Trastuzumab Deruxtecan (T-DXd) With or Without Pertuzumab Versus Taxane, Trastuzumab and Pertuzumab in HER2-positive Metastatic Breast Cancer (DESTINY-Breast09)

Study Overview
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Brief Summary
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The study will evaluate the efficacy and safety of trastuzumab deruxtecan (also known as T-DXd, DS-8201a), either alone or in combination with pertuzumab, in treating patients with Human epidermal growth factor receptor 2 (HER2)-positive breast cancer as a first line of treatment in the metastatic setting.

Detailed Description
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Eligible participants will be those diagnosed with HER2-positive (IHC 3+ or ISH+), metastatic breast cancer, who have received no prior chemotherapy or HER2-targeted therapy for advanced or metastatic breast cancer. The study aims to evaluate the efficacy, and safety of trastuzumab deruxtecan, alone or with pertuzumab, compared with the standard of care treatment (taxane [docetaxel or paclitaxel], trastuzumab and pertuzumab). This study aims to see if trastuzumab deruxtecan allows patients to live longer without the cancer getting worse, or simply to live longer, compared to patients receiving standard of care chemotherapy. This study is also looking to see how the treatment and the cancer affects patients' quality of life.

Official Title
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Phase III Study of Trastuzumab Deruxtecan (T-DXd) With or Without Pertuzumab Versus Taxane, Trastuzumab and Pertuzumab in HER2-positive, First-line Metastatic Breast Cancer (DESTINY-Breast09)

Conditions
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Breast Cancer; HER2-positive; Metastatic

