Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial

Abstract

Background: An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine.

Methods: This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0-1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5·4 mg/kg or trastuzumab emtansine 3·6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03529110.

Findings: Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab deruxtecan (n=261) or trastuzumab emtansine (n=263). Median duration of study follow-up was 28·4 months (IQR 22·1-32·9) with trastuzumab deruxtecan and 26·5 months (14·5-31·3) with trastuzumab emtansine. Median progression-free survival by blinded independent central review was 28·8 months (95% CI 22·4-37·9) with trastuzumab deruxtecan and 6·8 months (5·6-8·2) with trastuzumab emtansine (hazard ratio [HR] 0·33 [95% CI 0·26-0·43]; nominal p<0·0001). Median overall survival was not reached (95% CI 40·5 months-not estimable), with 72 (28%) overall survival events, in the trastuzumab deruxtecan group and was not reached (34·0 months-not estimable), with 97 (37%) overall survival events, in the trastuzumab emtansine group (HR 0·64; 95% CI 0·47-0·87]; p=0·0037). The number of grade 3 or worse treatment-emergent adverse events was similar in patients who received trastuzumab deruxtecan versus trastuzumab emtansine (145 [56%] patients versus 135 [52%] patients). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 39 (15%) patients treated with trastuzumab deruxtecan and eight (3%) patients treated with trastuzumab emtansine, with no grade 4 or 5 events in either group.

Interpretation: Trastuzumab deruxtecan showed a significant improvement in overall survival versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming trastuzumab deruxtecan as the standard of care in the second-line setting. A manageable safety profile of trastuzumab deruxtecan was confirmed with longer treatment duration.

Funding: Daiichi Sankyo and AstraZeneca.

