Study of Trastuzumab Deruxtecan (T-DXd) vs Investigator's Choice Chemotherapy in HER2-low, Hormone Receptor Positive, Metastatic Breast Cancer

Study Overview
=================
Brief Summary
-----------------
This study will evaluate the efficacy, safety and tolerability of trastuzumab deruxtecan compared with investigator's choice chemotherapy in human epidermal growth factor receptor (HER)2-low, hormone receptor (HR) positive breast cancer patients whose disease has progressed on endocrine therapy in the metastatic setting.

Detailed Description
-----------------
Eligible patients will be those patients who have had disease progression on at least 2 previous lines of endocrine therapies given for the treatment of metastatic disease or disease progression within 6 months of starting first line treatment for metastatic disease with an endocrine therapy combined with a CDK4/6 inhibitor. All patients must have historically confirmed HR positive (either estrogen receptor and/or progesterone receptor positive), HER2-low (defined as IHC2+/ISH- and IHC 1+) or HER2 IHC >0 <1+ expression, as determined by central laboratory testing results, advanced or metastatic breast cancer. The study aims to evaluate the efficacy, safety and tolerability of trastuzumab deruxtecan compared with investigator's choice chemotherapy. 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
-----------------
A Phase 3, Randomized, Multi-center, Open-label Study of Trastuzumab Deruxtecan (T-DXd) Versus Investigator's Choice Chemotherapy in HER2-Low, Hormone Receptor Positive Breast Cancer Patients Whose Disease Has Progressed on Endocrine Therapy in the Metastatic Setting (DESTINY-Breast06)

Conditions
-----------------
Advanced or Metastatic Breast Cancer

Intervention / Treatment
-----------------
* Drug: Trastuzumab deruxtecan
* Drug: Capecitabine
* Drug: Paclitaxel
* Drug: Nab-Paclitaxel


