Sorafenib Does Not Improve PFS in Phase III Breast Cancer Study

Joerg Moeller, MD

A phase III trial analyzing sorafenib for the treatment of patients with advanced breast cancer did not meet its primary endpoint of improving progression-free survival (PFS). This announcement comes from Bayer HealthCare and Onyx Pharmaceuticals Inc., the companies co-developing the drug.

Patients with HER2-negative breast cancer who had received ≤1 prior chemotherapy and were resistant to or failed taxane and anthracycline or had disease not indicated for further anthracycline were enrolled in the study. A statistically significant improvement in PFS was not observed. Full results will be presented at an upcoming meeting.

“We are disappointed that the trial did not show an improvement in progression-free survival in patients with advanced breast cancer,” Joerg Moeller, MD, Member of the Bayer HealthCare Executive Committee and Head of Global Development, said in a statement. “While the primary endpoint of this trial was not met, the trial results do not affect the currently approved indications for [sorafenib].”

The RESILIENCE trial enrolled 537 patients in more than 20 countries, including the U.S. In addition to PFS, safety was a primary endpoint of the trial. Secondary endpoints included overall survival (OS), time to progression, and overall response rate. Exclusion criteria included significant cardiovascular disease, active brain metastases, and prior treatment with a VEGF inhibitor.

Patients were randomized 1:1 to 1000 mg/m² of capecitabine twice daily (days 1-14) in combination with placebo or 600 mg of oral sorafenib daily (days 1-21) on a 21-day schedule. As tolerated, capecitabine and sorafenib/placebo dosages could be escalated to 1250 mg/m² twice daily and 800 mg daily, respectively, or reduced to manage side effects. Sorafenib/placebo dosages could be re-escalated after a reduction.

This phase III RESILIENCE trial follows a 229-patient phase IIb trial that looked at sorafenib in combination with capecitabine for locally advanced or metastatic HER2-negative breast cancer. The design of the trial was essentially the same, though patients randomized to sorafenib received a higher dosage (400 mg twice daily).

Patients in the sorafenib arm experienced a median PFS of 6.4 months compared with 4.1 months in the placebo arm (HR = 0.58; 95% CI, 0.41-0.81; P = .001). However, no significant improvement in OS was reported: 22.2 versus 20.9 months, respectively (HR = 0.86; 95% CI, 0.61-1.23; P = .42).

All-grade adverse events observed in the sorafenib arm included rash (22%), diarrhea (58%), mucosal inflammation (33%), neutropenia (13%), hypertension (18%), and hand-foot skin reaction/syndrome (90%). All rates were higher in the sorafenib arm compared with the placebo arm.

Grade 3/4 adverse events were similar between the arms, with the exception of hand-foot skin reaction/syndrome: 44% in the sorafenib arm versus 14% in the placebo arm.

The authors noted that the dose of sorafenib “resulted in unacceptable toxicity for many patients” in the trial.

Sorafenib is currently approved for the treatment of advanced renal cell carcinoma and unresectable hepatocellular carcinoma. Sorafenib is also the first and only agent approved for locally recurrent or metastatic, progressive, radioiodine-refractory differentiated thyroid carcinoma.

Sorafenib is currently being looked at in several types of cancer, including acute myeloid leukemia, melanoma, squamous cell carcinoma of the head and neck, and colorectal cancer.