Conflict of interest statement

Declaration of interests SAH has received support for the present manuscript from Daiichi Sankyo and AstraZeneca; has received grants or contracts from Ambrx, Amgen, Arvinas, Bayer, Cytomx, Dantar, Dignitana, Genentech/Roche, G1-Therapeutics, Gilead, GSK, Immunomedics, Eli Lilly, Macrogenics, Novartis, OBI, Pharma, Orinove, Pfizer, Phoenix Molecular Designs, Pieris, PUMA, Radius, Samumed, Sanofi, Seattle Genetics/Seagen, and Zymeworks; has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Daiichi Sankyo and continuing medical education (CME) companies (PER, Clinical Care Options, Research to Practice, etc); has received support for attending meetings or travel from San Antonio Breast Cancer Symposium, American Society of Clinical Oncology, National Comprehensive Cancer Network, and CME companies (PER, Clinical Care Options, and Research to Practice); has participated as a data safety monitoring board member for the I-SPY trial (unpaid); and has served a leadership or fiduciary role in another board for TRIO-US (unpaid chief medical officer of site management organisation). W-PC has received payment or honoraria for lectures and presentations from Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Everest Medicine, Foundation Medicine, Kyowa Kirin, MSD, Novartis, Pfizer, Roche, and Sanofi; has received support for attending meetings from Amgen, AstraZeneca, Pfizer, and Roche; has participated in advisory boards for Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Everest Medicine, MSD, Novartis, and Roche; and has participated in a data safety monitoring board for AstraZeneca. S-AI has received grants or contracts from AstraZeneca, Eisai, Daewoong Pharm, Daiichi Sankyo, Pfizer, Roche, and Boryung Pharm; and has received consulting fees from AstraZeneca, Hanmi, Eisai, Lilly, MSD, Idience, Novartis, Pfizer, Roche, GSK, Daiichi Sankyo, and Bertis. WJ has received grants or contracts from AstraZeneca and Daiichi Sankyo; has received support for attending meetings or travel from AstraZeneca, Eisai, Lilly France, Pfizer, Roche, Chugai Pharma, GlaxoSmithKline, Novartis, Pierre Fabre, and Sanofi Aventis; and has participated on a data safety monitoring board or advisory board for AstraZeneca, Eisai, Lilly France, Pfizer, Roche, BMS, Daiichi Sankyo, Novartis, MSD, and Seagen. JWYC has received honoraria for manuscript writing from Daiichi Sankyo. BX has received payment or honoraria for lectures and presentations from AstraZeneca, Pfizer Inc, Roche, and Eisai. EH has received institutional support for the present manuscript from Daiichi Sankyo and AstraZeneca; has received institutional grants or contracts from AbbVie, Acerta Pharma, Accutar Biotechnology, ADC Therapeutics, AKESOBIO Australia, Amgen, Aravive, ArQule, Artios, Arvinas, AtlasMedx, Black Diamond, Bliss BioPharmaceuticals, Boehringer Ingelheim, Cascadian Therapeutics, Clovis, Compugen, Cullen-Florentine, Curis, CytomX, Dana Farber Cancer Institute, Dantari, Deciphera, Duality Biologics, eFFECTOR Therapeutics, Ellipses Pharma, Elucida Oncology, EMD Serono, Fochon, FujiFilm, G1 Therapeutics, H3 Biomedicine, Harpoon, Hutchinson MediPharma, Immunogen, Immunomedics, Incyte, Infinity Pharmaceuticals, InvestisBio, Jacobio, Karyopharm, Leap Therapeutics, Lilly, Lycera, Mabspace Biosciences, Macrogenics, MedImmune, Merck, Mersana, Merus, Millenium, Molecular Templates, Myriad Genetic Laboratories, Novartis, Nucana, Olema, OncoMed, Onconova Therapeutics, ORIC Pharmaceuticals, Orinove, Pfizer, PharmaMar, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Plexxikon, Radius Health, Regeneron, Relay Therapeutics, Repertoire Immune Medicine, Rgenix, Roche/Genentech, Seagen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback, StemCentRx, Sutro, Syndax, Syros, Taiho, TapImmune, Tesaro, Tolmar, Torque Therapeutics, Treadwell Therapeutics, Verastem, Vincerx Pharma, Zenith Epigenetics, and Zymeworks; and has received consulting fees paid to the institution from Arcus, Eisai, Greenwich Lifesciences, H3 Biomedicine, iTeos, Janssen, Loxo, Orum Therapeutics, Propella Therapeutics, Puma Biotechnology, Arvinas, Black Diamond, Boehringer Ingelheim, CytomX, Dantari, Deciphera, Lilly, Merck, Mersana, Novartis, Pfizer, Relay Therapeutics, Roche/Genentech, Seagen, and Silverback. SM received consulting fees, support for attending meetings or travel, and participated in an advisory board for Daiichi Sankyo. HI has received consulting fees from Daicihi Sankyo, Chugai, AstraZeneca, Sanofi, Lilly, MSD, Pfizer, and Novartis; and payment or honoraria from Daiichi Sankyo, Chugai, AstraZeneca, Lilly, MSD, and Pfizer. SAl has received institutional payment for advisory boards from Eli Lilly, Pfizer, MSD, AstraZeneca, Novartis, and Bayer; institutional grants from Roche and Sanofi; and received travel and accommodations from Pfizer, Roche, PharmaMar, Novartis, AstraZeneca, Bayer, and Gilead. J-WH has received support for the present manuscript from AstraZeneca and Daiichi Sankyo; has received consulting fees from Novartis, Pfizer, Eli Lilly, Roche, AstraZeneca, Gilead Science, Knight Therapeutic; and has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Novartis and AstraZeneca. GC has received support for the present manuscript from AstraZeneca and Daiichi Sankyo; has received grants or contracts from Merck and AstraZeneca; has received consulting fees from Roche, BMS, Novartis, Lilly, Pfizer, Seagen, AstraZeneca, Ellipsis, Gilead, Merck, Celcuity, Sanofi, Exact Sciences, and Daiichi Sankyo; has