Sorafenib Works Well With Chemotherapy in Advanced Breast Cancer

SAN ANTONIO — Sorafenib (Nexavar), a multi-targeted tyrosine kinase inhibitor (TKI), showed promise when combined with chemotherapy for locally advanced or metastatic breast cancer in the phase IIb Solti-0701 trial reported at the San Antonio Breast Cancer Symposium. Based on the promising results of this trial, a phase III registration trial will begin in 2010 to evaluate the combination of sorafenib plus capecitabine for treatment of advanced breast cancer.

“The combination of sorafenib and capecitabine was tolerable, with clinically manageable toxicities, and no unexpected toxicity signal. The combination achieved a 42% reduction in disease progression and death, with confirmed robust findings across subgroups when used in both first- and second-line therapy. We conclude that sorafenib may be a valuable addition when given in combination with chemotherapy,” stated Jose Baselga, MD, Vall D’Hebron University Hospital, Barcelona, Spain.

Soliti-0701 was a multinational, double-blind, placebo-controlled, randomized, phase IIb study that enrolled 220 women with locally advanced unresectable or metastatic HER2-negative breast cancer. Women were allowed on 1 prior chemotherapy for advanced disease. They were stratified according to lines of therapy (first- or second-line) and visceral metastasis (presence or absence) and randomized 1:1 to receive either 400 mg of sorafenib orally twice a day plus 1000 mg/m² of capecitabine orally twice a day for 14 out of every 21-day cycle or to placebo plus capecitabine at the same dose and schedule.The dose of capecitabine was lower than the approved dose, which is 1250 mg/m² twice daily for 14 out of every 21 days, Dr Baselga said. Treatment was continued until disease progression or unacceptable toxicity.

At baseline, both groups were well balanced for demographic and disease characteristics. Median age was 55 years. Seventy percent were both estrogen receptor—positive and progesterone receptor–positive. Eighty percent had prior adjuvant or neoadjuvant therapy; of these, 40% were treated with taxanes and 90% with anthracyclines. No previous bevacizumab was allowed.Fifty-seven percent of patients in the experimental arm and 45% in the capecitabine plus placebo arm had 1 prior chemotherapy regimen for advanced/metastatic disease.

With the exception of hand/foot syndrome, there were few grade 3 adverse events in either group and virtually no grade 4 adverse events. However, 45% of patients in the sorafenib/capecitabine arm developed grade 3 hand/foot syndrome compared with 13% in the comparator arm. These patients were treated with pre-defined management, as this is an expected toxicity with sorafenib, Dr Baselga explained.

No dose adjustments were made for grade 1 hand/foot syndrome, but for grades 2 and 3, sorafenib was withheld until symptom resolution. Dose adjustments were made for grade 3.

Treatment discontinuations due to adverse events were reported in 65% of those on sorafenib and 79% for placebo; discontinuations due to progressive disease occurred in 45% and 66%, respectively.

For the primary endpoint of progression-free survival (PFS), median PFS was6.4 months for sorafenib/capecitabine versus 4.1 months for capecitabine/placebo. This difference of almost 2 months was highly statistically significant (P = .0006). Response rates were 38% and 30.7%, respectively.

In a pre-specified subgroup analysis of those being treated first-line for advanced/metastatic disease, PFS was 7.6 months for sorafenib/capecitabine and 4.1 months for capecitabine/placebo, representing a statistically significant 50% reduction in disease progression/death (P = .0022). In the second-line setting, PFSwas 5.7 months versus 4.1 months, respectively, representing a 35% reduction (P = .0339). SABCS Abstract 45.