Director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research.
The accelerated approval process does require that the drug receive further study, and the manufacturer, Glaxo SmithKline, is currently conducting a clinical trial in CLL patients to confirm that the addition of ofatumumab to standard chemotherapy delays the progression of the disease.
The product's effectiveness was evaluated in 59 patients with CLL whose disease no longer responded to the available therapies. Safety was studied in 181 patients in two studies in cancer patients, with the following side effects found to be common: decrease in normal white blood cells, pneumonia, fever, cough, diarrhea, reduced red blood cell counts, fatigue, shortness of breath, rash, nausea, and bronchitis and upper respiratory tract infections.
The most serious side effects of Arzerra are an increased chance of infections, including progressive multifocal leukoencephalopathy (PML). The company notes that patients at high risk for hepatitis B should be screened before being treated with Arzerra; and patients with evidence of inactive hepatitis should be monitored for re-activation of the infection during and after completing treatment.