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.
| Original language | English (US) |
|---|---|
| Article number | 131 |
| Journal | npj Breast Cancer |
| Volume | 7 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2021 |
| Externally published | Yes |
ASJC Scopus subject areas
- Oncology
- Radiology Nuclear Medicine and imaging
- Pharmacology (medical)
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In: npj Breast Cancer, Vol. 7, No. 1, 131, 12.2021.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer
AU - Yee, Douglas
AU - Isaacs, Claudine
AU - Wolf, Denise M.
AU - Yau, Christina
AU - Haluska, Paul
AU - Giridhar, Karthik V.
AU - Forero-Torres, Andres
AU - Jo Chien, A.
AU - Wallace, Anne M.
AU - Pusztai, Lajos
AU - Albain, Kathy S.
AU - Ellis, Erin D.
AU - Beckwith, Heather
AU - Haley, Barbara B.
AU - Elias, Anthony D.
AU - Boughey, Judy C.
AU - Kemmer, Kathleen
AU - Yung, Rachel L.
AU - Pohlmann, Paula R.
AU - Tripathy, Debu
AU - Clark, Amy S.
AU - Han, Hyo S.
AU - Nanda, Rita
AU - Khan, Qamar J.
AU - Edmiston, Kristen K.
AU - Petricoin, Emanuel F.
AU - Stringer-Reasor, Erica
AU - Falkson, Carla I.
AU - Majure, Melanie
AU - Mukhtar, Rita A.
AU - Helsten, Teresa L.
AU - Moulder, Stacy L.
AU - Robinson, Patricia A.
AU - Wulfkuhle, Julia D.
AU - Brown-Swigart, Lamorna
AU - Buxton, Meredith
AU - Clennell, Julia L.
AU - Paoloni, Melissa
AU - Sanil, Ashish
AU - Berry, Scott
AU - Asare, Smita M.
AU - Wilson, Amy
AU - Hirst, Gillian L.
AU - Singhrao, Ruby
AU - Asare, Adam L.
AU - Matthews, Jeffrey B.
AU - Hylton, Nola M.
AU - DeMichele, Angela
AU - Melisko, Michelle
AU - Perlmutter, Jane
AU - Rugo, Hope S.
AU - Fraser Symmans, W.
AU - van‘t Veer, Laura J.
AU - Berry, Donald A.
AU - Esserman, Laura J.
N1 - Funding Information: The authors wish to acknowledge the generous support of the study sponsors, Quantum Leap Healthcare Collaborative (2013 to present) and the Foundation for the National Institutes of Health (2010 to 2012), a grant from the Gateway for Cancer Research (G-16-900), and by a grant (28XS197) from the National Cancer Institute Center for Biomedical Informatics and Information Technology. The authors sincerely appreciate the ongoing support for the I-SPY2 TRIAL from the Safeway Foundation, the William K. Bowes, Jr. Foundation and Give Breast Cancer the Boot. Initial support was provided by Quintiles Transnational Corporation, Johnson & Johnson, Genentech, Amgen, the San Francisco Foundation, Eli Lilly, Pfizer, Eisai Co., Ltd., Side Out Foundation, Harlan Family, the Avon Foundation for Women, Alexandria Real Estate Equities, and private individuals and family foundations. We thank Anna Barker for leadership in helping to launch the I-SPY2 trial, the members of the data and safety monitoring committee, the trial coordinators, Ken Buetow and the staff of caBIG for input with the informatics design, the entire project oversight committee and the many investigators who have contributed. We are grateful for the input of our wonderful patient advocates: Susie Brain, Thelma Brown, Elly Cohen, Deborah Collyar, Coleen Crespo, Amy Delson, Peggy Devine, Sandra Finestone, Elizabeth Frank, Diane Heditsian, Patricia Haugen, Deborah Laxague, Marisa Leonardelli, Barbara LeStage, Beverly Parker, Susan Samson and Patty Spears. Thank you to all the patients who volunteered to participate in I-SPY2. Funding Information: Doug Yee has received unrelated research support from Boehringer Ingleheim. Claudine Isaacs has received consulting fees from Seattle Genetics, Genentech, AstraZeneca, Novartis, PUMA, Pfizer, and Esai. Christina Yau has consulted for NantOmics, LLC, part of the NantWorks