A Study of T-DXd in Participants With or Without Brain Metastasis Who Have Previously Treated Advanced or Metastatic HER2 Positive Breast Cancer (DESTINY-B12)

An Open-Label, Multinational, Multicenter, Phase 3b/4 Study of Trastuzumab Deruxtecan in Patients With or Without Baseline Brain Metastasis With Previously Treated Advanced/Metastatic HER2-Positive Breast Cancer (DESTINY-Breast12)

This is open-label, multicenter, international study, assessing the efficacy and safety of Trastuzumab deruxtecan (T-DXd) in participants with or without brain metastasis (BMs), with previously-treated advanced/metastatic HER2-positive breast cancer whose disease has progressed on prior anti-HER2-based regimens and who received no more than 2 lines/regimens of therapy in the metastatic setting (excluding tucatinib).

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Trastuzumab Deruxtecan

Detailed Description

Approximately 500 eligible participants will be enrolled into 1 of 2 cohorts (250 participants in each cohort) according to the presence or absence of BMs at baseline. Cohort 1 will include participants without BM at baseline and Cohort 2 will consist of participants with BM at baseline.

After study intervention discontinuation, all participants will undergo an end-of-treatment visit (within 7 days of discontinuation) and will be followed up for safety assessments 40 (+ up to 7) days after the discontinuation of all study intervention.

All participants will be followed up for survival status and duration of treatment on subsequent therapies after intervention discontinuation every 3 months (± 14 days) from the date of the safety follow-up until death, withdrawal of consent, or the end of the study, as per defined in the protocol.

• Study Type: Interventional
• Enrollment (Actual): 506
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia, 5000
    • Research Site
  • Auchenflower, Australia, 4066
    • Research Site
  • Clayton, Australia, 3168
    • Research Site
  • Heidelberg, Australia, 3084
    • Research Site
  • St Leonards, Australia, 2065
    • Research Site
  • Subiaco, Australia, 6008
    • Research Site
• Belgium
  • Anderlecht, Belgium, 1070
    • Research Site
  • Bruges, Belgium, 8000
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
  • Liège, Belgium, 4000
    • Research Site
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1H7
      • Research Site
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Research Site
• Denmark
  • Copenhagen, Denmark, 2100
    • Research Site
  • Herlev, Denmark, 2730
    • Research Site
  • Odense C, Denmark, 5000
    • Research Site
• Finland
  • Helsinki, Finland, 00290
    • Research Site
  • Tampere, Finland, FI-33521
    • Research Site
  • Turku, Finland, 20520
    • Research Site
• Germany
  • Berlin, Germany, 13125
    • Research Site
  • Dresden, Germany, 1307
    • Research Site
  • Erlangen, Germany, 91054
    • Research Site
  • Essen, Germany, 45136
    • Research Site
  • Frankfurt, Germany, 60389
    • Research Site
  • Hamburg, Germany, 20246
    • Research Site
  • Hanover, Germany, 30625
    • Research Site
  • Kiel, Germany, 24105
    • Research Site
  • Mannheim, Germany, 68167
    • Research Site
  • München, Germany, 80336
    • Research Site
  • München, Germany, 80637
    • Research Site
  • Münster, Germany, 48149
    • Research Site
  • Tübingen, Germany, 72076
    • Research Site
• Ireland
  • Cork, Ireland, T12 DV56
    • Research Site
  • Dublin, Ireland, 7
    • Research Site
  • Dublin, Ireland, D04 Y8V0
    • Research Site
• Italy
  • Ancona, Italy, 60122
    • Research Site
  • Bergamo, Italy, 24127
    • Research Site
  • Catania, Italy, 95126
    • Research Site
  • Milan, Italy, 20132
    • Research Site
  • Naples, Italy, 80131
    • Research Site
  • Padova, Italy, 35128
    • Research Site
  • Prato, Italy, 59100
    • Research Site
• Japan
  • Isehara, Japan, 259-1193
    • Research Site
  • Kawasaki-shi, Japan, 216-8511
    • Research Site
  • Sapporo, Japan, 003-0804
    • Research Site
  • Shinagawa-ku, Japan, 142-8666
    • Research Site
  • Yokohama, Japan, 241-8515
    • Research Site
• Netherlands
  • Maastricht, Netherlands, 6229 HX
    • Research Site
  • The Hague, Netherlands, 2545 AA
    • Research Site
• Norway
  • Bergen, Norway, 5009
    • Research Site
  • Oslo, Norway, 450
    • Research Site
  • Oslo, Norway, N-0379
    • Research Site
• Poland
  • Gdansk, Poland, 80-214
    • Research Site
  • Krakow, Poland, 31-501
    • Research Site
  • Opole, Poland, 45-060
    • Research Site
  • Warsaw, Poland, 02-781
    • Research Site
  • Warsaw, Poland, 04-141
    • Research Site
• Portugal
  • Lisbon, Portugal, 1649-035
    • Research Site
  • Lisbon, Portugal, 1400-048
    • Research Site
  • Porto, Portugal, 4099-001
    • Research Site
• Spain
  • Barcelona, Spain, 08036
    • Research Site
  • Barcelona, Spain, 8035
    • Research Site
  • Bilbao (Vizcaya), Spain, 48013
    • Research Site
  • Granada, Spain, 18014
    • Research Site
  • Madrid, Spain, 28034
    • Research Site
  • Madrid, Spain, 28041
    • Research Site
  • Madrid, Spain, 28005
    • Research Site
  • Salamanca, Spain, 37007
    • Research Site
  • Santander, Spain, 39008
    • Research Site
  • Santiago de Compostela-Coruña, Spain, 15706
    • Research Site
  • Seville, Spain, 41013
    • Research Site
  • Valencia, Spain, 46009
    • Research Site
• Sweden
  • Gothenburg, Sweden, 413 45
    • Research Site
  • Lund, Sweden, 221 85
    • Research Site
  • Uppsala, Sweden, 751 85
    • Research Site
• Switzerland
  • Basel, Switzerland, 4031
    • Research Site
  • Bellinzona, Switzerland, CH-6500
    • Research Site
  • Lausanne, Switzerland, 1011
    • Research Site
  • Lucerne, Switzerland, 6000
    • Research Site
• United Kingdom
  • Edinburgh, United Kingdom, EH4 2XR
    • Research Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Research Site
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion:

