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Neoadjuvant Trebananib plus Paclitaxel-based Chemotherapy for Stage II/III Breast Cancer in the Adaptively Randomized
Kathy S Albain1, Christina Yau2, Emanuel F Petricoin3
1Loyola University Chicago Stritch School of Medicine, Maywood, Illinois.
Purpose:
The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial.
Patients And Methods:
I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy "graduates" if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction.
Results:
There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%-99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease.
Conclusions:
The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.
Insights
Trebananib, an angiopoietin/Tie2 inhibitor, showed high probabilities of increasing pathologic complete response rates in high-risk breast cancer when combined with standard neoadjuvant therapy. Biomarkers predicted response, suggesting potential for targeted use.
Area of Science:
- Oncology
- Pharmacology
- Biomedical Engineering
Background:
- The angiopoietin (Ang)/Tie2 signaling pathway plays a crucial role in angiogenesis and tumor proliferation.
- Trebananib is a peptibody designed to neutralize angiopoietins, thereby inhibiting this pathway.
- High-risk, early-stage breast cancer presents a significant clinical challenge, necessitating novel therapeutic strategies.
Purpose of the Study:
- To evaluate the efficacy of trebananib in combination with standard neoadjuvant chemotherapy for high-risk, early-stage breast cancer.
- To assess the ability of trebananib to improve pathologic complete response (pCR) rates within specific breast cancer subtypes.
- To identify predictive biomarkers for trebananib response.
Main Methods:
- The I-SPY2 trial adaptively randomized patients with high-risk, early-stage breast cancer.
- Patients received weekly paclitaxel (with trastuzumab if HER2-positive) +/- weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery.
- Pathologic complete response (pCR) was the primary endpoint, with therapies graduating to Phase III based on Bayesian probability of success.
Main Results:
- Trebananib did not meet the graduation criteria for any subtype but demonstrated high probabilities of superior pCR rates (92%-99%) over control.
- Event-free survival at 3 years was improved with trebananib (HR 0.67), with no significant increase in adverse events.
- Biomarkers including Tie2 receptor activation and a CD8 T-cell gene signature predicted response in specific subtypes.
Conclusions:
- The combination of trebananib with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes with high probabilities of superiority.
- Further investigation of Ang/Tie2 axis inhibitors is warranted in validated, biomarker-predicted sensitive subtypes.
- Trebananib shows promise as a targeted therapy for specific breast cancer populations.
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