Study Design

DESTINY-Breast04: Study Design

Study Design
Statistical Analysis
Key Eligibility Criteria

Study Design

Study of T-DXd vs Investigator’s Choice for Patients With HER2-Low Unresectable and/or Metastatic BC¹

DESTINY-Breast04 is an open-label, multicenter, Phase III study of T-DXd versus TPC in patients with HER2-low, unresectable, and/or metastatic BC who were previously treated with 1-2 lines of chemotherapy in the metastatic setting. Patients with HR+ disease must have received ≥1 endocrine therapy.²
A total of 557 patients with HER2-low metastatic BC were randomly assigned 2:1 to receive T‑DXd 5.4 mg/kg (n=373) IV Q3W or TPC (n=184) (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel).²

Study Design.^2-4

^aIf patients had HR+ metastatic BC, prior endocrine therapy was required;^bPerformed on adequate archived or recent tumor biopsy per ASCO/CAP guidelines using the VENTANA HER2/neu (4B5) investigational use only [IUO] Assay system; ^cTPC was administered according to the label; ^dEfficacy in the HR− cohort was an exploratory endpoint; ^eThe patient-reported outcomes analysis was conducted in the HR+ cohort (per the statistical analysis plan) since the primary efficacy endpoint was evaluated in the HR+ cohort.

Statistical Analysis

Statistical Analysis and Hierarchical Testing^2,5

Hierarchical testing was used for DESTINY-Breast04 to control the overall family-wise type-I error and maintain the overall 2-sided type-I error rate of 0.05 or less.²
The primary and key secondary endpoints were hierarchically tested in the following order: PFS in the HR+ cohort, PFS in all patients, OS in the HR+ cohort until positive read-out (significant difference between treatment arms is observed), then OS in all patients.²
Therefore, PFS and OS were statistically powered to determine superiority in both the HR+ and all-patient cohorts.²

Key Eligibility Criteria

Key Eligibility Criteria^1,6

Key Eligibility Criteria in DESTINY-Breast04.

Key Inclusion Criteria	Key Exclusion Criteria
Age of majority in respective countries	Ineligible for all of the physician’s treatment of choice options
Pathologically documented breast cancer that is unresectable or metastatic, has HER2-low expression (IHC 2+/ISH− or IHC 1+), and was previously treated with 1-2 lines of chemotherapy/adjuvant in the metastatic setting12.	Prior treatment with an anti-HER2 therapy or an ADC that consist of a topoisomerase I inhibitor
Never previously HER2-positive (IHC 3+ or IHC 2+/ISH+) on prior pathology testing or was historically HER2 IHC 0 only	Uncontrolled or significant CVD
Never previously treated with anti-HER2 therapy	Medical history of (non-infectious) ILD/pneumonitis that required steroids or active or suspected ILD/pneumonitis
Documented radiologic progression of disease	Spinal cord compression or active CNS metastases that are untreated and symptomatic, or require therapy to control symptoms
Protocol-defined adequate cardiac, bone marrow, renal, hepatic, and blood clotting functions

¹Eligible patients must have received chemotherapy in the metastatic setting or have developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. If patients had HR+ mBC, prior endocrine therapy was required.

Abbreviations

ADC = antibody-drug conjugate

;

ASCO/CAP = American Society of Clinical Oncology/College of American Pathologists

;

BC = breast cancer

;

BICR = blinded independent central review

;

CDK4/6i = cyclin-dependent kinase 4/6 inhibitor

;

CNS = central nervous system

;

CVD = cardiovascular disease

;

DOR = duration of response

;

HER2 = human epidermal growth factor receptor 2

;

HR = hormone receptor

;

IHC = immunohistochemistry

;

ISH = in situ hybridization

;

IV = intravenous

;

ORR = objective response rate

;

OS = overall survival

;

PFS = progression-free survival

;

Q3W = every 3 weeks

;

T-DXd = trastuzumab deruxtecan

;

TPC = treatment of physician's choice

References

1. Daiichi Sankyo, Inc. 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 website. https://clinicaltrials.gov/ct2/show/NCT03734029
2. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer [article]. N Engl J Med. 2022;387:9-20
3. Harbeck N, Modi S, Jacot W, et al. Trastuzumab deruxtecan vs treatment of physician’s choice in patients with HER2-low unresectable and/or metastatic breast cancer: subgroup analyses from DESTINY-Breast04 [poster]. Poster presented at: San Antonio Breast Cancer Symposium (SABCS); December 6-10, 2022; San Antonio, TX. Poster P1-11-01.
4. Prat A, Modi S, Tsurutani J, et al. Determination of HER2-low status in tumors of patients with unresectable and/or metastatic breast cancer in DESTINY-Breast04 [poster]. Poster presented at: San Antonio Breast Cancer Symposium (SABCS) 2022, December 6-10, 2022; San Antonio, TX, USA. Poster HER2-18.
5. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan (T-DXd) Vs treatment of physician’s choice in patients with HER2-low unresectable and/or metastatic breast cancer: results of DESTINY-Breast04, a randomized, phase 3 study [abstract and presentation]. Presented at: American Society of Clinical Oncology (ASCO) Congress; June 3-5, 2022; Chicago, IL. J Clin Oncol. 2022;40(suppl 17). Abs LBA3.
6. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer [protocol]. N Engl J Med. 2022;387:9-20.

Please note that this content may contain some data and/or patient populations which are considered off-label in your country. Providing this information does not constitute any recommendation for use. AstraZeneca is providing this material as an information service and professional courtesy.

To help us improve our content for health care professionals, please take this short survey.

Feedback Survey

Privacy Notice Legal Notice Cookie Policy