• Participants should have pathologically documented breast cancer that is: unresectable/advanced or metastatic; confirmed HER2-positive status expression as determined according to American Society of Clinical Oncology/College of American Pathologists guidelines
• Participant must have either: no evidence of BM, or untreated BM on screening contrast brain magnetic resonance imaging/ computed tomography (MRI/CT) scan, not needing immediate local therapy or previously-treated stable or progressing BM
• Participants with BMs must be neurologically stable
• For participants requiring radiotherapy due to BMs, there should be an adequate washout period before day of first dosing:
• ≥ 7 days since stereotactic radiosurgery or gamma knife
• ≥ 21 days since whole brain radiotherapy
• Eastern Cooperative Oncology Group performance status 0-1
• Previous breast cancer treatment: radiologic or objective evidence of disease progression on or after HER2 targeted therapies and no more than 2 lines/regimens of therapy in the metastatic setting
• Participant with the following measurable: at least 1 lesion that can be accurately measured at baseline as ≥ 10 mm in the longest diameter with CT or MRI and is suitable for accurate repeated measurements; or following Non-measurable diseases: Non-measurable, bone-only disease that can be assessed by CT or MRI or X-Ray. Lytic or mixed lytic bone lesions that can be assessed by CT or MRI or X-ray in the absence of measurable disease as defined above is acceptable; Participants with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible; and Non-measurable CNS disease (Cohort 2 only)
• Adequate organ and bone marrow function within 14 days before the day of first dosing as defined in the protocol
• Left ventricular ejection fraction ≥ 50% within 28 days before enrollment
• Negative pregnancy test (serum) for women of childbearing potential

