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Supplementary Figure S1 from Neoadjuvant Trebananib plus Paclitaxel-based Chemotherapy for Stage II/III Breast Cancer in the Adaptively Randomized I-SPY2 Trial—Efficacy and Biomarker Discovery

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posted on 2024-02-16, 08:40 authored by Kathy S. Albain, Christina Yau, Emanuel F. Petricoin, Denise M. Wolf, Julie E. Lang, A. Jo Chien, Tufia Haddad, Andres Forero-Torres, Anne M. Wallace, Henry Kaplan, Lajos Pusztai, David Euhus, Rita Nanda, Anthony D. Elias, Amy S. Clark, Constantine Godellas, Judy C. Boughey, Claudine Isaacs, Debu Tripathy, Janice Lu, Rachel L. Yung, Rosa I. Gallagher, Julia D. Wulfkuhle, Lamorna Brown-Swigart, Gregor Krings, Yunn Yi Chen, David A. Potter, Erica Stringer-Reasor, Sarah Blair, Smita M. Asare, Amy Wilson, Gillian L. Hirst, Ruby Singhrao, Meredith Buxton, Julia L. Clennell, Ashish Sanil, Scott Berry, Adam L. Asare, Jeffrey B. Matthews, Angela M. DeMichele, Nola M. Hylton, Michelle Melisko, Jane Perlmutter, Hope S. Rugo, W. Fraser Symmans, Laura J. van't Veer, Douglas Yee, Donald A. Berry, Laura J. Esserman

Kaplan-Meier survival plot of pCR vs. non-pCR in both trebananib and control arms

Funding

Quantum Leap Healthcare Collaborative

William K Bowes Foundation

Safeway Foundation

Gateway for Cancer Research (GCR)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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ARTICLE ABSTRACT

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. 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. 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. 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.

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