Trastuzumab Deruxtecan (DS-8201a) Versus Investigator's Choice for HER2-low Breast Cancer That Has Spread or Cannot be Surgically Removed [DESTINY-Breast04]

<p>PFS based on BICR is defined as the time from the date of randomization to the earliest date of the first objective documentation of radiographic disease progression, assessed via BICR according to the modified response evaluation criteria in solid tumors (mRECIST) version 1.1, or death due to any cause.</p><p>First dose at Cycle 1 Day 1 should occur within 7 days after the date the subject is randomized.</p>

PFS based on BICR is defined as the time from randomization to the first objective (radiographic) documentation of disease progression or death.

at approximately 3 years

within approximately 3 years

DS-8201a is administered as an intravenous (IV) infusion every 21 days (Q3W), initially for approximately 90 minutes, then, if there is no infusion-related reaction, for a minimum of 30 minutes thereafter.

DS-8201a is administered as an intravenous (IV) infusion every 21 days (Q3W), initially for at least 90 minutes, then, if there is no infusion-related reaction, for a minimum of 30 minutes thereafter.

A lyophilized powder prepared by dilution for IV infusion

A lyophilized powder prepared by dilution for IV infusion at a dose of 5.4 mg/kg

<p>Inclusion Criteria:</p><ul><li>Is the age of majority in their country</li><li><p>Has pathologically documented breast cancer that:</p><ol><li>Is unresectable or metastatic.</li><li>Has a history of low HER2 expression, defined as IHC 2+&#x2F;ISH- or IHC 1+ (ISH- or untested).</li><li>Is assessed by a central laboratory as low HER2 expression, defined as IHC 2+&#x2F;ISH- or IHC 1+</li><li>Is HR-positive or HR-negative.
After ~60 HR-negative subjects are enrolled, further enrollment will be limited to only subjects who are HR-positive (either estrogen receptor positive or progesterone receptor positive per ASCO-CAP guidelines).</li><li>Is documented refractory to endocrine therapy, defined as having progressed on at least 1 endocrine therapy and determined by the Investigator that subject would no longer benefit from further treatment from endocrine therapy.</li><li>If HR-positive, has or has not been treated with a CDK4&#x2F;6 inhibitor.
After ~240 HR-positive subjects have been enrolled who have not had prior therapy with a CDK4&#x2F;6 inhibitor, further enrollment of HR-positive subjects will be limited to subjects who have had prior therapy with a CDK4&#x2F;6 inhibitor.</li><li>Has been treated with at least 1 and at most 2 prior lines of chemotherapy in the metastatic setting.
If recurrence occurred within 6 months of adjuvant chemotherapy, adjuvant therapy would count as 1 line of chemotherapy.</li><li>Was never previously HER2-positive (IHC 3+ or ISH+) on prior pathology testing (per ASCO-CAP guidelines.)</li><li>Was never previously treated with anti HER2 therapy.</li></ol></li><li>Has documented radiologic progression (during or after most recent treatment)</li><li>Has an adequate archival tumor sample available for assessment of HER2 status by central laboratory (based on most recent available tumor tissue sample).
If archival tissue is not available, a fresh biopsy is required.</li><li>Has a recent tumor sample after the most recent treatment regimen or agree to undergo a tissue biopsy prior to randomization</li><li>Has at least 1 measurable lesion based on computed tomography (CT) or magnetic resonance imaging (MRI), per modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1</li><li>Has left ventricular ejection fraction (LVEF) ≥50%</li><li>Has adequate renal function, defined as creatinine clearance ≥30 mL&#x2F;min, as calculated using the CockcroftGault equation</li><li><p>Has adequate hepatic function, defined as:</p><ol><li>Aspartate aminotransferase (AST)&#x2F; alanine aminotransferase (ALT) ≤5 × upper limit of normal (ULN)</li><li>Total bilirubin ≤1.5 × ULN) if no liver metastases or &lt;3 × ULN in the presence of documented Gilbert&#x27;s syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline</li></ol></li><li>If of reproductive&#x2F;childbearing potential, agrees to follow instructions for method(s) of contraception</li></ul><p>Exclusion Criteria:</p><ul><li>Is ineligible for all 5 of the options in the physician&#x27;s choice arm, either because of previously receiving treatment in the metastatic setting with the comparator, or having a contraindication to treatment</li><li>Has medical history of myocardial infarction within 6 months before randomization</li><li>Has history of symptomatic congestive heart failure (New York Heart Association Class II to IV)</li><li>Has corrected QT interval (QTc) prolongation to &gt;470 ms (females) or &gt;450 ms (male) based on average of Screening triplicate 12-lead electrocardiograms (ECGs)</li><li>Has a history of (noninfectious) interstitial lung disease (ILD)&#x2F;pneumonitis that required steroids, has current ILD&#x2F;pneumonitis, or where suspected ILD&#x2F;pneumonitis cannot be ruled out by imaging at Screening</li><li>Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms</li></ul><p>NOTE: 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 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment.</p>

