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

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

doi:10.1038/s41523-021-00337-2

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

NPJ Breast Cancer. 2021 Oct 5;7(1):131. doi: 10.1038/s41523-021-00337-2.

Authors

Douglas Yee¹, Claudine Isaacs², Denise M Wolf³, Christina Yau³, Paul Haluska⁴, Karthik V Giridhar⁵, Andres Forero-Torres⁶, A Jo Chien⁷, Anne M Wallace⁸, Lajos Pusztai⁹, Kathy S Albain¹⁰, Erin D Ellis¹¹, Heather Beckwith¹², Barbara B Haley¹³, Anthony D Elias¹⁴, Judy C Boughey⁵, Kathleen Kemmer¹⁵, Rachel L Yung¹⁶, Paula R Pohlmann², Debu Tripathy¹⁷, Amy S Clark¹⁸, Hyo S Han¹⁹, Rita Nanda²⁰, Qamar J Khan²¹, Kristen K Edmiston²², Emanuel F Petricoin²³, Erica Stringer-Reasor²⁴, Carla I Falkson²⁵, Melanie Majure²⁶, Rita A Mukhtar²⁶, Teresa L Helsten²⁷, Stacy L Moulder¹⁷, Patricia A Robinson¹⁰, Julia D Wulfkuhle²³, Lamorna Brown-Swigart³, Meredith Buxton²⁸, Julia L Clennell²⁹, Melissa Paoloni³⁰, Ashish Sanil³¹, Scott Berry³¹, Smita M Asare³², Amy Wilson³², Gillian L Hirst²⁶, Ruby Singhrao²⁶, Adam L Asare³², Jeffrey B Matthews²⁶, Nola M Hylton²⁶, Angela DeMichele¹⁸, Michelle Melisko²⁶, Jane Perlmutter²⁶, Hope S Rugo²⁶, W Fraser Symmans¹⁷, Laura J Van't Veer³, Donald A Berry³², Laura J Esserman²⁶

Affiliations

¹ Masonic Cancer Center, University of Minnesota, 420 Delaware St., SE, MMC 480, Minneapolis, MN, 55455, USA. [email protected].
² Georgetown University, 3800 Reservoir Rd, NW, Washington, DC, 20007, USA.
³ University of California San Francisco Department of Laboratory Medicine, 2340 Sutter Street, S433, San Francisco, CA, 94115, USA.
⁴ Mayo Clinic Rochester c/o Merck Corporation, 126 E. Lincoln Ave Rahway, New Jersey, 07065, USA.
⁵ Mayo Clinic Division of Medical Oncology, 200 1st St SW, Rochester, MN, 55905, USA.
⁶ University of Alabama at Birmingham c/o Seattle Genetics, 21823 30th Drive S.E., Bothell, WA, 98021, USA.
⁷ University of California San Francisco Division of Hematology-Oncology, 550 16th Street, San Francisco, CA, 94158, USA.
⁸ University of California San Diego Department of Surgery, 3855 Health Sciences Dr, M/C 0698, La Jolla, CA, 92093, USA.
⁹ Yale University Medical Onciology, 111 Goose Lane, Fl 2, Guilford, CT, 06437, USA.
¹⁰ Loyola University Chicago Stritch School of Medicine Cardinal Bernardin Cancer Center, 2160 South First Ave, Maywood, IL, 60153, USA.
¹¹ Swedish Cancer Institute Medical Oncology, 1221 Madison Street, Seattle, WA, 98104, USA.
¹² Masonic Cancer Center, University of Minnesota, 420 Delaware St., SE, MMC 480, Minneapolis, MN, 55455, USA.
¹³ UT Southwestern Medical Center Division of Hematology-Oncology, 5323 Harry Hines Blvd, Bldg E6.222D, Dallas, TX, 75390-9155, USA.
¹⁴ University of Colorado Anschutz Medical Center Division of Medical Oncology, 1665 Aurora Ct., Rm. 3200, MS F700, Aurora, CO, 80045, USA.
¹⁵ OHSU Knight Cancer Institute South Waterfront Center for Health and Healing, 3303 SW Bond Ave Building 1, Suite 7, Portland, OR, 97239, USA.
¹⁶ University of Washington Seattle Cancer Care Alliance, 825 Eastlake Ave East, Seattle, WA, 98109-1023, USA.
¹⁷ MD Anderson Cancer Center, 1515 Holcombe, Houston, Texas, 77030, USA.
¹⁸ University of Pennsylvania Division of Hematology-Oncology 3 Perelman Center, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA.
¹⁹ Moffit Cancer Center, 2902 USF Magnolia Drive, Tampa, FL, 33612, USA.
²⁰ University of Chicago Section of Hematology/Oncology, 5841S. Maryland Avenue, MC 2115, Chicago, IL, 60437, USA.
²¹ University of Kansas Division of Oncology, 2330 Shawnee Mission Pkwy, Ste 210, Westwood, KS, 66205, USA.
²² Inova Medical Group, 3580 Joseph Siewick Dr 101, Fairfax, VA, 22033-1764, USA.
²³ George Mason University Institute for Advanced Biomedical Research, 10920 George Mason Circle Room 2008, MS1A9, Manassas, Virginia, 20110, USA.
²⁴ University of Alabama at Birmingham Hematology/Oncology, 1802 Sixth Avenue South 2510, Birmingham, AL, 35294-3300, USA.
²⁵ Wilmot Cancer Institute Pluta Cancer Center, 125 Red Creek Drive, Rochester, NY, 14623, USA.
²⁶ University of California San Francisco, 550 16th Street, 6464, San Francisco, CA, 94158, USA.
²⁷ University of California San Diego Division of Hematology-Oncology, 9400 Campus Point Dr, La Jolla, CA, 92037, USA.
²⁸ University of California San Francisco c/o Global Coalition for Adaptive Research, 1661 Massachusetts Ave, Lexington, MA, 02420, USA.
²⁹ University of California San Francisco c/o IQVIA, 135 Main St 21 floor, San Francisco, CA, 94105, USA.
³⁰ Point Eden Way, Hayward, CA, 94545, USA.
³¹ Berry Consultants, LLC 3345 Bee Cave Rd Suite 201, Austin, TX, 78746, USA.
³² Quantum Leap Healthcare Collaborative, 3450 California St, San Francisco, CA, 94143, USA.

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.

Abstract

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