DS-8201a Versus T-DM1 for Human Epidermal Growth Factor Receptor 2 (HER2)-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane [DESTINY-Breast03]

A Phase 3, Multicenter, Randomized, Open-Label, Active-Controlled Study of DS-8201a (Trastuzumab Deruxtecan), an Anti-HER2 Antibody Drug Conjugate (ADC), Versus Ado Trastuzumab Emtansine (T-DM1) for HER2-Positive, Unresectable and/or Metastatic Breast Cancer Subjects Previously Treated With Trastuzumab and Taxane

Status

Active, not recruiting

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03529110

Enrollment

524

Registered

2018-05-18

Start date

2018-08-09

Completion date

2026-07-30

Last updated

2025-10-21

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Breast Cancer

Keywords

Breast Cancer, Metastatic breast cancer, DS-8201a, DESTINY - Breast 03

Brief summary

This study is designed to compare the anti-tumor activity as well as the safety and efficacy of DS-8201a versus T-DM1 in HER2-positive, unresectable and/or metastatic breast cancer subjects previously treated with trastuzumab and taxane.

Interventions

DRUGTrastuzumab deruxtecan (T-DXd)

T-DXd is sterile lyophilized powder reconstituted into a sterile aqueous solution (100 mg/5 mL) to be administered intravenously.

DRUGAdo-trastuzumab emtansine (T-DM1)

The treatment will be in accordance with the approved label.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Must be competent and able to comprehend, sign, and date an Institutional Review Board (IRB) or Ethics Committee (EC) approved ICF before performance of any study-specific procedures or tests. 2. Adults ≥18 y old. (Please follow local regulatory requirements if the legal age of consent for study participation is \>18 y old.) 3. Pathologically documented breast cancer that: 1. is unresectable or metastatic. 2. has confirmed HER2-positive expression as determined according to American Society of Clinical Oncology - College of American Pathologists guidelines evaluated at a central laboratory.23 3. was previously treated with trastuzumab and taxane in the advanced/ metastatic setting or progressed within 6 mo after neoadjuvant or adjuvant treatment involving a regimen including trastuzumab and taxane. 4. Documented radiologic progression (during or after most recent treatment or within 6 mo after completing adjuvant therapy). 5. Subjects must be HER2-positive as confirmed by central laboratory assessment of most recent tumor tissue sample available. If archived tissue is not available, a fresh biopsy is required. 6. Presence of at least 1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1

Exclusion criteria

1. Prior treatment with an anti-HER2 ADC (such as T-DM1) in the metastatic setting. Prior treatment in the adjuvant/neoadjuvant setting would be allowed if progression of disease did not occur within 12 mo of end of adjuvant therapy. 2. Uncontrolled or significant cardiovascular disease, including any of the following: 1. History of myocardial infarction within 6 mo before randomization; 2. History of symptomatic congestive heart failure (New York Heart Association Class II to IV); 3. Troponin levels consistent with myocardial infarction as defined according to the manufacturer within 28 d prior to randomization; 4. Corrected QT interval (QTc) prolongation to \> 470 ms (females) or \>450 ms (male) based on average of Screening triplicate 12-lead ECG; 5. LVEF \< 50% within 28 d prior to randomization 3. Has a history of (noninfectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening. 4. Spinal cord compression or clinically active central nervous system (CNS) metastases, defined as untreated or symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. * Subjects with clinically inactive brain metastases may be included in the study. * Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 wk must have elapsed between the end of whole brain radiotherapy and study enrollment. 5. Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product. 6. History of severe hypersensitivity reactions to other mAbs.

Design outcomes

Primary

Measure	Time frame	Description
Progression-Free Survival (PFS) Based on Blinded Independent Central Review (BICR) in Participants With HER2-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane	Up to 33 months (data cut-off)	Progression-free survival (PFS) by BICR was defined as the time from the date of enrollment to the earlier of the dates of the first objective documentation of disease progression (as per RECIST v1.1) or death due to any cause. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions.

