A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer

Gradishar, William J.; Kaklamani, Virginia; Sahoo, Tapan Kumar; Dasappa, Lokanatha; Raina, Vinod; Bondarde, Shailesh Arjun; Jain, Minish; Ro, Sunhee Kwon; Lokker, Nathalie A.; Schwartzberg, Lee S.

doi:10.1016/j.ejca.2012.08.005

Cited by 78 publications

(47 citation statements)

References 23 publications

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“…Although bevacizumab is no longer indicated for MBC in the United States, it may remain part of the off-label treatment armamentarium and remains a treatment option in Europe. Second, the findings in this study are consistent with the SOLTI-0701 and NU07B1 TIES studies, which also showed activity when sorafenib was added to capecitabine and paclitaxel, respectively (19,20). The other TIES study, FM-B01-07, did not demonstrate a clinical benefit when sorafenib was added to docetaxel/ letrozole (21).…”

Section: Discussionsupporting

confidence: 80%

“…Three of these studies have been completed. SOLTI-0701 and NU07B1 assessed the treatment effect of sorafenib when added to capecitabine and paclitaxel, respectively, in patients not previously treated with VEGF inhibitors (19,20). A separate TIES trial, investigating sorafenib in combination with docetaxel and/ or letrozole in specific subpopulations without prior VEGFtargeted treatment, reported primary analysis of PFS and is ongoing (21).…”

Section: Introductionmentioning

confidence: 99%

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

Schwartzberg

Tauer

Hermann

et al. 2013

Clinical Cancer Research

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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.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

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

Schwartzberg

Tauer

Hermann

et al. 2013

Clinical Cancer Research

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“…During clinical studies, the percentage of patients requiring a dose reduction of these molecularly targeted drugs is relatively high (44,45), and the outcome of treatment with these drugs has not been satisfactory, even when they have been used in combination with other anticancer agents (46)(47)(48)(49). The requirement for a washout period and/or dose reduction when using presently available VEGFR inhibitors may result in tumor regrowth and drug resistance (50).…”

Section: Discussionmentioning

confidence: 99%

The Novel VEGF Receptor/MET–Targeted Kinase Inhibitor TAS-115 Has MarkedIn VivoAntitumor Properties and a Favorable Tolerability Profile

Fujita

Miyadera

Kato

et al. 2013

Molecular Cancer Therapeutics

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VEGF receptor (VEGFR) signaling plays a key role in tumor angiogenesis. Although some VEGFR signaltargeted drugs have been approved for clinical use, their utility is limited by associated toxicities or resistance to such therapy. To overcome these limitations, we developed TAS-115, a novel VEGFR and hepatocyte growth factor receptor (MET)-targeted kinase inhibitor with an improved safety profile. TAS-115 inhibited the kinase activity of both VEGFR2 and MET and their signal-dependent cell growth as strongly as other known VEGFR or MET inhibitors. On the other hand, kinase selectivity of TAS-115 was more specific than that of sunitinib and TAS-115 produced relatively weak inhibition of growth (GI 50 > 10 mmol/L) in VEGFR signal-or MET signalindependent cells. Furthermore, TAS-115 induced less damage in various normal cells than did other VEGFR inhibitors. These data suggest that TAS-115 is extremely selective and specific, at least in vitro. In in vivo studies, TAS-115 completely suppressed the progression of MET-inactivated tumor by blocking angiogenesis without toxicity when given every day for 6 weeks, even at a serum-saturating dose of TAS-115. The marked selectivity of TAS-115 for kinases and targeted cells was associated with improved tolerability and contributed to the ability to sustain treatment without dose reduction or a washout period. Furthermore, TAS-115 induced marked tumor shrinkage and prolonged survival in MET-amplified human cancer-bearing mice. These data suggest that TAS-115 is a unique VEGFR/MET-targeted inhibitor with improved antitumor efficacy and decreased toxicity. Mol Cancer Ther; 12(12); 2685-96. Ó2013 AACR.

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“…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.…”

Section: Parp Inhibitionmentioning

confidence: 99%

Treating Triple-Negative Breast Cancer: Where Are We?

Morikawa

Seidman

2015

J Natl Compr Canc Netw

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Unlike estrogen receptor (ER)-positive and HER2-positive breast cancer, triple-negative breast cancer (TNBC) lacks a repertoire of targeted therapies. Hence, chemotherapy is the only available systemic option in current clinical practice. In general, survival of patients with TNBC is worse than that for those with ER-positive and HER2-positive breast cancer, especially for advanced-stage disease. Thus, a great unmet need exists. Conventional chemotherapeutic agents such as platinumsalts have been examined for specific benefit in TNBC; however, no one agent has yet been shown to offer a differential incremental benefit in metastatic TNBC. The hope is that ongoing research in targetable molecular pathways will lead to new therapeutic options for TNBC. Because these patients are likely to be increasingly subcategorized using potentially targetable molecular alterations, investigators will need to be mindful of the challenges in designing and conducting clinical trials in smaller subpopulations. The successful incorporation of targeted therapies in routine clinical practice for TNBC, which mirrors the success achieved by anti-HER2 and endocrine therapies, is awaited. (J Natl Compr Canc Netw 2015;13:(e8-e18) and rare types, such as adenoid cystic, metaplastic, apocrine, and neuroendocrine carcinoma.3 Nevertheless, the clinical utility of this categorization has been robust as a prognostic and predictive biomarker.Patients with TNBC are more likely to have a poor prognosis than those with estrogen receptor (ER)/ progesterone receptor (PR)-positive and/or HER2-positive breast cancer.4 This is likely partially attributable to a dearth of novel therapeutic options for TNBC, in contrast to the recent expansion of endocrine and anti-HER2 therapies (eg, ado-trastuzumab-emtansine, pertuzumab, everolimus with exemestane).5-7 Therefore, great interest has been shown in exploring potential biomarkers (prognostic and predictive) and developing new therapeutic options. This article reviews current treatment options ("where are we now?") and ongoing therapeutic research ("where are we going?") for TNBC. Heterogeneity of TNBCBecause the utilitarian definition of TNBC is simply based on the exclusion of ER/PR/HER2 expression, it is not unexpected that this clinical subtype remains biologically heterogeneous. Studies examining tumor characteristics have found correlations between TNBC and certain molecular genomic features, such as basal cytokeratin (eg, CK5/6) and epidermal growth factor receptor (EGFR) expression, checkpoint kinase (Chk1), p53 alterations, and BRCA1 germline mutations.8-13 TNBC has also been shown to have overlapping features with the basal-like subtype (intrinsic breast cancer classification), 14,15 including a high frequency of poorly differentiated tumors, expression of cytokeratins and EGFR, and p53 mutations. Although the basal-like-subtypes are most often triple-negative, they are not equivalent groups.16

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A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer

Cited by 78 publications

References 23 publications

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

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

The Novel VEGF Receptor/MET–Targeted Kinase Inhibitor TAS-115 Has MarkedIn VivoAntitumor Properties and a Favorable Tolerability Profile

Treating Triple-Negative Breast Cancer: Where Are We?

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