Trebananib (AMG 386) plus weekly paclitaxel with or without bevacizumab as first-line therapy for HER2-negative locally recurrent or metastatic breast cancer: A phase 2 randomized study

Dièras, Véronique; Wildiers, Hans; Jassem, Jacek; Dirix, Luc; Guastalla, Jean‐Paul; Bono, Petri; Hurvitz, Sara A.; Gonçalvès, Anthony; Romieu, Gilles; Limentani, Steven; Jérusalem, Guy; Lakshmaiah, K C; Roché, Henri; Sánchez‐Rovira, Pedro; Pieńkowski, Tadeusz; Palmer, Miguel Ángel Seguí; Ai, Li; Sun, Yu‐Nien; Pickett, Cheryl A.; Slamon, Dennis J.

doi:10.1016/j.breast.2014.11.003

Cited by 44 publications

(42 citation statements)

References 26 publications

(37 reference statements)

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“…In breast cancer, trebananib has been evaluated in a phase II study with HER2-negative, locally recurrent and metastatic breast cancer. That study found no prolongation in progression-free survival with the addition of trebananib to a regimen of paclitaxel and bevacizumab [11]. While this initial study appears to be at odds with our analysis, the study’s patient sample consisted almost exclusively of patients with distant, metastatic disease, limiting the ability to extrapolate from this data.…”

Section: Discussionmentioning

confidence: 72%

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Angiopoietin pathway gene expression associated with poor breast cancer survival

Ramanathan

Olex

Dozmorov

et al. 2017

Breast Cancer Res Treat

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Purpose Angiogenesis is one of the hallmarks of cancer and is essential for cancer progression and metastasis. However, clinical trials with vascular endothelial growth factor (VEGF) pathway inhibitors have failed to show overall survival benefit in breast cancer. Targeted therapy against the angiopoietin pathway, a downstream angiogenesis cascade, could be effective in breast cancer. This study investigates the association of angiopoietin pathway gene expression with breast cancer survival using a “big data” approach employing RNA sequencing data from The Cancer Genome Atlas (TCGA). Methods A total of 888 patients with adequate gene expression, disease-free survival (DFS) and overall survival (OS) data were selected for analysis. DFS and OS were calculated for patients with high and low expression of angiopoietin and VEGF pathway genes using TCGA data. Gene-specific thresholds to dichotomize patients into high and low expression were determined and survival plots were generated. Results The TCGA cohort was representative of national breast cancer patients with respect to stage, pathology and survival. High Ang2 gene expression was associated with not only decreased DFS (p=0.05), but also decreased OS (p<0.05). High co-expression of Ang2 and its receptor Tie2 was associated with both decreased DFS and OS (p<0.05). There was strong correlation between angiopoietin and VEGF pathway genes. While high expression of VEGFA alone was not associated with survival, high co-expression with Ang2 was associated with decreased OS. Conclusions This study validates TCGA as a representative database providing genomic data and survival outcomes in breast cancer. Our TCGA data supports the angiopoietin pathway as a key mediator in the pathologic angiogenic switch in breast cancer.

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Section: Discussionmentioning

confidence: 72%

“…It has undergone early phase human clinical trials in several cancers, including metastatic breast cancer. However, it remains unclear whether inhibition of the angiopoietin pathway will affect survival outcomes in breast cancer [11-13]. …”

Section: Introductionmentioning

confidence: 99%

Angiopoietin pathway gene expression associated with poor breast cancer survival

Ramanathan

Olex

Dozmorov

et al. 2017

Breast Cancer Res Treat

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“…It prevents Ang1/2 binding to Tie-2 receptor, therefore inhibits the growth of tumor in mouse xenograft models and currently is in phase III of clinical trials in ovarian cancer treatment 49 . Moreover, AMG-386 is under current investigation in glioblastoma therapy combined with bevacizumab, however this study has not been completed yet 50 . There are some interesting results indicating that sVEGFR-3 poses soluble extracellular ligand-binding domain, able to trap VEGF-C and leads to its inactivation, what results in inhibition of lymphangiogenesis.…”

