Sorafenib or Placebo with Either Gemcitabine or Capecitabine in Patients with HER-2–Negative Advanced Breast Cancer That Progressed during or after Bevacizumab

Abstract

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 IIb study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily) or matching placebo. Initially, chemotherapy was gemcitabine (1,000 mg/m 2 i.v., days 1, 8/21), but later, capecitabine (1,000 mg/m 2 orally twice daily, days 1-14/21) was allowed as an alternative. The primary endpoint was progressionfree 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; HR ¼ 0.65; 95% confidence interval (CI): 0.45-0.95; P ¼ 0.02], time to progression was increased (median, 3.6 vs. 2.7 months; HR ¼ 0.64; 95% CI: 0.44-0.93; P ¼ 0.02), and overall response rate was 19.8% versus 12.7% (P ¼ 0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR ¼ 1.01; 95% CI: 0.71À1.44; P ¼ 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 that were more frequent (51.9% vs. 7.8%).Conclusion: 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.

Risk of treatment-related mortality with sorafenib in cancer patients: a meta-analysis of 20 randomly controlled trials

“…Baseline characteristics of all included studies are listed in Table 1. Underlying malignancies for these trials included RCC [5,16,18,22,24] (five trials), HCC [7,13,17] (three), NSCLC [8][9][10]12] (four), breast cancer [11,14,19] (three), melanoma [6,15] (two), thyroid cancer [21] (one), urothelial cancer [23] (one) and CRC [20] (one); The starting dose and schedule of sorafenib was based on the US Food and Drug Administration guideline (400 mg, orally, twice daily) in each study.…”

“…Sorafenib is a new targeted oral tumor treatment that inhibits a variety of intercellular and cell-surface kinases, including RAF kinase, VEGF receptor-2 and -3 [2][3][4], platelet-derived growth factor receptor beta, KIT and PLT-3. Sorafenib has been tested in randomized controlled trials (RCTs) for patients who have hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), non-small-cell lung cancer (NSCLC), melanoma, colorectal cancer (CRC), breast cancer, urothelial cancer and thyroid cancer [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. Fatal adverse events (FAEs) are defined as deaths that are usually secondary to drug use.…”

Targeted Therapies in Triple-Negative Breast Cancer

“…There are no specific data for triplenegative patients from these trials. Sorafenib demonstrated activity in a phase IIb study in combination with either capecitabine or gemcitabine, although at the cost of a high rate of palmar-plantar erythema (45% grade 3) [54]. In the light of their modest activity but considerable toxicity, it is unlikely that anti-angiogenic TKIs will play an important role in the treatment of MBC, regardless of subtype.…”

Treating Triple-Negative Breast Cancer: Where Are We?

“…Sunitinib failed to show benefit as a monotherapy or in combination with chemotherapy in HER2-negative MBC, 63,64 whereas sorafenib in combination with chemotherapy has shown a modest association with PFS improvement in phase II studies, although results of the phase III trial are currently awaited. [65][66][67][68] Growth Factor Signaling Pathway EGFR is another receptor frequently expressed in TNBC and associated with the BL2 subtype. The EGFR-targeting antibody cetuximab has been evaluated in otherwise unspecified TNBC, with a suggestion of either modest benefit 69,70 or improved response rate but not PFS or OS.…”