TY - JOUR
T1 - Impact of Anti-HER2 Treatments Combined With Atezolizumab on the Tumor Immune Microenvironment in Early or Metastatic Breast Cancer
T2 - Results From a Phase Ib Study
AU - Hamilton, Erika P.
AU - Kaklamani, Virginia
AU - Falkson, Carla
AU - Vidal, Gregory A.
AU - Ward, Patrick J.
AU - Patre, Monika
AU - Chui, Stephen Y.
AU - Rotmensch, Jacob
AU - Gupta, Kushagra
AU - Molinero, Luciana
AU - Li, Yijin
AU - Emens, Leisha A.
N1 - Funding Information:
All authors have received grants and nonfinancial support from F. Hoffmann-La Roche during the conduct of the study. E.P.H. reports research funding to her institution from AbbVie, Acerta Pharma, Amgen, Aravive, ArQule, Arvinas, AstraZeneca, Black Diamond Therapeutics, Boehringer Ingelheim, Clovis Oncology, Compugen, Curis, CytomX, Daiichi Sankyo, Dana-Farber Cancer Hospital, Deciphera Pharmaceuticals, eFFECTOR Therapeutics, EMD Serono, Fochon Pharmaceuticals, Fujifilm, G1 Therapeutics, Genentech/Roche, H3 Biomedicine, Harpoon Therapeutics, Hutchison MediPharma, ImmunoGen, Immunomedics, Infinity Pharmaceuticals, InventisBio, Karyopharm, Leap Therapeutics, Lilly, Lycera, MacroGenics, MedImmune, Medivation, Merck, Mersana Therapeutics, Merus, Millennium Pharmaceuticals, Molecular Templates, Novartis, NuCana, Olema Oncology, OncoMed Pharmaceuticals, Onconova Therapeutics, Oncothyreon, Fosun Orinove PharmaTech, Pfizer, PharmaMar, Plexxikon, Polyphor, Puma Biotechnology, Radius Health, Regeneron Pharmaceuticals, Rgenix, Seattle Genetics, Sermonix Pharmaceuticals, Silverback Therapeutics, Stemcentrx, Sutro Biopharma, Syndax, Syros Pharmaceuticals, Taiho, Takeda, TapImmune, Tesaro, Torque Pharma, Verastem Oncology, Zenith Epigenetics, and Zymeworks; has acted in an advisory or consultancy role with fees paid to her institution from AstraZeneca, Black Diamond Therapeutics, Boehringer Ingelheim, CytomX, Daiichi Sankyo, Dantari, Genentech/Roche, H3 Biomedicine, Lilly, Merck, Mersana Therapeutics, Novartis, Pfizer, Puma Biotechnology, and Silverback Therapeutics; and has received travel support from AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, and Puma Biotechnology. V.K. reports research funding from Eisai; has acted in an advisory or consultancy role for Amgen, AstraZeneca, Athenex Oncology, Celldex Therapeutics, Daiichi Sankyo, Eisai, Puma Biotechnology, and Seattle Genomics; and has served on speakers bureaus for Celgene, Eisai, Genentech, Genomic Health, Novartis, Pfizer, and Puma Biotechnology. C.F. has acted in an advisory or consultancy role for Cardinal Health, EMD Serono, Lilly, Novartis, Pfizer, Genentech/Roche, and Seattle Genetics/Astellas. G.A.V. reports research funding from AstraZeneca, Bristol Myers Squibb, Celcuity, GTx Inc, Halozyme, Immunomedics, Lilly, Merck, Pfizer, Puma Biotechnology, Genentech/Roche, and Tesaro; has acted in an advisory or consultancy role for Immunomedics, Lilly, Pfizer, Puma Biotechnology, and Genentech/Roche; and has served on speakers bureaus for AstraZeneca, Lilly, Novartis, Pfizer, and Puma Biotechnology. P.J.W. has acted in an advisory or consultancy role with fees paid to her institution from Genentech/Roche. M.P. is an employee of and reports stock ownership in Roche. S.Y.C. is an employee of Genentech/Roche and reports stock ownership in Roche. J.R. is an employee of Genentech and reports stock ownership in Roche. K.G. is a contracted biostatistician for Genentech/Roche. L.M. is an employee of Genentech/Roche and reports stock ownership in Roche. Y.L. is an employee of Genentech/Roche and reports stock ownership in Roche. L.A.E. reports research funding from Aduro Biotech, AstraZeneca, Bristol Myers Squibb, Bolt Biotherapeutics, Breast Cancer Research Foundation, Corvus Pharmaceuticals, US Department of Defense, EMD Serono, Genentech, HeritX, MacroGenics, MaxCyte, Merck, NSABP Foundation, National Cancer Institute, Novartis, Roche, Silverback Therapeutics, and Tempest Therapeutics; has acted in an advisory or consultancy role for AbbVie, Amgen, AstraZeneca, Bayer, Celgene, Chugai, CytomX, Genentech, Gritstone Oncology, Lilly, MacroGenics, MedImmune, Peregrine Pharmaceuticals, Replimune, Roche, Shionogi, Syndax, and Vaccinex; has received travel support from Bristol Myers Squibb, Genentech/Roche, and Novartis; has received nonfinancial compensation from eTheRNA; and has received royalties or milestone payments from Aduro Biotech and MolecuVax.