Intervention / Treatment
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* Drug: Trastuzumab deruxtecan
* Drug: Placebo
* Drug: Taxane
* Drug: Pertuzumab
* Drug: Trastuzumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Patients must be ≥18 years of age Pathologically documented breast cancer that: is advanced or metastatic is locally assessed and prospectively centrally confirmed as HER2-positive (IHC3+ or ISH+) is documented by local testing as hormone receptor (HR)-positive or HR-negative disease in the metastatic setting No prior chemotherapy or HER2-targeted therapy for advanced or metastatic breast cancer or only 1 previous line of endocrine therapy in the metastatic setting. Participants who have received chemotherapy or HER2-targeted therapy in the neo-adjuvant or adjuvant setting are eligible if > 6 months from treatment to metastatic diagnosis. Has protocol-defined adequate organ and bone marrow function ECOG performance status 0 or 1 Key Exclusion Criteria: Ineligible for any of the agents on the study. Any substance abuse or other medical conditions that, in the investigator's opinion, may interfere with subject's participation or study results Patients with spinal cord compression or clinically active central nervous system metastases. Participants with clinically inactive brain metastases or treated brain metastases that are no longer symptomatic may be included in the study. Active or prior documented interstitial lung disease (ILD)/pneumonitis or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening Prior randomization or treatment in a previous trastuzumab deruxtecan study regardless of treatment arm assignment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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
Interventional Model Description: Study will consist of three arms: Arm A - trastuzumab deruxtecan with pertuzumab-matching placebo Arm B - trastuzumab deruxtecan with pertuzumab Arm C - standard of care (taxane [docetaxel or paclitaxel], trastuzumab and pertuzumab)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Trastuzumab deruxtecan (T-DXd) plus pertuzumab-matching placebo | Drug: Trastuzumab deruxtecan<br>* Administered by intravenous infusion<br>* Other names: DS-8201a; T-DXd;Drug: Placebo<br>* Administered by intravenous infusion<br>|
| Experimental: Arm B<br>Trastuzumab deruxtecan (T-DXd) plus pertuzumab | Drug: Trastuzumab deruxtecan<br>* Administered by intravenous infusion<br>* Other names: DS-8201a; T-DXd;Drug: Pertuzumab<br>* Administered by intravenous infusion<br>|
| Active Comparator: Arm C<br>Standard of care (Taxane (paclitaxel or docetaxel), trastuzumab, and pertuzumab) | Drug: Taxane<br>* Investigator's choice of docetaxel or paclitaxel administered by intravenous infusion<br>Drug: Pertuzumab<br>* Administered by intravenous infusion<br>Drug: Trastuzumab<br>* Administered by intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) assessment | Defined as time from date of randomisation until the date of objective radiological disease progression according to Blinded Independent Central Review (BICR) using RECIST 1.1 or death by any cause. | Until progression or death, assessed up to approximately 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) by Investigator assessment | Defined as time from date of randomisation until the date of objective radiological disease progression according to Investigator using RECIST 1.1 or death by any cause. | Until progression or death, assessed up to approximately 60 months | 
| Overall Survival (OS) | OS is defined as the time from randomisation until the date of death due to any cause. | Until death, assessed up to approximately 104 months | 
| Objective Response Rate (ORR) by BICR and Investigator assessment | ORR is defined as The proportion of participants who have a complete response (CR) or partial response (PR) based on BICR and investigator assessment using RECIST 1.1. | Until progression or death (in the absence of progression), assessed up to approximately 60 months | 
| Duration of Response (DoR) by BICR and Investigator Assessment | DoR is defined as the time from date of first detection of objective response until the date of objective radiological disease progression according to BICR and investigator assessment using RECIST 1.1 or death in the absence of progression. | Until progression or death (in the absence of progression), assessed up to approximately 60 months | 
| Time to second progression or death (PFS2) by Investigator assessment | PFS2 is defined as the time from randomisation until the date of tumor progression on next-line treatment (the earliest of the progression event subsequent to first subsequent anticancer therapy after the first progression) or death from any cause; second progression will be defined according to local standard clinical practice. | Assessed up to approximately 104 months | 
| To assess the effect of T-DXd ± pertuzumab relative to THP in terms of patient-reported pain in participants with HER2 positive, first-line mBC'. | Pain progression: Time to sustained deterioration of European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 Pain Scale. Scores range from 0-100 based on 2 items with responses ranging from 1-4. A lower score would mean better outcome. | Assessed up to approximately 60 months | 
| To assess patient-reported treatment tolerability | Proportion of participants experiencing treatment related symptoms as measured by selected items from the European Organisation for Research and Treatment of Cancer, general cancer module (EORTC QLQ-C30), score of 1-4. A lower score would mean better outcome. | Assessed up to approximately 60 months | 
| To assess patient-reported treatment tolerability | Proportion of patients reporting different levels of overall tolerability as measured by the Patient Global Impression of Treatment Tolerability (PGI-TT), score of 0-4. A lower score would mean a better outcome. | Assessed up to approximately 60 months | 
| To assess patient-reported treatment tolerability | Proportion of participants experiencing treatment related symptoms as measured by selected items from the European Organisation for Research and Treatment of Cancer, breast cancer module (EORTC QLQ-BR45), score of 1-4. A lower score would mean better outcome. | Assessed up to approximately 60 months | 
| To assess patient-reported treatment tolerability | Proportion of participants experiencing treatment related symptoms as measured by selected items from the Patient-Reported Outcomes- Common Terminology Criteria for Adverse Events (PRO-CTCAE). PRO-CTCAE responses are scored from 0 to 4 (or 0/1 for absent/present). A lower score would mean a better outcome. | Assessed up to approximately 60 months | 
| To assess patient-reported treatment tolerability | The proportion of participants with maintained or improved physical function while on treatment, based on the EORTC QLQ-C30 Physical Functioning scale. Scores range from 0-100, based on 5 items with responses ranging from 1-4. A higher score would mean a better outcome. | Assessed up to approximately 60 months | 
| Serum concentration of trastuzumab deruxtecan and pertuzumab | Determination of trastuzumab deruxtecan and pertuzumab concentrations in serum. | Up to Cycle 6, approximately Week 18; each cycle is 21 days | 
| Immunogenicity of trastuzumab deruxtecan. | Number and percentage of participants who develop anti-drug antibody (ADA) for trastuzumab deruxtecan. | Up to follow-up period, approximately 60 months | 
| Safety and tolerability of trastuzumab deruxtecan, alone or with pertuzumab | Number of AEs according to NCI-CTCAE Version 5.0 per each treatment arm | Assessed up to approximately 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Neoplasms; Breast Diseases; Trastuzumab; Antineoplastic Agents, Phytogenic; Anti-drug conjugate; Molecular Mechanisms of Pharmacological Action;