Section: The Anti-lymphangiogenic Therapiesmentioning

confidence: 99%

The dual role of tumor lymphatic vessels in dissemination of metastases and immune response development

et al. 2016

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Lymphatic vasculature plays a crucial role in the immune response, enabling transport of dendritic cells (DCs) and antigens (Ags) into the lymph nodes. Unfortunately, the lymphatic system has also a negative role in the progression of cancer diseases, by facilitating the metastatic spread of many carcinomas to the draining lymph nodes. The lymphatics can promote antitumor immune response as well as tumor tolerance. Here, we review the role of lymphatic endothelial cells (LECs) in tumor progression and immunity and mechanism of action in the newest anti-lymphatic therapies, including photodynamic therapy (PDT).

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“…As alluded to in the introduction, phase II evaluation of trebananib (AMG386, a bispecific peptibody against Ang2 and Ang1) in the advanced metastatic setting of HER2 − breast cancer showed no PFS benefit by adding trebananib to paclitaxel chemotherapy, with or without bevacizumab25. No Ang2 inhibitors have yet been evaluated in TNBC clinical trials in the neoadjuvant or adjuvant settings.…”

Section: Discussionmentioning

confidence: 99%

“…Within this class, trebananib (a bispecific peptibody against the Ang2 and Ang1 ligands) has failed two Phase III trials involving ovarian cancer24 and several Phase II trials including one that involved HER2 − mBC25. These setbacks have highlighted our incomplete understanding of how this complicated signaling pathway can be effectively targeted24.…”

mentioning

confidence: 99%

Aflibercept and Ang1 supplementation improve neoadjuvant or adjuvant chemotherapy in a preclinical model of resectable breast cancer

Páez-Ribes

et al. 2016

Sci Rep

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Phase III clinical trials evaluating bevacizumab (an antibody to the angiogenic ligand, VEGF-A) in breast cancer have found improved responses in the presurgical neoadjuvant setting but no benefits in the postsurgical adjuvant setting. The objective of this study was to evaluate alternative antiangiogenic therapies, which target multiple VEGF family members or differentially modulate the Angiopoietin/Tie2 pathway, in a mouse model of resectable triple-negative breast cancer (TNBC). Neoadjuvant therapy experiments involved treating established orthotopic xenografts of an aggressive metastatic variant of the MDA-MB-231 human TNBC cell line, LM2-4. Adjuvant therapies were given after primary tumor resections to treat postsurgical regrowths and distant metastases. Aflibercept (‘VEGF Trap’, which neutralizes VEGF-A, VEGF-B and PlGF) showed greater efficacy than nesvacumab (an anti-Ang2 antibody) as an add-on to neoadjuvant/adjuvant chemotherapy. Concurrent inhibition of Ang1 and Ang2 signaling (through an antagonistic anti-Tie2 antibody) was not more efficacious than selective Ang2 inhibition. In contrast, short-term perioperative BowAng1 (a recombinant Ang1 variant) improved the efficacy of adjuvant chemotherapy. In conclusion, concurrent VEGF pathway inhibition is more likely than Ang/Tie2 pathway inhibition (e.g., anti-Ang2, anti-Ang2/Ang1, anti-Tie2) to improve neoadjuvant/adjuvant chemotherapies for TNBC. Short-term perioperative Ang1 supplementation may also have therapeutic potential in conjunction with adjuvant chemotherapy for TNBC.

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Trebananib (AMG 386) plus weekly paclitaxel with or without bevacizumab as first-line therapy for HER2-negative locally recurrent or metastatic breast cancer: A phase 2 randomized study

Cited by 44 publications

References 26 publications

Angiopoietin pathway gene expression associated with poor breast cancer survival

Angiopoietin pathway gene expression associated with poor breast cancer survival

The dual role of tumor lymphatic vessels in dissemination of metastases and immune response development

Aflibercept and Ang1 supplementation improve neoadjuvant or adjuvant chemotherapy in a preclinical model of resectable breast cancer

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