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

• ClinicalTrials.gov Identifier: NCT03734029
• Recruitment Status: Active, not recruiting
• First Posted: November 7, 2018
• Results First Posted: June 15, 2023
• Last Update Posted: April 11, 2024
• Sponsor: Daiichi Sankyo
• Collaborators: Daiichi Sankyo Co., Ltd.; AstraZeneca
• Information provided by (Responsible Party): Daiichi Sankyo

Tracking Information

• First Submitted Date: November 6, 2018
• First Posted Date: November 7, 2018
• Results First Submitted Date: January 11, 2023
• Results First Posted Date: June 15, 2023
• Last Update Posted Date: April 11, 2024
• Actual Study Start Date: December 27, 2018
• Actual Primary Completion Date: January 11, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 15, 2023)

Progression-free Survival (PFS) Based on Blinded Independent Central Review (BICR) in the Hormone Receptor-Positive Cohort in Participants With HER2-low Breast Cancer [ Time Frame: From the date of randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause, up to approximately 3 years ]

Progression-free survival (PFS), defined as at least a 20% increase in the sum of diameters of target lesions, was assessed from the date of randomization to the date of the first radiographic disease progression or death due to any cause, whichever came first. PFS was based on blinded independent central review (BICR) in the hormone receptor-positive cohort according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1. Median PFS was from Kaplan-Meier analysis. Confidence interval for median was computed using the Brookmeyer-Crowley method.

Original Primary Outcome Measures (submitted: November 6, 2018)

Progression-free Survival (PFS) Based on Blinded Independent Central Review (BICR) [ Time Frame: at approximately 3 years ]

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. First dose at Cycle 1 Day 1 should occur within 7 days after the date the subject is randomized.

Current Secondary Outcome Measures (submitted: May 25, 2023)

• Progression-free Survival (PFS) Based on Blinded Independent Central Review (BICR) in Participants With HER2-low Breast Cancer (All Patients) Regardless of Hormone Receptor Status [ Time Frame: From the date of randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause, up to approximately 3 years ]
  Progression-free survival (PFS), defined as at least a 20% increase in the sum of diameters of target lesions, was assessed from the date of randomization to the date of the first radiographic disease progression or death due to any cause, whichever came first. PFS was based on blinded independent central review (BICR) according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1. Median PFS was from Kaplan-Meier analysis. Confidence interval for median was computed using the Brookmeyer-Crowley method.
• Progression-free Survival Based on Investigator Assessment in the Hormone Receptor-Positive Cohort in Participants With HER2-low Breast Cancer [ Time Frame: From the date of randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause, up to approximately 3 years ]
  Progression-free survival (PFS), defined as at least a 20% increase in the sum of diameters of target lesions, was assessed from the date of randomization to the date of the first radiographic disease progression or death due to any cause, whichever came first. PFS was based on investigator assessment in the hormone receptor-positive cohort according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1. Median PFS was from Kaplan-Meier analysis. Confidence interval for median was computed using the Brookmeyer-Crowley method.
• Progression-free Survival Based on Investigator Assessment in Participants With HER2-low Breast Cancer (All Patients) [ Time Frame: From the date of randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause, up to approximately 3 years ]
  Progression-free survival (PFS), defined as at least a 20% increase in the sum of diameters of target lesions, was assessed from the date of randomization to the date of the first radiographic disease progression or death due to any cause, whichever came first. PFS was based on investigator assessment according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1. Median PFS was from Kaplan-Meier analysis. Confidence interval for median was computed using the Brookmeyer-Crowley method.
• Overall Survival (OS) in the Hormone Receptor-Positive Cohort in Participants With HER2-low Breast Cancer [ Time Frame: From the date of randomization up to the date of death due to any cause, up to approximately 3 years ]
  Overall survival (OS) was defined as the time from the date of randomization to the date of death due to any cause. If there was no death reported for a participant before the data cutoff for OS analysis, OS was censored at the last contact date at which the participant was known to be alive.
• Number of Overall Survival Events (Deaths) [ Time Frame: From the date of randomization up to the date of death due to any cause, up to approximately 3 years ]
• Overall Survival (OS) in All Patients [ Time Frame: From the date of randomization up to the date of death due to any cause, up to approximately 3 years ]
  Overall survival (OS) was defined as the time from the date of randomization to the date of death due to any cause. If there was no death reported for a participant before the data cutoff for OS analysis, OS was censored at the last contact date at which the participant was known to be alive.
• Best Overall Response and Confirmed Objective Response Rate (ORR) in the Hormone Receptor-Positive Cohort in Participants With HER2-low Breast Cancer [ Time Frame: From screening and every 6 weeks up to withdrawal of subject consent, progressive disease (PD), or unacceptable toxicity, up to approximately 3 years ]
  Best overall response rate and confirmed objective response rate (ORR) were assessed by blinded independent central review (BICR) and investigator assessment. Complete response (CR) was defined as a disappearance of all target lesions, partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions. Confirmed ORR was defined as the number of participants with complete and partial responses and confirmed by a second assessment.
• Best Overall Response and Confirmed Objective Response Rate (ORR) in Participants With HER2-low Breast Cancer (All Patients) [ Time Frame: From screening and every 6 weeks up to withdrawal of subject consent, progressive disease (PD), or unacceptable toxicity, up to approximately 3 years ]
  Best overall response rate and confirmed objective response rate (ORR) were assessed by blinded independent central review (BICR) and investigator assessment. Complete response (CR) was defined as a disappearance of all target lesions, partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions. Confirmed ORR was defined as the number of participants with complete and partial responses and confirmed by a second assessment.
• Duration of Response in the Hormone Receptor-Positive Cohort in Participants With HER2-low Breast Cancer [ Time Frame: From the date of the first documented objective response (CR or PR) to the first documented disease progression or death, whichever occurs first, up to approximately 3 years ]
  Duration of Response (DoR) is defined as the date of the first documented objective response (complete response [CR] or partial response [PR]) to the first documented disease progression or death, whichever occurs first. DoR was based on blinded independent central review (BICR) and investigator assessment. Median was from Kaplan-Meier estimate. Confidence interval for median was computed using the Brookmeyer-Crowley method.
• Duration of Response in Participants With HER2-low Breast Cancer (All Patients) [ Time Frame: From the date of the first documented objective response (CR or PR) to the first documented disease progression or death, whichever occurs first, up to approximately 3 years ]
  Duration of Response (DoR) is defined as the date of the first documented objective response (complete response [CR] or partial response [PR]) to the first documented disease progression or death, whichever occurs first. DoR was based on blinded independent central review (BICR) and investigator assessment. Median was from Kaplan-Meier estimate. Confidence interval for median was computed using the Brookmeyer-Crowley method.