Funding Information:
This study was supported by F. Hoffmann-La Roche Ltd. Medical writing support was funded by F. Hoffman-La Roche Ltd. The sponsor directed the study design; the collection, analysis and interpretation of data; the writing of the report; and the decisions to submit the article for publication.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021
Y1 - 2021
N2 - Background: Despite advances, there continues to be unmet need in breast cancer. Combining anti–programmed death-ligand 1 (PD-L1) cancer immunotherapy atezolizumab with other targeted therapies may enhance T-cell–dependent cytolytic antitumor activity. Methods: This open-label, phase Ib study evaluated the safety of atezolizumab-based combinations with antibody-dependent cellular cytotoxicity or antibody-drug conjugate (ADC) agents. Patients with unresectable human epidermal growth factor receptor 2–positive (HER2+) locally advanced or metastatic breast cancer (mBC) received atezolizumab with trastuzumab/pertuzumab, atezolizumab with the ADC ado-trastuzumab emtansine (T-DM1), or atezolizumab with trastuzumab/pertuzumab and docetaxel. In an early–breast cancer (eBC) “window of opportunity” study, patients with operable HER2+ locally advanced or inflammatory eBC received neoadjuvant atezolizumab with trastuzumab/pertuzumab or atezolizumab/T-DM1, followed by docetaxel, carboplatin, and trastuzumab/pertuzumab. Exploratory outcomes included tumor response and biomarkers. Results: By March 15, 2019, 73 patients were enrolled. Safety findings were consistent with the treatment components’ individual profiles. Objective responses were observed in 2 of 6 and 5 of 14 patients in 2 mBC cohorts receiving atezolizumab/T-DM1 and in 6 of 6 patients with mBC receiving atezolizumab, trastuzumab/pertuzumab, and docetaxel. PD-L1 in immune cells was the only biomarker that increased with atezolizumab/T-DM1. In the window of opportunity cohorts, PD-L1 levels and CD8+ T-cell infiltration increased from baseline in HER2+ eBC tumors receiving atezolizumab with trastuzumab/pertuzumab or T-DM1, irrespective of response. Despite increases in T-cell and B-cell gene signatures with trastuzumab/pertuzumab, but not T-DM1, neither combination promoted T-cell receptor clonal expansion. Conclusion: Atezolizumab with antibody-dependent cellular cytotoxicity or ADC agents appears safe and may activate the adaptive immune system of patients with HER2+ eBC tumors more than those with mBC tumors.
AB - Background: Despite advances, there continues to be unmet need in breast cancer. Combining anti–programmed death-ligand 1 (PD-L1) cancer immunotherapy atezolizumab with other targeted therapies may enhance T-cell–dependent cytolytic antitumor activity. Methods: This open-label, phase Ib study evaluated the safety of atezolizumab-based combinations with antibody-dependent cellular cytotoxicity or antibody-drug conjugate (ADC) agents. Patients with unresectable human epidermal growth factor receptor 2–positive (HER2+) locally advanced or metastatic breast cancer (mBC) received atezolizumab with trastuzumab/pertuzumab, atezolizumab with the ADC ado-trastuzumab emtansine (T-DM1), or atezolizumab with trastuzumab/pertuzumab and docetaxel. In an early–breast cancer (eBC) “window of opportunity” study, patients with operable HER2+ locally advanced or inflammatory eBC received neoadjuvant atezolizumab with trastuzumab/pertuzumab or atezolizumab/T-DM1, followed by docetaxel, carboplatin, and trastuzumab/pertuzumab. Exploratory outcomes included tumor response and biomarkers. Results: By March 15, 2019, 73 patients were enrolled. Safety findings were consistent with the treatment components’ individual profiles. Objective responses were observed in 2 of 6 and 5 of 14 patients in 2 mBC cohorts receiving atezolizumab/T-DM1 and in 6 of 6 patients with mBC receiving atezolizumab, trastuzumab/pertuzumab, and docetaxel. PD-L1 in immune cells was the only biomarker that increased with atezolizumab/T-DM1. In the window of opportunity cohorts, PD-L1 levels and CD8+ T-cell infiltration increased from baseline in HER2+ eBC tumors receiving atezolizumab with trastuzumab/pertuzumab or T-DM1, irrespective of response. Despite increases in T-cell and B-cell gene signatures with trastuzumab/pertuzumab, but not T-DM1, neither combination promoted T-cell receptor clonal expansion. Conclusion: Atezolizumab with antibody-dependent cellular cytotoxicity or ADC agents appears safe and may activate the adaptive immune system of patients with HER2+ eBC tumors more than those with mBC tumors.
KW - Immunotherapy
KW - Pertuzumab
KW - T-DM1
KW - Trastuzumab
KW - Trastuzumab emtansine
UR - http://www.scopus.com/inward/record.url?scp=85108280696&partnerID=8YFLogxK
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U2 - 10.1016/j.clbc.2021.04.011
DO - 10.1016/j.clbc.2021.04.011
M3 - Article
AN - SCOPUS:85108280696
JO - Clinical Breast Cancer
JF - Clinical Breast Cancer
SN - 1526-8209
ER -