LBA1 - Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): Results of the randomized phase III DESTINY-Breast03 study

Background

T-DXd is a HER2-targeting antibody–drug conjugate approved for pts with advanced HER2+ mBC based on the results from DESTINY-Breast01 (NCT03248492). This is the first report of DESTINY-Breast03 (NCT03529110), a multicenter, open-label, randomized phase 3 study comparing the efficacy and safety of T-DXd vs T-DM1 in pts with HER2+ mBC previously treated with trastuzumab and taxane. This is the first reported randomized study of T-DXd in BC.

Methods

Pts were randomized 1:1. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR). Secondary endpoints include overall survival (OS), objective response rate (ORR), duration of response, PFS by investigator, and safety.

Results

As of May 21, 2021, 524 pts were randomized. Median age was 54 years (range, 20-83). The hazard ratio (HR) for PFS was 0.2840 (P = 7.8 x 10^-22); median PFS not reached for T-DXd vs 6.8 mo for T-DM1. The estimated 12-month OS event rates were 94.1% (95% CI, 90.3-96.4) for T-DXd and 85.9% (95% CI, 80.9-89.7) for T-DM1; HR: 0.5546 (95% CI, 0.3587-0.8576; P = 0.007172 did not cross pre-specified boundary for significance). Median treatment duration was 14.3 mo (range, 0.7-29.8) with T-DXd vs 6.9 mo (range, 0.7-25.1) with T-DM1; similar rates of TEAEs were observed. No drug-related deaths occurred in either arm. Adjudicated drug-related interstitial lung disease (ILD) occurred in 10.5% of pts with T-DXd (most [9.7%] grade 1/2; 0 grade 4/5) vs 1.9% with T-DM1 (all grade 1/2). Table: LBA1

Summary of results

^aTwo-sided. ^bBy BICR. ^cOf 524 pts, 257 and 261 received ³1 dose of T-DXd and T-DM1, respectively.

Conclusions

T-DXd demonstrated a highly statistically significant and clinically meaningful improvement in PFS vs T-DM1 in pts previously treated with trastuzumab and taxane for HER2+ mBC. These data confirm that T-DXd is tolerable with manageable toxicity and a significant improvement in ILD profile vs studies performed in more heavily pretreated pts. This study will lead to a paradigm shift in the treatment of HER2+ mBC.

Clinical trial identification

NCT03529110.

Editorial acknowledgement

Under the guidance of authors, assistance in medical writing and editorial support was provided by Irene Park, PhD, and Alya Raphael, PhD, of ApotheCom, and was funded by Daiichi Sankyo, Inc.

Legal entity responsible for the study

Daiichi Sankyo, Inc., and AstraZeneca.

Funding

Daiichi Sankyo, Inc., and AstraZeneca.