Original Secondary Outcome Measures (submitted: November 6, 2018)

• PFS based on Investigator Assessment [ Time Frame: at approximately 3 years ]
  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.
• Overall Survival (OS) [ Time Frame: at 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.
• Confirmed Objective Response Rate (ORR) [ Time Frame: at approximately 3 years ]
  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.
• Duration of Response (DoR), based on BICR and Investigator assessment [ Time Frame: at 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.

Current Other Pre-specified Outcome Measures (submitted: May 25, 2023)

All-Cause Mortality [ Time Frame: From the date of randomization up to the date of death due to any cause, up to approximately 3 years ]

All-cause mortality is defined as all anticipated and unanticipated deaths due to any cause, with the number and frequency of such events by arm or comparison group of the clinical study.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Trastuzumab Deruxtecan (DS-8201a) Versus Investigator's Choice for HER2-low Breast Cancer That Has Spread or Cannot be Surgically Removed [DESTINY-Breast04]
• Official Title: A Phase 3, Multicenter, Randomized, Open-label, Active Controlled Trial of DS-8201a, an Anti-HER2-antibody Drug Conjugate (ADC), Versus Treatment of Physician's Choice for HER2-low, Unresectable and/or Metastatic Breast Cancer Subjects

Brief Summary

This study will compare DS-8201a to physician choice standard treatment.

Participants must have HER2-low breast cancer that has been treated before.

Participants' cancer:

• Cannot be removed by an operation
• Has spread to other parts of the body

Detailed Description

This is a randomized, 2-arm, Phase 3, open-label, multicenter study to compare the safety and efficacy of trastuzumab deruxtecan versus the physician's choice (2:1) in HER2-low, unresectable and/or metastatic breast cancer participants.

