DESTINY-Breast04 Trial

ENHERTU was investigated in DESTINY-Breast04—a landmark phase 3, international trial designed to evaluate a HER2-directed therapy in HER2-low mBC (IHC 1+ or IHC 2+/ISH–)1-3

  • A phase 3, multicenter, randomized, open-label trial that included patients with1,3,a:
    • Unresectable or metastatic HER2-low (HER2 IHC 1+b or IHC 2+/ISH–) breast cancer
    • Tumors previously not classified as HER2-positive on any prior pathology testing2
The study design for the DESTINY-Breast04 trial evaluated ENHERTU 5.4 mg/kg in patients with HER2-low (IHC 1+ or IHC 2+/ISH–) mBC compared with physician's choice single-agent chemotherapy The study design for the DESTINY-Breast04 trial evaluated ENHERTU 5.4 mg/kg in patients with HER2-low (IHC 1+ or IHC 2+/ISH–) mBC compared with physician's choice single-agent chemotherapy

The key efficacy endpoints in DESTINY-Breast04 were tested hierarchically1:

The major efficacy endpoints in the DESTINY-Breast04 trial were PFS in the HR+ population, as determined by BICR (primary endpoint); secondary endpoints included PFS (BICR) in the overall study population (HR+ and HR–), OS in the HR+ population, and OS in the overall study population (HR+ and HR–) The major efficacy endpoints in the DESTINY-Breast04 trial were PFS in the HR+ population, as determined by BICR (primary endpoint); secondary endpoints included PFS (BICR) in the overall study population (HR+ and HR–), OS in the HR+ population, and OS in the overall study population (HR+ and HR–)
Select secondary endpoints3,e,f:
  • Confirmed ORR and DOR in the HR+ population
  • Confirmed ORR and DOR in the overall study population (HR+ or HR–)
Select exploratory endpoints included4,5:
  • PFS, OS, ORR, and DOR in the HR– population
Stratification factors4:
  • HER2 IHC status (IHC 1+ or IHC 2+/ISH–)
  • Number of prior lines of chemotherapy in the metastatic setting (1 or 2)
  • HR status/prior CDK4/6 inhibitor (HR+ with prior CDK4/6 inhibitor, HR+ without prior CDK4/6 inhibitor, or HR–)

Patients with HER2-low mBC in DESTINY-Breast04 had 1 or 2 prior lines of chemotherapy in the metastatic setting, and, if HR+, were ineligible for or had progressed on endocrine therapy1

aPatients had received no prior HER2-directed therapy.3

bIHC 1+ tumors were ISH– or ISH untested.3

cTreatment was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity.1

dIn the control arm, 51.1% of patients received eribulin, 20.1% received capecitabine, 10.3% received nab-paclitaxel, 10.3% received gemcitabine, and 8.2% received paclitaxel.4

eAccording to mRECIST v1.1.3

fBoth BICR and investigator assessment were performed.3

DESTINY-Breast04 evaluated patients with HER2-low mBC (IHC 1+ and IHC 2+/ISH–)1

Select baseline patient demographics and disease characteristics1,4,5,g,h

DESTINY-Breast04 (N=557)
Age, median
   ≥65 years, %
57 years (range: 28 to 81)
24%
Hormone receptor status, % HR+ 89%
HR– 11%
HER2 IHC score, % 1+ 58%
2+/ISH– 42%
Number of prior lines of endocrine therapy in the metastatic setting in HR+/HER2-low mBC patients (n=494), % 0 9%
1 31%
2 33%
≥3 27%
Prior CDK4/6 inhibitor in HR+/HER2-low mBC patients (n=494), % 70%
Number of prior chemotherapy regimens in the metastatic setting, % 1 58%
2 41%
Prior lines of systemic therapy in the metastatic setting, mediani 3 (range: 1 to 9)
Sites of metastases, % Liver metastases 70%
Lung metastases 33%
Brain metastasesj 6%
  • Gender: 99.6% were female, 0.4% were male1
  • Race/ethnicity: 48% were White, 40% were Asian, 3.8% were Hispanic/Latino, and 2% were Black or African American1
  • ECOG PS: 55% had ECOG PS 0 and 45% had ECOG PS 1 at baseline1
  • In HR+ cohort, median prior lines of ET: 2 (range: 0 to 9)1
  • Early progressors (progression in the neo/adjuvant setting): 3.9%1

In DESTINY-Breast04, 58% of patients were IHC 1+ and 42% were IHC 2+/ISH−1

gPatients with HR-negative mBC were not included in the primary efficacy analysis.4

hIn some instances, percentages do not add up to 100% due to rounding.

iIn the overall study population (N=557), 10% of patients had received 1 prior line of systemic therapy in the metastatic setting, 27% had received 2 prior lines, and 62% had received ≥3 prior lines.4

jPatients with treated brain metastases who were no longer symptomatic and who required no treatment with corticosteroids or anticonvulsants could be included in the study if they had 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.3

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BICR, blinded independent central review; CDK4/6, cyclin-dependent kinases 4 and 6; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; HR+, hormone receptor-positive; HR–, hormone receptor-negative; IHC, immunohistochemistry; ISH, in situ hybridization; mBC, metastatic breast cancer; mRECIST, Modified Response Evaluation Criteria in Solid Tumors; ORR, objective response rate; OS, overall survival; PS, performance score; PFS, progression-free survival; Q3W, every 3 weeks.