Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer.

Abstract

I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY's prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers.

• Authors: Douglas Yee, Claudine Isaacs, Denise M Wolf, Christina Yau, Paul Haluska, Karthik V Giridhar, Andres Forero-Torres, A Jo Chien, Anne M Wallace, Lajos Pusztai, Kathy S Albain, Erin D Ellis, Heather Beckwith, Barbara B Haley, Anthony D Elias, Judy C Boughey, Kathleen Kemmer, Rachel L Yung, Paula R Pohlmann, Debu Tripathy, Amy S Clark, Hyo S Han, Rita Nanda, Qamar J Khan, Kristen K Edmiston, Emanuel F Petricoin, Erica Stringer-Reasor, Carla I Falkson, Melanie Majure, Rita A Mukhtar, Teresa L Helsten, Stacy L Moulder, Patricia A Robinson, Julia D Wulfkuhle, Lamorna Brown-Swigart, Meredith Buxton, Julia L Clennell, Melissa Paoloni, Ashish Sanil, Scott Berry, Smita M Asare, Amy Wilson, Gillian L Hirst, Ruby Singhrao, Adam L Asare, Jeffrey B Matthews, Nola M Hylton, Angela DeMichele, Michelle Melisko, Jane Perlmutter, Hope S Rugo, W Fraser Symmans, Laura J Van't Veer, Donald A Berry, Laura J Esserman
• Journal: NPJ breast cancer (NPJ Breast Cancer) Vol. 7 Issue 1 Pg. 131 (Oct 05 2021) ISSN: 2374-4677 [Print] United States
• PMID: 34611148 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).