. 2021 Nov 5;12(1):6428.

doi: 10.1038/s41467-021-26019-y.

Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2⁺ breast cancer in the adaptively randomized I-SPY2 trial

Amy S Clark¹, Christina Yau², Denise M Wolf², Emanuel F Petricoin³, Laura J van 't Veer², Douglas Yee⁴, Stacy L Moulder⁵, Anne M Wallace⁶, A Jo Chien², Claudine Isaacs⁷, Judy C Boughey⁸, Kathy S Albain⁹, Kathleen Kemmer¹⁰, Barbara B Haley¹¹, Hyo S Han¹², Andres Forero-Torres¹³, Anthony Elias¹⁴, Julie E Lang¹⁵, Erin D Ellis¹⁶, Rachel Yung¹⁷, Debu Tripathy⁵, Rita Nanda¹⁸, Julia D Wulfkuhle⁵, Lamorna Brown-Swigart², Rosa I Gallagher⁵, Teresa Helsten⁶, Erin Roesch⁶, Cheryl A Ewing², Michael Alvarado², Erin P Crane⁷, Meredith Buxton¹⁹, Julia L Clennell¹⁹, Melissa Paoloni¹⁹, Smita M Asare², Amy Wilson², Gillian L Hirst², Ruby Singhrao², Katherine Steeg², Adam Asare², Jeffrey B Matthews², Scott Berry¹⁹, Ashish Sanil¹⁹, Michelle Melisko², Jane Perlmutter²⁰, Hope S Rugo², Richard B Schwab⁶, W Fraser Symmans⁵, Nola M Hylton², Donald A Berry¹⁹, Laura J Esserman², Angela M DeMichele²¹

Affiliations

¹ University of Pennsylvania, Philadelphia, PA, USA. Amy.Clark@pennmedicine.upenn.edu.
² University of California San Francisco, San Francisco, CA, USA.
³ George Mason University, Fairfax, VA, USA.
⁴ University of Minnesota, Minneapolis, MN, USA.
⁵ MD Anderson Cancer Center, Houston, TX, USA.
⁶ University of California San Diego, San Diego, CA, USA.
⁷ Georgetown University, Washington, DC, USA.
⁸ Mayo Clinic, Rochester, MN, USA.
⁹ Loyola University, Chicago, IL, USA.
¹⁰ Oregon Health & Science University, Portland, OR, USA.
¹¹ University of Texas Southwestern, Dallas, TX, USA.
¹² Moffitt Cancer Center, Tampa, FL, USA.
¹³ University of Alabama Birmingham, Birmingham, AL, USA.
¹⁴ University of Colorado Denver, Aurora, CO, USA.
¹⁵ University of Southern California, Los Angeles, CA, USA.
¹⁶ Swedish Cancer Institute, Seattle, WA, USA.
¹⁷ University of Washington, Seattle, WA, USA.
¹⁸ University of Chicago, Chicago, IL, USA.
¹⁹ Berry Consultants, LLC, Houston, TX, USA.
²⁰ Gemini Group, Ann Arbor, MI, USA.
²¹ University of Pennsylvania, Philadelphia, PA, USA.

PMID: 34741023
PMCID: PMC8571284
DOI: 10.1038/s41467-021-26019-y

Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2⁺ breast cancer in the adaptively randomized I-SPY2 trial

Amy S Clark et al. Nat Commun. 2021.

. 2021 Nov 5;12(1):6428.

doi: 10.1038/s41467-021-26019-y.

Authors

Affiliations

¹ University of Pennsylvania, Philadelphia, PA, USA. Amy.Clark@pennmedicine.upenn.edu.
² University of California San Francisco, San Francisco, CA, USA.
³ George Mason University, Fairfax, VA, USA.
⁴ University of Minnesota, Minneapolis, MN, USA.
⁵ MD Anderson Cancer Center, Houston, TX, USA.
⁶ University of California San Diego, San Diego, CA, USA.
⁷ Georgetown University, Washington, DC, USA.
⁸ Mayo Clinic, Rochester, MN, USA.
⁹ Loyola University, Chicago, IL, USA.
¹⁰ Oregon Health & Science University, Portland, OR, USA.
¹¹ University of Texas Southwestern, Dallas, TX, USA.
¹² Moffitt Cancer Center, Tampa, FL, USA.
¹³ University of Alabama Birmingham, Birmingham, AL, USA.
¹⁴ University of Colorado Denver, Aurora, CO, USA.
¹⁵ University of Southern California, Los Angeles, CA, USA.
¹⁶ Swedish Cancer Institute, Seattle, WA, USA.
¹⁷ University of Washington, Seattle, WA, USA.
¹⁸ University of Chicago, Chicago, IL, USA.
¹⁹ Berry Consultants, LLC, Houston, TX, USA.
²⁰ Gemini Group, Ann Arbor, MI, USA.
²¹ University of Pennsylvania, Philadelphia, PA, USA.