received payment or honoraria for presentations, lectures, speaker bureaus, manuscript writing, or educational events from Novartis, Lilly, Pfizer, Seagen, and Daiichi Sankyo; has received support for attending meetings or travel from AstraZeneca and Daiichi Sankyo; and has participated on a data safety monitoring board or advisory board for Roche, BMS, Novartis, Lilly, Pfizer, Seagen, Ellipsis, Gilead, Merck, Celcuity, AstraZeneca, and Daiichi Sankyo. JMP-G has received consulting fees from Roche/AstraZeneca, Daiichi Sankyo, Lilly/Eisai, and Seattle Genetics and has received support for attending meetings or travel from Roche. S-BK has received institutional grants or contracts from Novartis, Sanofi Aventis, and DongKook Pharmaceutical; has received consulting fees from Novartis, AstraZeneca, Lilly, DaeHwa Pharmaceutical, ISU Abxis, Beigene, OBI Pharma, and Daiichi Sankyo; has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Novartis, Pfizer, OBI Pharma, and Legochem Bioscience; has participated on a data safety monitoring board or advisory board for Novartis, AstraZeneca, MSD, Lilly, and Daiichi Sankyo; and has purchased stock or stock options from Genopeaks and NeoGene TC. VP has received consulting fees for advisory boards from Daiichi Sankyo; has received fees for non-CME services received directly from commercial interests or their agents for speakers' bureaus from AstraZeneca, Novartis, Daiichi Sankyo, and Pfizer; and has received travel support for congresses from Roche and Daiichi Sankyo. C-SH has received research grants to his institution for the present manuscript from Daiichi Sankyo; has received institutional grants or contracts from Daiichi Sankyo, AstraZeneca, EirGenix, Eli Lilly, MSD, OBI Pharma, Pfizer, Roche, Novartis; has received payment or honoraria for speakers bureaus from Daiichi Sankyo, AstraZeneca, Pfizer, Novartis, Roche; has received support for travel from AstraZeneca, Pfizer, Roche, and Novartis; and has participated on advisory boards for Daiichi Sankyo, AstraZeneca, Eli Lilly, Pfizer, Novartis, and Roche. J-SF has received consulting fees from Pfizer, Lilly, Novartis, AstraZeneca, Clovis Oncology, GSK, Gilead, Daiichi Sankyo, and Seagen; has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Lilly, Novartis, AstraZeneca, Gilead, Daiichi Sankyo, and Seagen; and has received support for attending meetings or travel from Pfizer, Lilly, Novartis, AstraZeneca, Clovis Oncology, GSK, Gilead, Daiichi Sankyo, and Seagen. SAn has received consulting fees for advisory boards from Roche, Daiichi Sankyo, Pierre Fabre, and Lilly; and has received fees for non-CME services received directly from commercial interest or their agents (eg, speakers' bureaus) from Roche, Pierre Fabre, and Pfizer. WY has received payment or honoraria for lectures, presentations, advisory boards or educational events from Roche, AstraZeneca, Daiichi Sankyo, Lilly, MSD, Mundipharma, Eisai, and Novartis. GB has received consulting fees from Roche, AstraZeneca, MSD, Daiichi Sankyo, Gilead, Sanofi, and Seagen; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, AstraZeneca, Daiichi Sankyo, Lilly, MSD, Chugai, Eisai, Gilead, and Seagen; has received support for attending meetings or travel from Roche, Pfizer, MSD, Chugai, Novartis, and AstraZeneca; and has participated on a data safety monitoring board or advisory board for Roche, Pfizer, AstraZeneca, Lilly, Novartis, Amgen, MSD, Chugai, Daiichi Sankyo, Eisai, Gilead, Seagen, Exact Science, and Agendia. SL has received institutional grants or contracts from Novartis, Bristol Myers Squibb, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, Roche-Genentech, and Seattle Genetics; has received consulting fees paid to her institution from Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Pfizer, Gilead Therapeutics, Seattle Genetics, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly, and Bristol Myers Squibb; and serves as a consultant (not paid) for Seattle Genetics, Novartis, Bristol Myers Squibb, Merck, AstraZeneca, Eli Lilly, Pfizer, Gilead Therapeutics, and Roche-Genentech. JT has received support for the present manuscript in the form of grants, contracts, or consulting fees from Daiichi Sankyo and AstraZeneca; has received payment or honoraria for lectures from Daiichi Sankyo and AstraZeneca; has received payment for expert testimony from Daiichi Sankyo and Taiho; has received support for attending meetings or travel from Daiichi Sankyo and Chugai; and has served as an advisor for West Japan Oncology Group. AE, YL, JCa, and SAs are employees of Daiichi Sankyo and AE and YL have stock in Daiichi Sankyo. JCo has received support for the present manuscript from Daiichi Sankyo and AstraZeneca; has received institutional grants or contracts from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F Hoffman-La Roche, Guardant Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma C, and Queen Mary University of London; has received consulting fees from Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, and Reveal Genomics; has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, and Daiichi Sankyo; has received support for attending meetings or travel from Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, AstraZeneca, and Gilead; has patents planned, issued, or pending (WO 2014/199294 A; US 2019/ 0338368 A1); and has stock or stock options with MedSIR, Nektar Pharmaceuticals, and Leuko. All other authors declare no completing interests.

Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.