In an updated analysis of DESTINY-Breast03, a head-to-head study vs T-DM1,

ENHERTU demonstrated 28.8 months mPFS in 2L in patients with HER2+ mBC (6.8 months with T-DM1)1

  • Initial analysis of mPFS (primary endpoint; BICR; May 2021 data cutoff): NR mPFS with ENHERTU (95% CI: 18.5, NE) vs 6.8 months with T-DM1 (95% CI: 5.6, 8.2); HR: 0.28 (95% CI: 0.22, 0.37; P<0.0001)2,3,a

Updated analysis (July 2022): Progression-free survival1,b

  • Updated exploratory PFS analysis was not tested for statistical significance and not powered to show differences between treatment arms
  • DESTINY-Breast03 is a Phase 3, multicenter, open-label, randomized, head-to-head study to compare efficacy and safety of ENHERTU vs T-DM1 of 524 adults with HER2+ unresectable and/or mBC who received prior trastuzumab and taxane therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy. ENHERTU patients received 5.4 mg/kg IV Q3W until unacceptable toxicity or disease progression. Primary endpoint was PFS (BICR) according to RECIST v1.1. Secondary endpoints included OS and ORR. The FDA has not reviewed the updated analysis for mPFS, mOS, and ORR.2,3

aMedian duration of follow-up for PFS (BICR) at initial data cutoff: 16.2 months (range: 0-32.7) for ENHERTU and 15.3 months (range: 0-31.3) for T-DM1.3

bMedian duration of follow-up for PFS (BICR) at updated analysis: 28.4 months (range: 22.1-32.9) for ENHERTU and 26.5 months (range: 14.5-31.3) for T-DM1.1

In an updated analysis of DESTINY-Breast03, a head-to-head study vs ado-trastuzumab emtansine (T-DM1),

Superior overall survival with ENHERTU vs T-DM11

  • Initial analysis of OS (key secondary endpoint; May 2021 data cutoff): OS was immature (16% of patients had died)2,3

Updated analysis (July 2022): Overall survival1,c

  • The 24-month landmark analysis is based on Kaplan-Meier estimates and is descriptive only; the DESTINY-Breast03 trial was not powered to assess a statistical difference between treatment groups at this time point
  • NR mOS with ENHERTU (95% CI: 40.5 months, NE); NR mOS with T-DM1 (95% CI: 34.0 months, NE)

cEfficacy boundary for superiority: P=0.013 (based on 169 events).1

In an updated analysis of DESTINY-Breast03, a head-to-head study vs ado-trastuzumab emtansine (T-DM1),

ENHERTU delivered 82.1% confirmed ORR, more than double the 36.7% T-DM1 response4

  • Initial analysis of confirmed ORR as assessed by BICR (secondary endpoint; May 2021 data cutoff)2,3,d:
    • 82.7% with ENHERTU (n=205/248; 95% CI: 77.4, 87.2; 15.7% CR [n=39] + 66.9% PR [n=166])
    • 36.1% with T-DM1 (n=87/241; 95% CI: 30.0, 42.5; 8.3% CR [n=20] + 27.8% PR [n=67])
  • ~98% of patients had disease control with ENHERTU (15.7% CR [n=39] + 66.9% PR [n=166] + 14.9% SD [n=37])4

Updated analysis (July 2022): Confirmed objective response rate1,4,e

  • ORR was not tested for statistical significance and not powered to show differences between treatment arms

dAnalysis was performed based on the patients with measurable disease assessed by BICR at baseline (n=248 patients randomized to receive ENHERTU; n=241 for T-DM1).2

eAnalysis was performed based on the patients with measurable disease assessed by BICR at baseline (n=246 patients randomized to receive ENHERTU; n=240 for T-DM1).4

    Initial analysis of safety data from DESTINY-Breast03

  • Most common (≥20%) ARs, including laboratory abnormalities, of patients receiving ENHERTU (n=257)2
    • Nausea (76%), decreased white blood cell count (74%), decreased neutrophil count (70%), increased aspartate aminotransferase (67%), decreased hemoglobin (64%), decreased lymphocyte count (55%), increased alanine aminotransferase (53%), decreased platelet count (52%), fatigue (49%), vomiting (49%), increased blood alkaline phosphatase (49%), alopecia (37%), hypokalemia (35%), constipation (34%), musculoskeletal pain (31%), diarrhea (29%), decreased appetite (29%), respiratory infection (22%), headache (22%), abdominal pain (21%), increased blood bilirubin (20%), and stomatitis (20%)
  • Serious ARs occurred in 19% of patients receiving ENHERTU2
    • Serious ARs in >1% of patients: vomiting, ILD, pneumonia, pyrexia, and urinary tract infection
    • Fatalities due to ARs occurred in 0.8% of patients (1 due to COVID-19 and 1 due to sudden death)
  • Dose modifications due to ARs2
    • Discontinuations: 14% of patients; ILD/pneumonitis accounted for 8%
    • Dose interruptions: 44% of patients; most frequent associated ARs (>2%) were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis
    • Dose reductions: 21% of patients; most frequent associated ARs (>2%) were nausea, neutropenia, and fatigue
  • In DESTINY-Breast03, ILD and pneumonitis were reported; the majority of events were Grade 1 or 2 in the ENHERTU arm (n=25/27)2,4
    • No Grade 4 or 5 adjudicated drug-related ILD/pneumonitis events were observed in DESTINY-Breast-03f
    • For ENHERTU 5.4 mg/kg in pooled clinical studies (N=984), ILD occurred in 12% of patients (n=118/984); fatal outcomes due to ILD and/or pneumonitis occurred in 1% of patients (n=10/984)g
    • Symptom identification is key to diagnosis; monitor patients and initiate management at first sign of ILD

Updated analysis (July 2022): Safety data1

  • The median duration of treatment increased to 18 months for ENHERTU (IQR: 9.0 to 29.4) and remained 7 months for T-DM1 (IQR: 2.8 to 12.3)
  • Discontinuations, dose interruptions, and dose reductions due to ARs were 20%, 42%, and 25%, respectively, for ENHERTU
  • No new safety signals were observed for ENHERTU
  • Overall incidence of ILD was 15% in the ENHERTU arm and 3% in the T-DM1 arm
  • No Grade 4 or 5 adjudicated drug-related ILD/pneumonitis events were observed

fGrade 5=fatal cases.4

gStudy DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast03, DESTINY-Breast04, and DL-02 were all included in this pooled safety analysis.2

2L, second line; AR, adverse reaction; BICR, blinded independent central review; CI, confidence interval; CR, complete response; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; ILD, interstitial lung disease; IQR, interquartile range; IV, intravenous; mBC, metastatic breast cancer; mOS, median overall survival; mPFS, median progression-free survival; NE, not evaluable; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; Q3W, every 3 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; T-DM1, ado-trastuzumab emtansine.