The Sponsor proposes to define a new HER2-low population in this trial including tumors with IHC 1+ and IHC 2+/ISH- HER2 expression.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Parallel model, randomized at a 2:1 ratio

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Breast Cancer

Intervention

• Drug: Trastuzumab deruxtecan (DS-8201a)
  DS-8201a is a lyophilized powder reconstituted into a sterile aqueous solution (100 mg/5 mL) to be administered intravenously
  Other Name: DS-8201a
• Drug: Capecitabine
  Administered according to label, as one option for Physician's Choice (determined before randomization)
• Drug: Eribulin
  Administered according to label, as one option for Physician's Choice (determined before randomization)
• Drug: Gemcitabine
  Administered according to label, as one option for Physician's Choice (determined before randomization)
• Drug: Paclitaxel
  Administered according to label, as one option for Physician's Choice (determined before randomization)
• Drug: Nab-paclitaxel
  Administered according to label, as one option for Physician's Choice (determined before randomization)

Study Arms

• Experimental: Trastuzumab deruxtecan
  HER2-low, unresectable, and/or metastatic breast cancer participants previously treated with chemotherapy randomized to DS8201a
  Intervention: Drug: Trastuzumab deruxtecan (DS-8201a)
• Active Comparator: Physician's Choice

  HER2-low, unresectable, and/or metastatic breast cancer participants previously treated with chemotherapy randomized to Physician's choice from the following options:

  • Capecitabine
  • Eribulin
  • Gemcitabine
  • Paclitaxel
  • Nab-paclitaxel
  Interventions:

  • Drug: Capecitabine
  • Drug: Eribulin
  • Drug: Gemcitabine
  • Drug: Paclitaxel
  • Drug: Nab-paclitaxel

• Publications *: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. doi: 10.1056/NEJMoa2203690. Epub 2022 Jun 5.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 7, 2021): 557
• Original Estimated Enrollment (submitted: November 6, 2018): 540
• Estimated Study Completion Date: October 1, 2025
• Actual Primary Completion Date: January 11, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Is the age of majority in their country

• Has pathologically documented breast cancer that:

  1. Is unresectable or metastatic
  2. Has low-HER2 expression defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested)
  3. Is HR-positive or HR-negative
  4. Has progressed on, and would no longer benefit from, endocrine therapy
  5. Has been treated with 1 to 2 prior lines of chemotherapy/adjuvant in the recurrent or metastatic setting
  6. Was never previously HER2-positive (ICH 3+ or ISH+) on prior pathology testing (per American Society of Clinical Oncology-College of American Pathologists [ASCO-CAP] guidelines)
• Has documented radiologic progression (during or after most recent treatment)

• Has adequate archival tumor samples available or is wiling to provide fresh biopsies prior to randomization for:

  1. assessment of HER2 status
  2. assessment of post-treatment status
• Has at least 1 measurable lesion per Response Evaluation Criteria In Solid Tumors 1.1
• Has protocol-defined adequate cardiac, bone marrow, renal, hepatic and blood clotting functions
• Male and female participants of reproductive/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)

Exclusion Criteria:

• Is ineligible for all options in the physician's choice arm
• Has breast cancer ever assessed with high-HER2 expression
• Has previously been treated with any anti-HER2 therapy, including an antibody drug conjugate
• Has uncontrolled or significant cardiovascular disease
• Has spinal cord compression or clinically active central nervous system metastases
• Has history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening
• Has any medical history or condition that per protocol or in the opinion of the investigator is inappropriate for the study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Belgium, Canada, China, France, Germany, Greece, Hungary, Israel, Italy, Japan, Korea, Republic of, Portugal, Russian Federation, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT03734029
• Other Study ID Numbers: DS8201-A-U303; 2018-003069-33 ( EudraCT Number ); 184223 ( Registry Identifier: JAPIC CTI ); DESTINY-B04 ( Other Identifier: Daiichi Sankyo and AstraZeneca )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• URL: https://vivli.org/ourmember/daiichi-sankyo/

• Current Responsible Party: Daiichi Sankyo
• Original Responsible Party: Same as current
• Current Study Sponsor: Daiichi Sankyo
• Original Study Sponsor: Same as current

Collaborators

• Daiichi Sankyo Co., Ltd.
• AstraZeneca

Investigators

• Study Director: Global Clinical Leader; Daiichi Sankyo

• PRS Account: Daiichi Sankyo
• Verification Date: April 2024