Trastuzumab-Deruxtecan (T-DXd; DS-8201) vs trastuzumab emtansine (T-DM1) in high-risk patients with HER2-positive, residual invasive early breast cancer (BC) after neoadjuvant therapy (NAT): a randomized, phase 3 trial (DESTINY-Breast05)

Background Patients with residual invasive disease after NAT are at greater risk for disease recurrence or death than those with a pathological complete response. The antibody-drug conjugate (ADC) T-DM1 was recently approved as postneoadjuvant treatment for patients with residual invasive disease (in breast and/or axillary nodes) after NAT and anti-HER2-treatment. T-DXd is a potent HER2-targeted ADC that was recently approved following phase 2 evidence (Modi NEJM 2020) for the treatment of patients with HER2-positive, unresectable/metastatic BC with ≥2 prior anti-HER2─based regimens (US) or prior chemotherapy and being refractory to or intolerant of standard treatments (Japan).

Methods DESTINY-Breast05 is a multicenter, open-label, randomized, phase 3 trial comparing efficacy and safety of T-DXd with T-DM1 in patients with HER2-positive (IHC 3+ or ISH+, centrally confirmed on pretreatment biopsy), invasive BC with residual invasive disease (breast and/or axillary lymph nodes) at presentation after NAT. Patients are eligible with either inoperable (cT4, N0-3, M0 or cT1-3, N2-3, M0) or operable BC (cT1-3, N0-1, M0) with axillary node-positive disease after NAT and anti-HER2-treatment. Approximately 1600 patients from 400 sites globally will be randomized (1:1) to T-DXd (5.4mg/kg) or T-DM1 (3.6mg/kg) intravenously once every 3 weeks for 14 cycles, stratified by operative status, hormone-receptor status, pathological nodal status, and anti-HER2-therapy. Primary endpoint is invasive disease-free survival, key secondary endpoint is disease-free survival. Other secondary endpoints are overall survival, distant recurrence-free interval, brain metastasis-free interval, safety. Pharmacokinetics of T-DXd, biomarkers, and health-related quality of life will be evaluated. Study start in Germany is planned for April 2021.

 

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Interessenkonflikt

Aleix Prat reports grants and personal fees from Novartis, during the conduct of the study; personal fees from Pfizer, grants and personal fees from Roche, personal fees from MSD Oncology, personal fees from Lilly, personal fees from Daiichi Sankyo, personal fees from Amgen, personal fees from Bristol-Myers Squibb, personal fees from Boehringer, grants and personal fees from Puma, personal fees from Oncolytics Biotech, personal fees from Daiichi Sankyo, personal fees from AbbVie, personal fees from Nanostring Technologies, grants from Incyte, other from Oncolytics and Peptomyc, S.L, other from Reveal Genomics, outside the submitted work; In addition, Dr. Prat has a patent HER2 pending, and a patent chemoendocrine score predictors pending.Dr. Prat reports grants and personal fees from Novartis, during the conduct of the study; personal fees from Pfizer, grants and personal fees from Roche, personal fees from MSD Oncology, personal fees from Lilly, personal fees from Daiichi Sankyo, personal fees from Amgen, personal fees from Bristol-Myers Squibb, personal fees from Boehringer, grants and personal fees from Puma, personal fees from Oncolytics Biotech, personal fees from Daiichi Sankyo, personal fees from AbbVie, personal fees from Nanostring Technologies, grants from Incyte, other from Oncolytics and Peptomyc, S.L, other from Reveal Genomics, outside the submitted work; . Charles Geyer reports grants, non-financial support and other from Genentech/Roche, grants, non-financial support and other from Daiichi/Sankyo, grants, non-financial support and other from AstraZeneca, during the conduct of the study; personal fees from Exact Sciences, personal fees from Athenex, outside the submitted work; . Elton Mathias reports other from Daiichi Sankyo Inc., during the conduct of the study; . Lee Anne McLean reports personal fees from Daiichi Sankyo Inc., during the conduct of the study; . Michael Untch reports personal fees and non-financial support from Abbvie, personal fees and non-financial support from Amgen GmbH, personal fees and non-financial support from Astra Zeneca, personal fees from BMS, personal fees and non-financial support from Celgene GmbH, personal fees and non-financial support from Daiji Sankyo, personal fees and non-financial support from Eisai GmbH, personal fees from Lilly Deutschland, personal fees and non-financial support from Lilly Int., personal fees and non-financial support from MSD Merck, personal fees and non-financial support from Mundipharma, personal fees and non-financial support from Myriad Genetics, personal fees and non-financial support from Pfizer GmbH, personal fees and non-financial support from Roche Pharma AG, personal fees and non-financial support from Sanofi Aventis Deutschland GmbH, personal fees and non-financial support from TEVA Pharmaceuticals Ind Ltd, personal fees and non-financial support from Novartis, personal fees from Pierre Fabre, personal fees and non-financial support from Clovis Oncology, personal fees from Seatlle Genetics, outside the submitted work; Naoki Niikura reports personal fees from Chugai, AstraZeneca, Kyowa-Kirin, Pfizer, Novartis, Eisai, Nippon Mediphysics, Takeda, Tiho, Nippon Kayaku, Daiichi-Sankyo, Lilly, MSD, and grant from Chugai, Daiichi-Sankyo, Pfizer, Novartis, Eisai, outside the submitted work. Priya Rastogi reports other from Genentech/Roche, other from Lilly, other from AstraZeneca, outside the submitted work; Sibylle Loibl reports grants and other from Abbvie, grants and other from Amgen, grants and other from AstraZeneca, grants and other from Celgene, grants, personal fees and other from Daiichi-Sankyo, grants and other from Novartis, grants and other from Pfizer, grants and other from Roche, other from BMS, other from Eirgenix, other from Lilly, other from Merck, other from MSD, other from SeaGen, other from Prime/Medscape, other from Puma, other from Samsung, other from Pierre Fabre, grants from Teva, grants from Vifor, grants from Immunomedics, personal fees from Chugai, outside the submitted work; In addition, Dr. Loibl has a patent EP14153692.0 pending. Yibin Wang is an employee of Daiichi Sankyo Inc.

Publication History

Article published online:
01 June 2021