A Phase III Randomized, Double-Blind, Trial Comparing Sorafenib Plus Capecitabine Versus Placebo Plus Capecitabine in the Treatment of Locally Advanced or Metastatic Her2-Negative Breast Cancer (Resilience)

Abstract

ABSTRACT Aim: A phase III randomized, double-blinded, placebo (PLC)-controlled study of sorafenib (S) in combination with capecitabine (C) was conducted in patients with HER2-negative, locally advanced or metastatic breast cancer. The primary endpoint was progression-free survival (PFS) per independent review. Secondary endpoints included overall survival (OS), time to progression (TTP), objective response rate (ORR), disease control rate (DCR) and safety. Methods: Patients resistant to prior taxane and resistant to prior anthracycline or for whom further anthracycline was not indicated, and having received no more than one prior regimen for advanced disease were randomized 1:1 to PLC or S (600 mg daily, po, 21-day schedule) in combination with C (1000 mg/m2, bid, po, 14/7 days on/off). Results: A total of 537 patients were randomized: 266 to S + C and 271 to PLC + C. The two arms were generally well balanced; median age 54 years; 69% hormone receptor positive and 31% triple negative; and 43%/57% having received 0/1 prior lines of chemotherapy for metastatic disease. Median PFS was 5.5 mo for S + C and 5.4 mo for PLC + C; HR 0.973 (95% CI: 0.779, 1.217; one-sided p-value = 0.406). Median OS was 18.9 mo for S + C and 20.3 mo for PLC + C; HR 1.195 (95% CI: 0.943, 1.513; one-sided p-value = 0.930). There were no differences in TTP, ORR or DCR. The incidence of grade 3 AEs was 58.5% vs 39.3%, grade 4 AEs 5.8% vs 4.5%, and grade 5 AEs 6.2% vs 4.5%, S + C vs PLC + C arms, respectively. The most commonly reported grade 3 AEs included palmar-plantar erythrodysesthesia syndrome (16% vs 8%), hypertension (14% vs 2%), fatigue (7% vs 3%) diarrhea (4% vs 6%), neutropenia (4% vs 5%), and anemia (5% vs 2%). The average daily dose for C was 1734 mg/m2 vs 1914 mg/m2 with a median duration of 18 wks vs 23 wks for C in S + C and PLC + C arms, respectively. There was one drug-related grade 5 AE (hepatic failure) reported in the S + C arm. Conclusions: S + C did not improve PFS compared to PLC + C for patients with HER2-negative, locally advanced or metastatic breast cancer. The types of AEs observed were consistent with the known safety profiles of S and C. There was a trend toward worse OS in the S + C arm that is not readily explained by study treatment-related toxicity. Disclosure: P. Gomez: Honoraria: Bayer; B. Melichar: Honoraria: Bayer, Roche; J. Bergh: Clinical research: Bayer, Amgen, Astra-Zeneca, Merck, Pfizer, Roche and Sanofi-Aventis; P. Maeda, L. Huang and J. Zhang: Employment: Bayer HealthCare Pharmaceuticals. All other authors have declared no conflicts of interest.