PMID: 34741023
PMCID: PMC8571284
DOI: 10.1038/s41467-021-26019-y

Abstract

HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2⁺ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms 'graduate' in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2⁺ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome.

PubMed Disclaimer

Conflict of interest statement

Amy S. Clark has received unrelated research support from Novartis. Christina Yau has consulted for NantOmics, LLC, part of the NantWorks network. 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. Laura J. van ‘t Veer is a part-time employee and stockholder in Agendia N.V. Doug Yee has received unrelated research support from Boehringer Ingleheim. StacyMoulder has been an employee of Eli Lilly since 2021. A. Jo Chein reports institutional research support from Seagen, Merck, Amgen and Puma Biotechnology. Claudine Isaacs has received consulting fees from Seattle Genetics, Genentech, AstraZeneca, Novartis, PUMA, Pfizer, and Esai. Judy C. Boughey has received support from Eli Lilly. Barbara Haley reports that UTSouthwestern Medical Center Dallas receives funding for her research as PI from Pfizer, Lilly, Daiichi Sankyo, Roche, Puma, Astra Zeneca and Sanofi. Hyo S. Han reports institutional research support from GlaxoSmithKline, Abbvie, Prescient, G1 therapeutics, Marker therapeutics, Novartis, Horizon Pharma, Pfizer, Seattle Genetics, Arvinas and Zymeworks; she has received a grant from the Department of Defence and is a member of Lilly’ Speaker’s Bureau. Andres Forero-Torres became a Seattle Genetics employee in 2018 and holds stock option from this employment. Julie Lang has previously received a research grant from ANGLE Parsortix and has received honoraria as part of the Genomic Health’s speakers’ bureau and a Puma Biotechnology advisory board. Debu Tripathy receives research support from Novartis, Pfizer, Polyphor and has been a paid consultant for services on steering committees or advisory boards for Novartis, Pfizer, AstraZeneca, GlaxoSmithKline, OncoPep, Gilead, Exact Sciences. Rita Nanda has received research support from Arvinas, AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Immunomedics/Gilead, Merck, OBI Pharm, Inc., Odonate Therapeutics, OncoSec, Pfizer, Taiho and SeaGen. J.D. Wulfkuhle received honoraria from DAVA Oncology and consults for Baylor College of Medicine. Melissa Paolini is an employee and stock holder in Arcus Biosciences. Donald Berry and Scott Berry are co-owners of Berry Consultants, LLC, a company that designs adaptive Bayesian clinical trials (including I-SPY 2) for pharmaceutical and medical device companies, NIH cooperative groups, patient advocacy groups, and international consortia. 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. W. Fraser Symmans is a co-founder with equity in Delphi Diagnostics that licensed intellectual property, is a co-inventor of an issued patent for the algorithm to calculate residual cancer burden that is freely available on the internet, holds publicly traded shares in IONIS Pharmaceuticals and Eiger Biopharmaceuticals, and is an unpaid scientific advisor to Roche for translational research related to the KAITLIN trial and unpaid steering committee member for the KATHERINE trial. 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. 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. All other authors declare no competing interests.

Figures

**Fig. 1. Consort diagram for the T-DM1/Pertuzumab, THP, and control populations.**
Consort diagram shows the number of patients screening, randomized, and receiving allocated therapy from the start of I-SPY2 to the close of the T-DM1/Pertuzumab and THP arms. I-SPY2 is modified intent-to-treat, where patients receiving their allocated therapy are considered evaluable for analysis.

**Fig. 2. Primary efficacy analysis.**
pCR probablility distribution curves of TDM1/P (red) vs TH (blue) and THP (orange) vs TH (blue). Arrows below x-axis indicate 95% probability interval derived from the I-SPY2 Bayesian time and covariate-adjusted logistic model described in the methods.