<p>Inclusion Criteria:</p><ul><li>Is the age of majority in their country</li><li><p>Has pathologically documented breast cancer that:</p><ol><li>Is unresectable or metastatic</li><li>Has low-HER2 expression defined as IHC 2+&#x2F;ISH- or IHC 1+ (ISH- or untested)</li><li>Is HR-positive or HR-negative</li><li>Has progressed on, and would no longer benefit from, endocrine therapy</li><li>Has been treated with 1 to 2 prior lines of chemotherapy&#x2F;adjuvant in the metastatic setting</li></ol></li><li>Has documented radiologic progression (during or after most recent treatment)</li><li><p>Has adequate tumor samples available or is wiling to provide fresh biopsies prior to randomization for:</p><ol><li>assessment of HER2 status</li><li>assessment of post-treatment status</li></ol></li><li>Has Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1</li><li>Has at least 1 protocol-defined measurable lesion</li><li>Has protocol-defined adequate cardiac, bone marrow, renal, hepatic and blood clotting functions</li><li>If of reproductive&#x2F;childbearing potential, agrees to follow instructions for method(s) of contraception and agrees to avoid preserving ova or sperm for at least 4.5 months after treatment (or longer, per locally approved labels)</li></ul><p>Exclusion Criteria:</p><ul><li>Is ineligible for all options in the physician&#x27;s choice arm</li><li>Has breast cancer ever assessed with high-HER2 expression</li><li>Has previously been treated with any anti-HER2 therapy, including an antibody drug conjugate</li><li>Has uncontrolled or significant cardiovascular disease</li><li>Has spinal cord compression or clinically active central nervous system metastases</li><li>Has history, current, or suspicion of interstitial lung disease&#x2F;pneumonitis</li><li>Has any medical history or condition that per protocol or in the opinion of the investigator is inappropriate for the study</li></ul>

PFS based on Investigator Assessment is defined as the time from the date of randomization to the earliest date of the first clinical observation of disease progression or death due to any cause, assessed by BICR review using mRECIST version 1.1.

PFS based on Investigator Assessment is defined as the time from randomization to the first clinical observation of disease progression or death.

at approximately 3 years

within approximately 3 years

OS is defined as the time from the date of randomization to the date of death for any cause, assessed by BICR review using mRECIST version 1.1.

OS is defined as the time from randomization to death

at approximately 3 years

within approximately 3 years

Confirmed Objective Response Rate (ORR)

Objective Response Rate (ORR)

Confirmed ORR is defined as the sum of complete response (CR) rate and partial response (PR) rate, based on BICR and Investigator Assessment, and confirmed by a second assessment by BICR review using mRECIST version 1.1.