Exclusion Criteria

• Known or suspected leptomeningeal disease
• Prior exposure to tucatinib treatment
• Refractory nausea and vomiting, chronic gastrointestinal disease, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of T-DXd
• History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence
• Based on screening contrast brain MRI/CT scan, participants must not have any of the following: any untreated brain lesions > 2.0 cm in size; ongoing use of systemic corticosteroids for control of symptoms of BMs; any brain lesion thought to require immediate local therapy; have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to BMs not withstanding CNS-directed therapy
• Has spinal cord compression
• Known active hepatitis B or C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1 Day 1. Participants with past or resolved hepatitis B virus infection are eligible, if negative for hepatitis B surface antigen and positive for anti-hepatitis B core antigen
• Participants positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
• Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
• Receipt of live, attenuated vaccine within 30 days prior to the first dose of T-DXd
• Participants with a medical history of myocardial infarction within 6 months before screening, symptomatic congestive heart failure (New York Heart Association Class II to IV)
• History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
• Lung-specific intercurrent clinically significant illnesses and any autoimmune, connective tissue or inflammatory disorders
• Prior exposure, without adequate treatment washout period before the day of first dosing, to chloroquine/hydroxychloroquine: < 14 days
• Anticancer chemotherapy: immunotherapy (non-antibody-based therapy), retinoid therapy, hormonal therapy: < 3 weeks
• < 6 weeks for nitrosoureas or mitomycin
• Antibody-based anticancer therapy: < 4 weeks
• Any concurrent anticancer treatment. Concurrent use of hormonal therapy for noncancer- related conditions is allowed
• Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline
• Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation, radiation to the chest, or to more than 30% of the bone marrow within 4 weeks before the first dose of study intervention
• Participants with prior exposure to immunosuppressive medication within 14 days prior to first study dose
• Participants with a known hypersensitivity to study intervention or any of the excipients of the product or other monoclonal antibodies

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Trastuzumab Deruxtecan; Participants with or without BM at baseline will receive intravenous (IV) T-DXd, 5.4 mg/kg, every 3 weeks (21-day cycle) until Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) defined radiological progression outside central nervous system, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation is met.	Drug: Trastuzumab Deruxtecan; Participants will receive T-DXd administered using an IV bag containing 5% (w/v) dextrose injection infusion solution.; Other Names: fam-trastuzumab deruxtecan-nxki