Disclosure

J. Cortés: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Cellestia; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Biothera; Financial Interests, Personal, Advisory Board: Merus; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Erytech; Financial Interests, Personal, Advisory Board: Athenex; Financial Interests, Personal, Advisory Board: Polyphor; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Servier; Financial Interests, Personal, Advisory Board: Merck Sharp& Dohme; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: LEUKO; Financial Interests, Personal, Advisory Board: Bioasis; Financial Interests, Personal, Advisory Board: Clovis oncology; Financial Interests, Personal, Advisory Board: Boehringer; Financial Interests, Personal, Advisory Board: Kyowa Kyrin; Financial Interests, Personal, Advisory Board: 4D Pharma PLC; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Celgene; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Samsung Bioepis; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Invited Speaker: Merck Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares: MedSIR; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Ariad Pharmaceuticals; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Baxalta GMBH/Servier Affaires,; Financial Interests, Institutional, Research Grant: Bayer healthcare; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: Guardanth health,; Financial Interests, Institutional, Research Grant: Merck Sharp&Dohme,; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Piqur Therapeutics; Financial Interests, Institutional, Research Grant: Puma B; Financial Interests, Institutional, Research Grant: Queen Mary University of London; Other, Travel cost and expenses: Roche; Other, Travel cost and expenses: Novartis; Other, Travel cost and expenses: Eisai; Other, Travel cost and expenses: Daiichi Sankyo. S. Kim: Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Novartis, AstraZeneca, Lilly, Dae Hwa Pharmacuetical Co. Ltd, ISU Abxis, Daiichi Sankyo; Other, Personal, Leadership Role: ESMO Breast 2021-2022 Co-chair; Financial Interests, Personal, Stocks/Shares: Genepeaks, Neogene TC; Financial Interests, Institutional, Research Grant: Novartis, Sanofi-Aventis, and DongKook Pharm Co. W. Chung: Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Novartis, AstraZeneca, Pfizer, Amgen, Eli Lilly, MSD, and Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau, Speaker Bureau/Expert Testimony: Novartis, Roche, AstraZeneca, Pfizer, Amgen, Kyowa Kirin, Foundation Medicine, Chugai Pharma, Takeda, Eli Lilly, and Sanofi. S. Im: Financial Interests, Personal, Advisory Role, Advisory/Consultancy: AstraZeneca, Amgen, Eisai, Hanmi, Novartis, Pfizer, Roche, Eli-Lilly, MSD, GSK, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca, Eisai, Pfizer, Roche, Daiichi Sankyo, Dae Woong. Y.H. Park: Non-Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Research Grant, Contracted research: AstraZeneca; Non-Financial Interests, Institutional, Principal Investigator, Contracted research: AstraZeneca; Non-Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Institutional, Research Grant, Contracted research: Pfizer; Non-Financial Interests, Institutional, Principal Investigator, Contracted research: Pfizer; Non-Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Institutional, Research Grant, Contracted research: Roche; Non-Financial Interests, Institutional, Principal Investigator, Contracted research: Roche; Non-Financial Interests, Institutional, Principal Investigator, Contracted research: Daiichi Sankyo; Non-Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Other, Speaker fee: Novartis; Non-Financial Interests, Institutional, Principal Investigator, Contracted research: Novartis; Non-Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Institutional, Research Grant, Contracted research: Merck; Non-Financial Interests, Institutional, Principal Investigator, Contracted research: Merck; Non-Financial Interests, Personal, Other, Medical writing support for this abstract, furnished by Daniel Clyde, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. V. Petry: Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau, Speaker's Bureau/Expert Testimony: Novartis; Financial Interests, Personal, Speaker’s Bureau, Speaker's Bureau/Expert Testimony: Pfizer; Financial Interests, Personal, Other, Travel expenses, including accommodations: Roche; Financial Interests, Personal, Other, Travel expenses, including accommodations: Lilly; Financial Interests, Personal, Other, Travel expenses, including accommodations: Pfizer. C. Chung: Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Pfizer; Financial Interests, Personal, Advisory Board, Advisory/Consultancy: Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau, Speaker Bureau/Expert Testimony: Roche. H. Iwata: Financial Interests, Personal, Other, Honoraria: Daiichi Sankyo; Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Daiichi Sankyo; Financial Interests, Personal, Research Grant: Daiichi Sankyo; Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Personal, Advisory Role, Advisory/Consultancy: AstraZeneca; Financial Interests, Personal, Research Grant: AstraZeneca. E. Hamilton: Financial Interests, Institutional, Advisory Role: Genentech/Roche, Boehringer Ingelheim, Novartis, Dantari, Lilly, Merck, Puma Biotechnology, Silverback Therapeutics, CytomX, Pfizer, Mersana, Black Diamond, H3 Biomedicine, Daiichi Sankyo, AstraZeneca, Arvinas, Deciphera Pharmaceuticals, Eisai, Seagen; Financial Interests, Institutional, Research Grant: Paid to institution - OncoMed, Genentech/Roche, Zymeworks, Rgenix, ArQule, Clovis, Silverback Therapeutics, Millenium, Acerta Pharma, Sermonix Pharmaceuticals, Torque, Black Diamond, Karyopharm, Infinity Pharmaceuticals, Curis, Syndax, Novartis, Boehringe. G. Curigliano: Financial Interests, Personal, Other, Honoraria: Roche, Pfizer, Lilly, AstraZeneca, Daichi Sankyo, Ellipsis, Roche, Veracyte, BMS, Merck; Financial Interests, Personal, Advisory Role: Roche, Pfizer, Lilly, AstraZeneca, Daichi Sankyo, Ellipsis, Roche, Veracyte, BMS, Merck; Financial Interests, Personal, Speaker’s Bureau: Roche, Pfizer, Lilly, AstraZeneca , Daichi Sankyo, Roche, Merck; Financial Interests, Personal, Other, Travel Expenses: Roche, Pfizer. B. Xu: Financial Interests, Personal, Advisory Role, Consultant: Roche; Financial Interests, Personal, Speaker’s Bureau: Astra, Pfizer, Eisai. C. Lee: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. Y. Liu: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo. J. Cathcart: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. E. Bako: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. S. Verma: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. S.A. Hurvitz: Financial Interests, Institutional, Research Grant: Ambrx; Financial Interests, Institutional, Principal Investigator: Ambrx; Financial Interests, Institutional, Principal Investigator: Arvinas; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Bayer; Financial Interests, Institutional, Principal Investigator: Daiichi Sankyo; Financial Interests, Institutional, Principal Investigator: Dignitana; Financial Interests, Institutional, Principal Investigator: Genentech/Roche; Financial Interests, Institutional, Principal Investigator: Gilead; Financial Interests, Institutional, Principal Investigator: GSK; Financial Interests, Institutional, Principal Investigator: Immunomedics; Financial Interests, Institutional, Principal Investigator: Lilly; Financial Interests, Institutional, Principal Investigator: Macrogenics; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: OBI Pharma; Financial Interests, Institutional, Principal Investigator: Pfizer; Financial Interests, Institutional, Principal Investigator: Phoenix Molecular Designs, Ltd; Financial Interests, Institutional, Principal Investigator: Pieris; Financial Interests, Institutional, Principal Investigator: PUMA; Financial Interests, Institutional, Principal Investigator: Radius; Financial Interests, Institutional, Research Grant: Samumed; Financial Interests, Institutional, Principal Investigator: Sanofi; Financial Interests, Institutional, Principal Investigator: Seattle Genetics; Financial Interests, Institutional, Principal Investigator: Zymeworks. All other authors have declared no conflicts of interest.