TY - JOUR
T1 - Neoadjuvant Trebananib plus Paclitaxel-based Chemotherapy for Stage II/III Breast Cancer in the Adaptively Randomized I-SPY2 Trial-Efficacy and Biomarker Discovery
AU - Albain, Kathy S.
AU - Yau, Christina
AU - Petricoin, Emanuel F.
AU - Wolf, Denise M.
AU - Lang, Julie E.
AU - Chien, A. Jo
AU - Haddad, Tufia
AU - Forero-Torres, Andres
AU - Wallace, Anne M.
AU - Kaplan, Henry
AU - Pusztai, Lajos
AU - Euhus, David
AU - Nanda, Rita
AU - Elias, Anthony D.
AU - Clark, Amy S.
AU - Godellas, Constantine
AU - Boughey, Judy C.
AU - Isaacs, Claudine
AU - Tripathy, Debu
AU - Lu, Janice
AU - Yung, Rachel L.
AU - Gallagher, Rosa I.
AU - Wulfkuhle, Julia D.
AU - Brown-Swigart, Lamorna
AU - Krings, Gregor
AU - Chen, Yunn Yi
AU - Potter, David A.
AU - Stringer-Reasor, Erica
AU - Blair, Sarah
AU - Asare, Smita M.
AU - Wilson, Amy
AU - Hirst, Gillian L.
AU - Singhrao, Ruby
AU - Buxton, Meredith
AU - Clennell, Julia L.
AU - Sanil, Ashish
AU - Berry, Scott
AU - Asare, Adam L.
AU - Matthews, Jeffrey B.
AU - DeMichele, Angela M.
AU - Hylton, Nola M.
AU - Melisko, Michelle
AU - Perlmutter, Jane
AU - Rugo, Hope S.
AU - Symmans, W. Fraser
AU - van't Veer, Laura J.
AU - Yee, Douglas
AU - Berry, Donald A.
AU - Esserman, Laura J.
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2024/2/15
Y1 - 2024/2/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85185226769&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-22-2256
DO - 10.1158/1078-0432.CCR-22-2256
M3 - Article
C2 - 38109213
AN - SCOPUS:85185226769
SN - 1078-0432
VL - 30
SP - 729
EP - 740
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -