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]

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab deruxtecan (T-DXd)
* Drug: Ado-trastuzumab emtansine (T-DM1)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is the age of majority in their country Has pathologically documented breast cancer that: is unresectable or metastatic has confirmed HER2-positive expression as determined according to American Society of Clinical Oncology - College of American Pathologists guidelines evaluated at a central laboratory was previously treated with trastuzumab and taxane in the advanced/metastatic setting or progressed within 6 months after neoadjuvant or adjuvant treatment involving a regimen including trastuzumab and taxane Has documented radiologic progression (during or after most recent treatment or within 6 months after completing adjuvant therapy) Is HER2 positive as confirmed by central laboratory assessment of most recent tumor tissue sample available. If archived tissue is not available, agrees to provide a fresh biopsy. If of reproductive/childbearing potential, agrees to use a highly effective form of contraception or avoid intercourse during and upon completion of the study for 7 months after the last dose of DS-8201a (females); 4.5 months after last dose of DS-8201a (males) or 7 months after the last dose of T-DM1 Has adequate renal and hepatic function Exclusion Criteria: Has previously been treated with an anti-HER2 antibody drug conjugate (ADC) in the metastatic setting. Prior treatment in the adjuvant/neo-adjuvant setting would be allowed if progression of disease did not occur within 12 months of end of adjuvant therapy Has uncontrolled or significant cardiovascular disease Has a history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening Has spinal cord compression or clinically active central nervous system (CNS) metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with clinically inactive brain metastases may be included in the study. Participants 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 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trastuzumab deruxtecan (T-DXd)<br>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). | Drug: Trastuzumab deruxtecan (T-DXd)<br>* T-DXd is sterile lyophilized powder reconstituted into a sterile aqueous solution (100 mg/5 mL) to be administered intravenously.<br>* Other names: DS-8201a;|
| Active Comparator: Ado-trastuzumab emtansine (T-DM1)<br>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. | Drug: Ado-trastuzumab emtansine (T-DM1)<br>* The treatment will be in accordance with the approved label.<br>* Other names: T-DM1;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 33 months (data cut-off) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in Participants With HER2-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane | 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. | Up to 33 months (data cut-off) | 
| 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 | 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. | Up to 33 months (data cut-off) | 
| 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 | 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. | Up to 33 months (data cut-off) | 
| 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 | 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. | Up to 33 months (data cut-off) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, Metastatic breast cancer, DS-8201a, DESTINY - Breast 03