ORR is defined as the percentage of participants who achieved objective CR or PR, confirmed by a second assessment

at approximately 3 years

within approximately 3 years

DoR is defined as the time from the date of the first documentation of objective response (CR or PR) to the date of the first documentation of disease progression, based on BICR and Investigator assessment, or death.
Duration of response will be measured for responding subjects (PR or CR) only, and be assessed by BICR review using mRECIST version 1.1.

DoR is defined as the time from the first documented objective response (CR or PR) to the first documented disease progression or death

at approximately 3 years

within approximately 3 years

2018-11

2018-12

2018-11-06

2018-12-13

2018-11-07

2018-12-17

<p>The reason for this trial is to compare DS-8201a to other treatments being used for breast cancer.</p><p>DS-8201a is a new medicine for breast cancer that has not been approved yet by the Food and Drug Administration.
It is made of a drug and an antibody.</p><p>Each participant has a 2 out of 3 chance of receiving the new medicine.</p>

<p>The reason for this trial is to compare DS-8201a to other treatments being used for HER2-low breast cancer that has spread to other parts of the body.</p><p>DS-8201a is a new medicine for breast cancer that has not been approved yet by the Food and Drug Administration.
It is made of a drug and an antibody.</p><p>Each participant has a 2 out of 3 chance of receiving the new medicine.</p>

<p>This is a randomized, 2-arm, Phase 3, open-label, multicenter study to compare the safety and efficacy of DS8201a versus the physician&#x27;s choice in HER2-low, unresectable and&#x2F;or metastatic breast cancer subjects.</p><p>The study is expected to enroll ~360 DS-8201a subjects and ~180 physician&#x27;s choice subjects.
After ~60 hormone receptor (HR)-negative subjects have been enrolled, further enrollment will be limited to only subjects who have HR-positive disease.
After ~240 HR-positive subjects who have not had prior therapy with a cyclin-dependent kinase (CDK) 4&#x2F;6 inhibitor have been enrolled, further enrollment will be limited to only subjects who have had prior therapy with a CDK4&#x2F;6 inhibitor.</p><p>The ~540 subjects will be randomized 2:1 to DS8201a versus the physician&#x27;s choice of 1 of the following drugs:</p><ul><li>Capecitabine</li><li>Eribulin</li><li>Gemcitabine</li><li>Paclitaxel</li><li>Nab-paclitaxel</li></ul><p>There will be approximately 164 sites, including but not limited to, North America, Western Europe, and Asia.</p><p>The Sponsor proposes to define a new HER2-low population in this trial including tumors with IHC 1+ and IHC 2+&#x2F;ISH- HER2 expression.</p>

<p>This is a randomized, 2-arm, Phase 3, open-label, multicenter study to compare the safety and efficacy of DS8201a versus the physician&#x27;s choice (2:1) in HER2-low, unresectable and&#x2F;or metastatic breast cancer subjects.</p><p>The study is expected to enroll ~360 DS-8201a subjects and ~180 physician&#x27;s choice subjects:</p><ul><li>60 hormone receptor (HR)-negative</li><li>240 HR-positive who have had prior therapy with a cyclin-dependent kinase (CDK) 4&#x2F;6 inhibitor</li><li>240 HR-positive who are naive to treatment with CDK 4&#x2F;6</li></ul><p>There will be approximately 161 sites, including but not limited to, North America, Western Europe, and Asia.</p><p>There are planned follow-up visits after permanent discontinuation of study treatment to obtain information about subsequent treatment(s) and survival status.</p><p>The Sponsor proposes to define a new HER2-low population in this trial including tumors with IHC 1+ and IHC 2+&#x2F;ISH- HER2 expression.</p>

DS-8201a Compared to Treatment of Physician's Choice for Participants With a Certain Kind of Breast Cancer That Has Spread or Cannot be Surgically Removed [DESTINY-Breast04]

DS-8201a Versus Investigator's Choice for HER2-low Breast Cancer That Has Spread or Cannot be Surgically Removed [DESTINY-Breast04]