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) in Cohort 1 (Participants Without Brain Metastasis at Baseline)	The ORR is defined as the percentage (%) of participants who have a confirmed complete response (CR) or confirmed partial response (PR), as determined by independent central review (ICR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.	From first dose (Day 1) to progression of disease (up to 2 years 7 months)
Progression-free Survival (PFS) Rate at 12 Months in Cohort 2 (Participants With Brain Metastasis at Baseline)	The PFS rate is the percentage of participants alive and free of disease progression at 12 months, estimated by the Kaplan-Meier method.	At 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival Rate at 12 Months	Survival rate is the percentage of participants alive at 12 months, estimated by the Kaplan-Meier method.	At 12 Months
Objective Response Rate in Cohort 2 (Participants With Brain Metastasis at Baseline)	The ORR is defined as the percentage of participants who have a confirmed CR or confirmed PR, as determined by ICR per RECIST 1.1.	From first dose (Day 1) to progression of disease (up to 2 years 7 months)
Duration of Response (DoR)	Duration of response is defined as the time from the date of first documented confirmed response until date of documented progression per RECIST 1.1 as assessed by ICR or death due to any cause.	From the date of first documented confirmed response until date of documented progression (up to 2 years 7 months)
Time to Progression	Time to progression by RECIST 1.1 per ICR is defined as the time from the date of the first dose of study intervention to the date of documented disease progression.	From first dose (Day 1) to progression of disease (up to 2 years 7 months)
Duration of Treatment on Subsequent Lines of Therapy	Duration of treatment on subsequent therapy is defined as the time from the date of first dose of a subsequent therapy until date of the last dose of that therapy.	From the date of first dose of a subsequent therapy until date of last dose of therapy (up to 2 years 7 months)
Second Progression-Free Survival Rate at 12 Months	Second progression-free survival rate is the percentage of participants alive and free from a second progression on next-line treatment at 12 months, estimated by the Kaplan-Meier method. The second progression is defined as the earliest progression event subsequent to the first anti-cancer therapy after the initial progression.	At 12 Months
Incidence of New Symptomatic Central Nervous System (CNS) Metastasis During Treatment Without CNS Metastasis at Baseline (Cohort 1)	The incidence rate is defined as proportion of participants with new symptomatic CNS metastases during treatment period in participants without symptomatic CNS metastasis at baseline.	From first dose (Day 1) to end of treatment (up to 2 years 7 months)
Time to Next Progression (CNS or Extracranial) or Death	The time to next progression is defined as the time from the date of the first documented isolated CNS progression to the date of the next documented disease progression (CNS or extracranial) per RECIST 1.1 or death and has been summarized descriptively in participants who have developed isolated CNS progression, receive local therapy, and continue on protocol therapy.	From date of first documented isolated CNS progression to the date of the next documented disease progression (up to 2 years 7 months)
Site (CNS vs Extracranial vs Both) of Next Progression	Site of next progression (CNS [CNS RECIST 1.1] or extracranial [systemic RECIST 1.1] in participants who developed isolated CNS progression, received local therapy, and continued on protocol therapy.	From the date of the first documented isolated CNS progression to the date of the next documented CNS disease progression (up to 2 years 7 months)
Central Nervous System Progression-free Survival Rate at 12 Months in Participants With Brain Metastasis at Baseline (Cohort 2)	Central nervous system progression free survival rate is the percentage of participants free from central nervous system progression at 12 months, estimated by the Kaplan-Meier method.	At 12 Months
Time to New CNS Lesions in Participants With Brain Metastasis at Baseline (Cohort 2)	The time to new CNS lesions is defined as the time from the date of the first dose of study intervention to the date of documented new CNS lesions by RECIST 1.1 per ICR.	From first dose (Day 1) to the date of documented new CNS lesions (up to 2 years 7 months)
Central Nervous System Objective Response Rate in Participants With Brain Metastasis at Baseline by ICR (Cohort 2)	The CNS ORR is defined as the percentage of participants with measurable brain metastasis at baseline who have a confirmed CR or confirmed PR of brain lesions, as determined by ICR per CNS RECIST 1.1.	From first dose (Day 1) until CNS progression of disease (up to 2 years 7 months)
Central Nervous System Duration of Response in Participants With Brain Metastasis at Baseline (Cohort 2)	The CNS DoR is defined as the time from the date of first documented confirmed CNS response until date of documented CNS progression per CNS RECIST 1.1 as assessed by ICR or death due to any cause.	From date of first documented confirmed CNS response until CNS progression of disease (up to 2 years 7 months)
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30)	The EORTC QLQ-C30 is a 30-item questionnaire for cancer assessment. Increased scores indicate improvement; decreased scores indicate deterioration. Physical function: ≥+9= improvement, ≤-10=deterioration, otherwise=no change; Role functioning: ≤-6=deterioration, otherwise=no change; Social functioning: ≥+8=improvement, ≤-7=deterioration, otherwise=no change; Cognitive functioning: ≥+ 5=improvement, ≤- 4=deterioration, otherwise=no change; Global Health Status: ≥+2=improvement, ≤-8=deterioration, otherwise=no change; Fatigue: ≥+8=improvement, ≤-8=deterioration, otherwise=no change; Nausea and vomiting: ≤-11=deterioration, otherwise=no change; Appetite loss: ≤-14=deterioration, otherwise=no change; rest of scales: ≥+10=improvement, ≤-10=deterioration, otherwise=no change. Best on treatment response is best response category (improvement, no change, and deterioration) achieved by participants between first dose and 47 days after last dose, and prior to starting any anticancer therapy.	Time from first dose up to 47 days after last dose, or prior to starting any subsequent therapy, or for up to 2 years 7 months, whichever occurred first
Number of Participants With Neurologic Assessment in Neuro-Oncology Scale (NANO Scale)	The NANO scale is a clinician-reported assessment of neurologic functioning in neuro-oncology participants. The instrument captures 9 domains (gait, strength, ataxia, sensation, visual fields, facial strength, language, level of consciousness, and behavior) and was developed to provide a simple, objective assessment of neurologic function that would be combined with radiographic assessment to provide an overall outcome assessment for neuro-oncology participants in clinical trials and in daily practice. The soring scale for Gait consists of score range 0-3, Strength consists of score range 0-2, ataxia (upper extremity) consists of scale range 0-2 and sensation as 0. Higher scores indicate worse neurologic function. The response categories reported are changes from first post-baseline score to worst on-treatment score at any point of treatment.	Time from first dose up to 47 days after last dose, or prior to starting any subsequent therapy, or for up to 2 years 7 months, whichever occurred first
