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

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 LuRachel 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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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%), andMP2 (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.

Original languageEnglish
Pages (from-to)729-740
Number of pages12
JournalClinical Cancer Research
Volume30
Issue number4
DOIs
StatePublished - 15 Feb 2024
Externally publishedYes

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