Sorafenib With Gemcitabine or Capecitabine in Patients With HER-2 Negative Advanced Breast Cancer That Progressed During or After Bevacizumab
Mené sur 160 patientes atteintes d'un cancer du sein HER- de stade avancé ayant progressé pendant ou après un traitement à l'aide de bevacizumab, cet essai de phase IIb évalue, du point de vue de la survie sans progression, l'ajout de sorafenib à la gemcitabine ou la capécitabine
Purpose:We assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab. Experimental Design:This double-blind, randomized, placebo-controlled phase 2b study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic HER2-negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily [BID]) or matching placebo. Initially, chemotherapy was gemcitabine (1000 mg/m2 intravenously, Days 1, 8/21), but later, capecitabine (1000 mg/m2 orally BID, Days 1−14/21) was allowed as an alternative. The primary endpoint was progression-free survival (PFS). Results:One hundred and sixty patients were randomized. More patients received gemcitabine (82.5%) than capecitabine (17.5%). Sorafenib plus gemcitabine/capecitabine was associated with a statistically significant prolongation in PFS versus placebo plus gemcitabine/capecitabine (3.4 vs 2.7 months; hazard ratio [HR]=0.65; 95% confidence interval [CI], 0.45-0.95; P=0.02), time to progression was increased (median, 3.6 vs 2.7 months; HR=0.64; 95% CI, 0.44-0.93; P=0.02), and overall response rate was 19.8% versus 12.7% (P=0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR=1.01; 95% CI, 0.71−1.44; P=0.95). Addition of sorafenib versus placebo increased grade 3/4 hand-foot skin reaction (39% vs 5%), stomatitis (10% vs 0%), fatigue (18% vs 9%), and dose reductions were more frequent (51.9% vs 7.8%) Conclusions: The addition of sorafenib to gemcitabine/capecitabine provided a clinically small but statistically significant PFS benefit in HER2-negative advanced breast cancer patients whose disease progressed during/after bevacizumab. Combination treatment was associated with manageable toxicities but frequently required dose reductions.