Cognitive Functions Tests: Paired Associates Learning (PAL) First Attempt Memory Score (PALFAMS)	The PAL is a computerized, self-completed cognitive test used to capture cognitive function, including attention, memory, and executive function. This gamified test included PAL and was a low-burden, highly sensitive, precise measure of cognitive function. The PALFAMS is the number of times a participant chose the correct box on their first attempt when recalling the pattern locations, calculated across all assessed trials. A higher number of events of selecting correct boxes indicates better cognitive function. Here, baseline was the last non-missing value prior to administration of the first dose of study intervention.	Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle)
Cognitive Functions Tests: Paired Associates Learning Total Errors Adjusted (PALTEA)	The PAL is a computerized, self-completed cognitive test used to capture cognitive function, including attention, memory, and executive function. This gamified test included PALTEA and was a low-burden, highly sensitive, precise measure of cognitive function. PALTEA is the number of times a participant chose the incorrect box for a stimulus on assessment problems, plus an adjustment for the estimated number of errors they would have made on any problems, attempts, and recalls they did not reach. A higher number of events of selecting incorrect boxes indicates worse cognitive function. Here, baseline was the last non-missing value prior to administration of the first dose of study intervention.	Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle)
Cognitive Functions Tests: Reaction Time (RTI)	This is a computerized, self-completed cognitive test used to capture cognitive function, including attention, memory, and executive function. This gamified test included Reaction Time Task (RTI) and was low-burden, highly sensitive, precise measures of cognitive function. RTI Median Five-Choice Movement Time: median time taken for a participant to release response button and select target stimulus after it flashed yellow on screen. Calculated across correct, assessed trials in which stimulus could appear in any one of five locations. RTI Median Five-Choice Reaction Time: median duration it took for a participant to release response button after presentation of target stimulus. Calculated across correct, assessed trials in which stimulus could appear in any one of five locations. Measured in milliseconds. Higher reaction times indicate worse cognitive function. Here, baseline was the last non-missing value prior to administration of the first dose of study intervention.	Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle)
Cognitive Functions Tests: Spatial Working Memory (SWM)	The SWM is a computerized cognitive test. The SWM Between Errors (SWMBE) is number of times a participant incorrectly revisits a box in which a token has previously been found, calculated across all 4, 6, and 8 token trials. SWM Between Errors 4 Boxes (SWMBE4), SWM Between Errors 6 Boxes (SWMBE6), and SWM Between Errors 8 Boxes (SWMBE8) are number of times a participant revisits a box in which a token has previously been found. These are calculated across all trials with 4 tokens only for SWMBE4, 6 tokens only for SWMBE6, and 8 tokens only for SWMBE8. SWM Total Errors is number of times a box is selected that is certain not to contain a token and therefore should not have been visited by participant. A higher number of incorrect revisit events to previously found token boxes indicates worse cognitive function, and a lower number of revisit events indicates better cognitive function. Here, baseline was last non-missing value prior to administration of first dose of study intervention.	Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle)
Cognitive Functions Tests: Spatial Working Memory Strategy (SWMS)	The SWM is a computerized cognitive test. The SWMS, the number of times a participant restarted search patterns from the same initial box, indicating their use of a planned strategy to find tokens. An increased number of events where search patterns started from the same initial box suggested participants were using a planned strategy to find tokens, which indicated better cognitive function. Here, a low score indicated high strategy use (1 = they always began the search from the same box). Conversely, high scores represented a decrease in events of beginning searches from the same box. Instead, starting from many different boxes suggested the participant was not using a consistent strategy, which indicated worse cognitive function. This was calculated across assessed trials with 6 tokens or more. Here, baseline was the last non-missing value prior to administration of the first dose of study intervention.	Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle)
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis	The effect of T-DXd on symptoms, functioning, and HRQoL in HER2+ MBC participants with or without baseline brain metastasis was evaluated. The SGRQ-I is an idiopathic pulmonary fibrosis-specific version of the instrument developed and validated for use among participants with idiopathic pulmonary fibrosis, a type of ILD. The SGRQ-I was used to assess the HRQoL among participants who have been diagnosed with ILD/pneumonitis. It includes 34 of the original SGRQ items determined to be most reliable for assessing the HRQoL of participants with idiopathic pulmonary fibrosis. The instrument yields 3 domain scores (symptoms, activity, and impact) as well as a total score, with scores ranging from 0 to 100. Higher scores indicate greater impairment in HRQoL.	From time of ILD/pneumonitis diagnosis (every week) until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants	The T-DXd on symptoms, functioning, and HRQoL in HER2+ MBC participants with or without baseline brain metastasis was evaluated. The MDASI brain tumor module includes 9 symptoms specific to brain tumors (weakness on one side of the body, difficulty understanding, difficulty speaking, seizures, difficulty concentrating, problems with vision, change in appearance, change in bowel pattern (diarrhea or constipation), and irritability). These 9 items will be used to capture symptoms associated with brain metastasis for those diagnosed with brain metastasis. Each item is rated on an 11-point numeric rating scale on a scale of 0-10, with higher scores indicating greater symptom severity. Here, baseline was the last non-missing value prior to administration of the first dose of study intervention.	Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 39 Day 1 (21 days cycle)
Number of Participants With Adverse Events (AEs)	The safety and tolerability of the participants who received T-DXd was evaluated. SAE=Serious adverse events; CTCAE=Common Terminology for Adverse Events	From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Number of Participants With Investigator-assessed ILD/Pneumonitis	The number of participants with ILD/Pneumonitis were by grouped term based on Investigator-reported preferred terms. No adjudication was performed.	From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Number of Participants With ILD Clinical Symptoms Resolution Among ILD/Pneumonitis Participants Who Have Been Treated With High Dose Steroid	The number of participants with ILD clinical symptoms resolution in ILD/Pneumonitis participants who have been treated with high dose steroid (>2 mg dexamethasone) were evaluated.	From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Daiichi Sankyo
• Investigators: Principal Investigator: Nadia Harbeck, MD, PhD, Head, Breast Center, Ludwig-Maximilians-University of Munich Department of Obstetrics and Gynecology Marchioninistr. 15, 81377 Munich, Germany; Principal Investigator: Nancy U. Lin, MD, Associate Chief, Division of Breast Oncology, Susan F. Smith Center for Women's Cancers Director, Metastatic Breast Cancer Program, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215