**Fig. 3. Associations between HER family mRNA-, protein- and phosphoprotein-based pathway activation and pCR.**
A Mosaic plot showing the proportion of patients who had pCR (purple) or did not have pCR (yellow) as a function of HER2 IHC level (1+, 2+, 3+; left to right), in the TDM1/P (top), THP (center), and control (bottom) rows. Barplots in B show these data by arm. Pink: IHC 1+; Light Blue: IHC 2+; Blue: IHC 3+. Panels C, D show response-association boxplots of a HER2 mRNA signature overall (C; n = 127) and by arm (D; n = 52 (TDM1/P), 44 (THP), and 31 (Ctr)) Yellow box is non-pCR, light blue box is pCR. Color of data points correspond to IHC level as in panel B. Panels E, F show response-association boxplots of HER2 total protein overall (E; n = 117) and by arm (F; n = 49 (TDM1/P), 43 (THP), and 25 (Ctr)). Yellow box is non-pCR, light blue box is pCR. Color of data points correspond to IHC level as in panel B. G Two-way scatter plot of phosphorylated HER2 (Y1248) (y-axis) and phosphorylated EGFR (Y1173) (x-axis) relative intensity (RI) values generated from the LCM-RPPA data in the pretreatment biopsy samples are shown along with pCR YES (green) and pCR NO (red) designations. For box plots, 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.

**Fig. 4. Associations between HR/luminal and proliferation biomarkers and pCR.**
A, B shows HR expression (ESR1 and PGR averaged) response-association boxplots in all patients (A; n = 127) and by arm (B; n = 52 (TDM1/P), 44 (THP), and 31 (Ctr)). For all box plots, yellow box indicates non-pCR, light blue indicates pCR. C Bar plot showing the prevalence of PAM50 subtypes (LumA: light blue; LumB: dark blue; HER2:red; Basal: magenta) in patients achieving pCR compared to non-responders in the population as a whole (left pair of bars, n=126) and by arm (right pairs, n = 51 (TDM1/P), 44 (THP), and 31 (Ctr) n = 51 (TDM1/P), 44 (THP), and 31 (Ctr)). D–F show response-association boxplots of proliferation biomarkers on the mRNA (D; n = 83), protein (E; n = 78) and phospho-protein (F; n = 78) levels in the HR⁺/HER2⁺ subset by arm. *Association is significant (LR p < 0.05) only for TDM1/P, broken rectangle. For box plots, 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.

**Fig. 5. A view to the future.**
Top graphic represents the current treatment paradigm: patients with HER2⁺ breast cancer as determined by IHC or FISH receive the same neoadjuvant chemotherapy and HER2-directed therapy. Bottom graphic illustrates how implementation of the RPPA assay and gene expression profiling following positive IHC or FISH will enable de-escalation or escalation of chemotherapy and HER2-directed therapy. Original illustration: A. Haymond.

See this image and copyright information in PMC

References

1. Cortazar P, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384:164–172. doi: 10.1016/S0140-6736(13)62422-8. - DOI - PubMed
1. Carey LA, et al. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J. Clin. Oncol. 2016;34:542–549. doi: 10.1200/JCO.2015.62.1268. - DOI - PMC - PubMed
1. Corrigan PA, Cicci TA, Auten JJ, Lowe DK. Ado-trastuzumab emtansine: a HER2-positive targeted antibody-drug conjugate. Ann. Pharmacother. 2014;48:1484–1493. doi: 10.1177/1060028014545354. - DOI - PubMed
1. Gagliato D, de M, Jardim DLF, Marchesi MSP, Hortobagyi GN. Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer. Oncotarget. 2016;7:64431–64446. doi: 10.18632/oncotarget.7043. - DOI - PMC - PubMed
1. Gwin WR, Spector NL. Pertuzumab protects the achilles’ heel of trastuzumab–emtansine. Clin. Cancer Res. 2014;20:278–280. doi: 10.1158/1078-0432.CCR-13-2626. - DOI - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information
Molecular Biology Databases
- NIAID Data Ecosystem - Find datasets on Infectious and Immune-mediated Diseases
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2⁺ breast cancer in the adaptively randomized I-SPY2 trial

Affiliations

Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2⁺ breast cancer in the adaptively randomized I-SPY2 trial

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials

Miscellaneous