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Patients must be ≥18 years of age Pathologically documented breast cancer that: is advanced or metastatic has a history of HER2-low or negative expression by local test, defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested) or HER2 IHC 0 (ISH- or untested) has HER2-low or HER2 IHC >0 <1+ expression as determined by the central laboratory result established on a tissue sample taken in the metastatic setting was never previously HER2-positive is documented HR+ disease in the metastatic setting. No prior chemotherapy for advanced or metastatic breast cancer. Has adequate tumor samples for assessment of HER2 status Must have either: disease progression within 6 months of starting first line metastatic treatment with an endocrine therapy combined with a CDK4/6 inhibitor or disease progression on at least 2 previous lines of endocrine therapy with or without a targeted therapy in the metastatic setting. Of note with regards to the ≥2 lines of previous ET requirement: disease recurrence while on the first 24 months of starting adjuvant ET, will be considered a line of therapy; these patients will only require 1 line of ET in the metastatic setting. Has protocol-defined adequate organ and bone marrow function Key Exclusion Criteria: Ineligible for all options in the investigator's choice chemotherapy arm Lung-specific intercurrent clinically significant illnesses Uncontrolled or significant cardiovascular disease or infection Prior documented interstitial lung disease (ILD)/ pneumonitis that required steroids, current ILD/ pneumonitis, or suspected ILD/ pneumonitis that cannot be ruled out by imaging at screening. Patients with spinal cord compression or clinically active central nervous system metastases Prior randomization or treatment in a previous trastuzumab deruxtecan study regardless of treatment arm assignment Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study during the follow up period of a prior interventional study (prescreening for this study while a patient is on treatment in another clinical study is acceptable)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 105 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study consists of 2 independent open label treatment arms: trastuzumab deruxtecan and Investigator's choice chemotherapy (paclitaxel, nab-paclitaxel or capecitabine).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trastuzumab deruxtecan<br>Trastuzumab deruxtecan (T-DXd; DS-8201a) arm | Drug: Trastuzumab deruxtecan<br>* Trastuzumab deruxtecan by intravenous infusion<br>* Other names: DS-8201a; T-DXd;|
| Active Comparator: Standard of Care<br>Investigator's choice standard of care chemotherapy (capecitabine, paclitaxel, nab-paclitaxel) arm | Drug: Capecitabine<br>* Investigator's choice standard of care single agent chemotherapy; capecitabine tablets will be given orally.<br>Drug: Paclitaxel<br>* Investigator's choice standard of care single agent chemotherapy; paclitaxel by intravenous infusion.<br>Drug: Nab-Paclitaxel<br>* Investigator's choice standard of care single agent chemotherapy; nab-paclitaxel by intravenous infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) - in HR+, HER2-low populaton | Defined as time from date of randomization until the date of objective radiological disease progression by blinded independent central review (BICR) assessment according to RECIST 1.1 or death. | Until progression or death, assessed up to approximately 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) - in HR+, HER2-low population | Defined as the time from randomization to death due to any cause | Until death, assessed up to approximately 60 months | 
| Progression Free Survival (PFS) - in intent to treat (ITT) population (HER2-Low and HER2 IHC >0<1+) | PFS by BICR according to RECIST 1.1 in ITT population | Until progression or death, assessed up to approximately 60 months | 
| Overall Survival - in intent to treat (ITT) population (HER2-Low and HER2 IHC >0<1+) | OS in the ITT population | Until death, assessed up to approximately 60 months | 
| Objective Response Rate (ORR) in HR+, HER-2 low populaton | ORR defined as the percentage of patients with at least one visit response of complete or partial response (CR or PR) by BICR and Investigator assessment according to RECIST 1.1. | Until progression, assessed up to approximately 60 months | 
| Duration of response (DoR) - in HR+, HER-2 low populaton | DoR defined as the time from the date of first documented response (CR/PR) until the first progression or death in the absence of disease progression by BICR and Investigator assessment according to RECIST 1.1 | Until progression, assessed up to approximately 60 months | 
| Progression Free Survival by Investigator assessment - in the HR+, HER2-low population | PFS using investigator assessments according to RECIST 1.1 in the HER2-low population | Until progression or death, assessed up to approximately 60 months | 
| Objective Response Rate (ORR) in the ITT population | ORR by BICR and by Investigator assessment according to RECIST 1.1 in the ITT population | Until progression, assessed up to approximately 60 months | 
| Duration of response (DoR) - in the ITT population | DoR by BICR and by Investigator assessment according to RECIST 1.1 in the ITT population | Until progression, assessed up to approximately 60 months | 
| PFS2 by Investigator assessment, time to first subsequent therapy (TFST) and time to second subsequent treatment or death (TSST) - in HR+, HER2-low and the ITT population | PFS2 defined as time from randomisation to second progression or death. TFST defined as a time elapsed from randomization to first subsequent therapy or death. TSST defined as a time elapsed from randomization to second subsequent therapy or death. | Assessed up to approximately 60 months | 
| Safety and tolerability of drugs; number of adverse events (AEs) | Number of AEs according to NCI-CTCAE Version 5.0 per each treatment arm | Up to follow-up period, approximately 60 months | 
| Serum concentration of trastuzumab deruxtecan | Determination of trastuzumab deruxtecan concentration in serum at different time points after trastuzumab deruxtecan administration | Up to Cycle 8, approximately Week 24; each cycle is 21 days | 
| Immunogenicity of trastuzumab deruxtecan | Percentage of patients who develop ADA for trastuzumab deruxtecan | Up to follow-up period, approximately 60 months | 
| Health-related quality of life - EORTC-QLQ-C30 | Change from baseline in the physical functioning subscale of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) scores. Scale scores range from 0-100. For functioning and global health status/ QoL scales, higher scores indicate better functioning or global health status/QoL. For symptom scales, higher scores indicate greater symptom burden. | Assessed up to approximately 60 months | 
| Time to deterioration in EORTC-QLQ-C30 scores | Time to deterioration from baseline in European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) scores. Scale scores range from 0-100. For functioning and global health status/QoL scales, higher scores indicate better functioning or global health status/QoL. For symptom scales, higher scores indicate greater symptom burden. | Assessed up to approximately 60 months | 
| Health-related quality of life - EORTC QLQ-BR45 | Change from baseline in the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Breast Cancer Module (EORTC QLQ-BR45) score. Scale scores range from 0-100. For functioning and global health status/QoL scales, higher scores indicate better functioning or global health status/QoL. For symptom scales, higher scores indicate greater symptom burden. | Assessed up to approximately 60 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Breast Cancer, HR positive, HER2-Low, HER2-Negative, Trastuzumab Deruxtecan (T-DXd; DS-8201a), Anti-HER2-Antibody Drug Conjugate (ADC), DESTINY-Breast06