Secondary

Measure	Time frame	Description
Overall Survival (OS) in Participants With HER2-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane	Up to 33 months (data cut-off)	Overall survival (OS) was defined as the time from the date of first dose of study drug to the date of death due to any cause.
Percentage of Participants With Objective Response Rate (ORR) Based on BICR and Investigator Assessment in Participants With HER2-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane	Up to 33 months (data cut-off)	The Objective Response Rate (ORR) was defined as the percentage of participants who achieved a best overall response of confirmed Complete Response (CR) or Partial Response (PR), assessed by BICR and investigator assessment based on RECIST version 1.1. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions. Confirmed ORR is reported.
Duration of Response (DoR) Based on BICR and Investigator Assessment in Participants With HER2-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane	Up to 33 months (data cut-off)	Duration of Response (DoR) was defined as the time from the date of the first documentation of objective response (complete response \[CR\] or partial response \[PR\]) to the date of the first objective documentation of progressive disease (PD) or death due to any cause. DoR in participants with confirmed CR/PR based on BICR and investigator assessment is reported.
Progression-Free Survival (PFS) Based on Investigator Assessment in Participants With HER2-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane	Up to 33 months (data cut-off)	Progression-free survival (PFS) by investigator assessment was defined as the time from the date of enrollment to the earlier of the dates of the first objective documentation of disease progression (as per RECIST v1.1) or death due to any cause. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions.

Countries

Australia, Belgium, Brazil, Canada, China, France, Germany, Hong Kong, Italy, Japan, South Korea, Spain, Taiwan, United Kingdom, United States

Participant flow

Recruitment details

A total of 524 participants were enrolled and treated at study sites in 14 countries. Primary results reported is from first participant randomized up to data cut-off date of 21 May 2021. The results presented are based on primary analysis up to 33 months. Data collection is still on-going and additional results will be provided after study completion.

Participants by arm

Arm	Count
Trastuzumab Deruxtecan (T-DXd) Participants with HER2-positive, unresectable and/or metastatic breast cancer participants previously treated with trastuzumab and taxane who received T-DXd as a sterile intravenous (IV) solution at a dose of 5.4 mg/kg every 3 weeks (Q3W).	261
Ado-trastuzumab Emtansine (T-DM1) Participants with HER2-positive, unresectable and/or metastatic breast cancer participants previously treated with trastuzumab and taxane who received T-DM1 in accordance with the approved label.	263
Total	524

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	35	17
Overall Study	Clinical Progression	4	12
Overall Study	Lack of Efficacy	3	3
Overall Study	Miscellaneous	2	5
Overall Study	Physician Decision	2	8
Overall Study	Progressive Disease	66	158
Overall Study	Withdrawal by Subject (from treatment only)	13	11

Baseline characteristics

Characteristic	Trastuzumab Deruxtecan (T-DXd)	Ado-trastuzumab Emtansine (T-DM1)	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	49 Participants	57 Participants	106 Participants
Age, Categorical Between 18 and 65 years	212 Participants	206 Participants	418 Participants
Age, Continuous	54.5 years STANDARD_DEVIATION 11.11	54.2 years STANDARD_DEVIATION 11.84	54.4 years STANDARD_DEVIATION 11.47
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	152 Participants	162 Participants	314 Participants
Race (NIH/OMB) Black or African American	10 Participants	9 Participants	19 Participants
Race (NIH/OMB) More than one race	2 Participants	0 Participants	2 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	26 Participants	20 Participants	46 Participants
Race (NIH/OMB) White	71 Participants	72 Participants	143 Participants
Sex: Female, Male Female	260 Participants	262 Participants	522 Participants
Sex: Female, Male Male	1 Participants	1 Participants	2 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	33 / 257	53 / 261
other Total, other adverse events	256 / 257	249 / 261
serious Total, serious adverse events	49 / 257	47 / 261

Outcome results

Primary

Progression-Free Survival (PFS) Based on Blinded Independent Central Review (BICR) in Participants With HER2-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane

Progression-free survival (PFS) by BICR was defined as the time from the date of enrollment to the earlier of the dates of the first objective documentation of disease progression (as per RECIST v1.1) or death due to any cause. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions.