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Study of T-DXd vs T-DM1 for Patients With High-Risk HER2 positive Primary BC in the Post Neoadjuvant Setting

Study of T-DXd vs T-DM1 for Patients With High-Risk HER2 positive Primary BC in the Post Neoadjuvant Setting1,2

A Phase III, multicenter, randomized, open-label, active-controlled trial of T-DXd vs T-DM1 for patients with high-risk HER2 positive primary BC following neoadjuvant therapy (North America, South America, Europe, Asia, Australia)1

Study Design2

Study Design2

Endpoints1,2

Primary:

  • IDFSa

Secondary:

  • DFSa
  • DRFIa
  • BMFIa
  • OS
  • Safety and tolerability
  • PK
  • Incidence of ADA

Key Eligibility Criteria

Key Eligibility Criteria1,2

Key Eligibility Criteria in DESTINY-Breast051,2
Key Inclusion CriteriaKey Exclusion Criteria
Adults ≥ 18 years old (local regulatory requirements may apply if the legal age for study participation is >18 years)Stage IV (metastatic) BC
Histologically confirmed invasive BC at presentationHistory of prior (ipsi- or contralateral) BC except LCIS
Clinical stage at presentation: T1-4,N0-3, M0 (T1N0 tumors are not eligible)Clinically evident gross residual or recurrent disease following neoadjuvant therapy and surgery
Centrally confirmeda HER2-positive BC (IHC3+ or ISH+) based on pretreatment biopsy or surgical specimenPrior treatment with T-DXd, T-DM1, or other anti-HER2 ADC
Completion of neoadjuvant systemic chemotherapy and HER2 directed treatment
  • ≥6 cycles of chemotherapy with a total duration of ≥16 weeks
  • ≥9 weeks of trastuzumab (± pertuzumab) and ≥9 weeks of taxane-based chemotherapy (± anthracycline)

History of exposure to the following cumulative doses of anthracyclines:

  • Doxorubicin >240 mg/m2
  • Epirubicin or Liposomal Doxorubicin-Hydrochloride >480 mg/m2
  • For other anthracyclines, exposure equivalent to doxorubicin >240 mg/m2
Pathologic evidence of residual invasive carcinoma in the breast and/or axillary lymph nodes following completion of neoadjuvant therapy meeting one of the following high-risk criteria:
  • Inoperable at presentation (prior to neoadjuvant therapy), defined as clinical stages T4,N0-3, M0 or T1-3, N2-3,M0
  • Operable at presentation, defined as clinical stages T1-3, N0-1,M0, with axillary node positive disease (ypN1-3) following neoadjuvant therapy
History of other malignancy within the last 5 years except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, stage I melanoma skin carcinoma, stage I uterine cancer, or other non-breast malignancies
Adequate excision confirmed per medical records: surgical removal of all clinically evident disease in the breast and lymph nodesHistory of (non-infectious) ILD/pneumonitis that required steroids, current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by screening imaging
Adequate organ function within 14 days before randomization, ≤12 weeks between date of last surgery and randomization, and LVEF ≥50% within 28 days prior to randomizationMedical history of myocardial infarction within 6 months, symptomatic CHF, troponin levels consistent with myocardial infarction 28 days prior to randomization
Known HR (estrogen receptor, progesterone receptor) status per local laboratory assessmentQTcF prolongation >450 ms in males and >470 ms in females
 Known pulmonary compromise resulting from intercurrent pulmonary illnesses or any autoimmune, connective tissue, or inflammatory disorders with pulmonary involvement
aPretreatment biopsy to be used. If material is insufficient, residual tumor tissue taken at definitive surgery can be used instead..

Abbreviations

ADA = anti-drug antibody

;

ADC = antibody-drug conjugate

;

BC = breast cancer

;

BMFI = brain metastases-free interval

;

CHF = congestive heart failure

;

DFS = disease-free survival

;

DRFI = distant recurrence-free interval

;

ECOG = Eastern Cooperative Oncology Group

;

HER2 = human epidermal growth factor receptor 2

;

HR = hormone receptor

;

IDFS = invasive disease-free survival

;

IHC = immunohistochemistry

;

ILD = Interstitial Lung Disease

;

ISH = in-situ hybridization

;

LCIS = lobular carcinoma in situ

;

LVEF = left ventricular ejection fraction

;

mo = months

;

OS = overall survival 

;

PK = pharmacokinetics

;

PS = performance status

;

q3w = every 3 weeks

;

QTcF = QT interval corrected using Fridericia’s formula

;

T-DM1 = trastuzumab emtansine

;

T-DXd = trastuzumab deruxtecan

References

1. Daiichi Sankyo, Inc. A study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in high-risk HER2-positive participants with residual invasive breast cancer following neoadjuvant therapy (DESTINY-Breast05). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT04622319
2. Geyer Jr CE, Untch M, Prat A, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) vs trastuzumab emtansine (T-DM1) in high-risk patients with HER2-positive, residual, invasive, early breast cancer after neoadjuvant therapy: a randomized phase 3 trial (DESTINY-Breast05) [poster and abstract]. Poster presented at: San Antonio Breast Cancer Symposium (SABCS) Virtual Annual Meeting; December 8-11, 2020. Cancer Res. 2021;81(suppl 4). Abs OT-03-01.

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