network. Paul Haluska was employed at BMS after the work was conducted on this paper and currently holds stock options. A. Jo Chein reports institutional research support from Seagen, Merck, Amgen and Puma Biotechnology. Lajos Pusztai has received consulting fees and honoraria from Seattle Genetics, Pfizer, Astra Zeneca, Merck, Novartis, Bristol-Myers Squibb, Pfizer, Genentech, Eisai, Pieris, Immunomedics, Clovis, Syndax, H3Bio, Radius Health, and Daiichi, institutional research support from Seattle Genetics, AstraZeneca, Merck, Pfizer and Bristol Myers Squibb. Barbara Haley reports institutional support from Pfizer, Lilly, Daiichi Sankyo, Roche, Puma, Astra Zeneca and Sanofi. Judy C. Boughey has received support from Eli Lilly. Debu Tripathy has received support from Novartis, Pfizer, AstraZeneca, GSK and Immunomedics. Amy S. Clark has received unrelated research support from Novartis. Hyo S. Han reports institutional support from GlaxoSmithKline, Abbvie, Prescient, G1 therapeutics, Marker Therapeutics, Novartis, Horizon Pharma, Pfizer, Seattle Genetics, Arvinas and Zymeworks, and is part of Lilly’s speaker’s bureau. E.F. Petricoin reports: leadership roles with: Perthera and Ceres Nanosciences; stock or other ownership interests in Perthera, Ceres Nanosciences and Avant Diagnostics; consulting or advisory roles with Perthera, Ceres Nanos-ciences, AZGen, Avant Diagnostics; institutional research support from Ceres Nanosciences, GlaxoSmithKline), Abbvie, Symphogen, and Genentech; patents, royalties, other intellectual property from National Institutes of Health patents licensing fee distribution/royalty, co-inventor on filed George Mason University–assigned patents related to phosphorylated HER2 and EGFR response predictors for HER family-directed therapeutics, as such can receive royalties and licensing distribution on any licensed IP; travel, accommodations, expenses received from Perthera and Ceres Nanosciences. Erica Stringer-Reasor reports receiving research funds or consulting fees from Lilly, Immunomedics and Mylan. J.D. Wulfkuhle received honoraria from DAVA Oncology and consults for Baylor College of Medicine. Angela DeMichele has received honoraria or consulting fees from Pfizer and Context Therapeutics and reports institutional research support from Novartis, Pfizer, Genentech, Calithera and Menarini. Michelle Melisko has consulted for Biotheranostics and reports institutional research support from AstraZeneca, Novartis, KCRN Research and Puma Biotechnology. Hope Rugo reports institutional research support from Pfizer, Merck, Novartis, Lilly, Genentech, Odonate, Daiichi, Seattle Genetics, Eisai, Macrogenics, Sermonix, Boehringer Ingelheim, Polyphor, Astra Zeneca and Immunomedics, and has received honoraria from Puma Biotechnology, Mylan and Samsung. Laura J. van ‘t Veer is a part-time employee and stockholder in Agendia N.V. Laura Esserman is an unpaid member of the board of directors of Quantum Leap Healthcare Collaborative (QLHC) and received grant support from QLHC for the I-SPY2 Trial; she is a member of the Blue Cross/Blue Shield Medical Advisory Panel and receives reimbursement for her time and travel; Dr. Esserman has received unrelated research support from Merck. The remaining authors declare no competing interests. Publisher Copyright: © 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85116387935&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85116387935&partnerID=8YFLogxK
U2 - 10.1038/s41523-021-00337-2
DO - 10.1038/s41523-021-00337-2
M3 - Article
C2 - 34611148
AN - SCOPUS:85116387935
SN - 2374-4677
VL - 7
JO - npj Breast Cancer
JF - npj Breast Cancer
IS - 1
M1 - 131
ER -