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

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. yeexx006@umn.edu.
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.

PMID: 34611148
PMCID: PMC8492731
DOI: 10.1038/s41523-021-00337-2

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

Douglas Yee et al. NPJ Breast Cancer. 2021.

. 2021 Oct 5;7(1):131.

doi: 10.1038/s41523-021-00337-2.

Authors

Affiliations

¹ Masonic Cancer Center, University of Minnesota, 420 Delaware St., SE, MMC 480, Minneapolis, MN, 55455, USA. yeexx006@umn.edu.
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.

PMID: 34611148
PMCID: PMC8492731
DOI: 10.1038/s41523-021-00337-2

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.

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Conflict of interest statement

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 Nanosciences, 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.

Figures

**Fig. 1**
CONSORT diagram for paclitaxel, ganitumab, metformin arm in I-SPY2.

**Fig. 2. Changes in HbA1c at baseline and subsequent levels measured while on PGM therapy for patients with more than one measurement.**
(a) all patients (n = 72); (b) those with normal baseline HbA1c (n = 52); (c) elevated baseline HbA1c (n = 20).

**Fig. 3. Candidate expression biomarkers in the IGF-1R pathway.**
a Heatmap of biomarkers evaluated. Patients are along columns and biomarkers are along the rows. Red indicates higher expression and blue lower. Annotation tracks reflects response (purple: pCR), HR status (black: HR+), MP 1/2 class (gray: MP2), and arm (dark blue: ganitumab). b Scatter plot showing IGF-1-ligand score vs IGFR Signature, (c) boxplots showing IGFR Signature levels in pCR vs. non-pCR patients in each arm (center line is group median; upper and lower limits of the box correspond to the 1st and 3rd quartile with whiskers extending to 1.5 times the interquartile range from top/bottom of the box); d–e pCR rate in (d) the MP1 vs. MP2 class and (e) IGFR-Signature groups by arm.

See this image and copyright information in PMC

References

1. Sachdev D, Yee D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol. Cancer Ther. 2007;6:1–12. doi: 10.1158/1535-7163.MCT-06-0080. - DOI - PubMed
1. Ekyalongo RC, Yee D. Revisiting the IGF-1R as a breast cancer target. npj Precis. Oncol. 2017;1:14. doi: 10.1038/s41698-017-0017-y. - DOI - PMC - PubMed
1. Gradishar WJ, et al. Clinical and translational results of a phase II, randomized trial of an anti-IGF-1R (Cixutumumab) in women with breast cancer that progressed on endocrine therapy. Clin. Cancer Res. 2016;22:301–309. doi: 10.1158/1078-0432.CCR-15-0588. - DOI - PMC - PubMed
1. Yee D. A tale of two receptors: insulin and insulin-like growth factor signaling in cancer. Clin. Cancer Res. 2015;21:667–669. doi: 10.1158/1078-0432.CCR-14-2056. - DOI - PMC - PubMed
1. Ulanet DB, Ludwig DL, Kahn CR, Hanahan D. Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy. Proc. Natl Acad. Sci. 2010;107:10791–10798. doi: 10.1073/pnas.0914076107. - DOI - PMC - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Research Materials

Miscellaneous