Publications and helpful links

General Publications

• Harbeck N, Ciruelos E, Jerusalem G, Muller V, Niikura N, Viale G, Bartsch R, Kurzeder C, Higgins MJ, Connolly RM, Baron-Hay S, Gion M, Guarneri V, Bianchini G, Wildiers H, Escriva-de-Romani S, Prahladan M, Bridge H, Kuptsova-Clarkson N, Scotto N, Verma S, Lin NU; DESTINY-Breast12 study group. Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Nat Med. 2024 Dec;30(12):3717-3727. doi: 10.1038/s41591-024-03261-7. Epub 2024 Sep 13.

Helpful Links

• Redacted Statistical Analysis Plan
• Redacted CSP
• Redacted CSR synopsis

Study record dates

Study Major Dates

• Study Start (Actual): June 22, 2021
• Primary Completion (Actual): February 8, 2024
• Study Completion (Estimated): May 26, 2027

Study Registration Dates

• First Submitted: January 20, 2021
• First Submitted That Met QC Criteria: February 2, 2021
• First Posted (Actual): February 5, 2021

Study Record Updates

• Last Update Posted (Actual): May 12, 2026
• Last Update Submitted That Met QC Criteria: April 29, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Brain Metastasis; Trastuzumab deruxtecan; Human epidermal growth factor receptor 2 Positive Breast Cancer
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Nervous System Neoplasms; Central Nervous System Neoplasms; Skin and Connective Tissue Diseases; Breast Neoplasms; Brain Neoplasms; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Immunoconjugates; trastuzumab deruxtecan
• Other Study ID Numbers: D9673C00007; 2020-005048-46 (EudraCT Number); 2024-510588-53-00 (Registry Identifier: CTIS (EU))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes