Adjuvant T-DXd vs. T-DM1 in high-risk HER2+ early breast cancer with residual invasive disease after neoadjuvant therapy — AstraZeneca / Daiichi Sankyo
HER2+ Early Breast Cancer · Residual DiseaseTrastuzumab Deruxtecan (Enhertu)SABCS 2025 · NEJM 2026 · NCT04622319✓ FDA APPROVED MAY 15 2026
[Slide 1]
16:30 - 18:15 Presidential Symposium |
CHAIRS: GIUSEPPE CURIGLIANO, BRIGETTE MA
FUTURE STUDIES NEEDED
HOW COULD WE INTEGRATE DB11 AND DB05?
Can we use a response-guided approach?
HP
pCR
X 14 cycles
ctDNA
cT≥3 or cN+
THP
Breast MRI
undetectable
Surgery
TDXd
HER2+ BC
x12 wks
(at C2D1)
response
RD
x14 cycles
Any HR status
Sara Tolaney
Check ctDNA:
If no response
Baseline &
Baseline breast MRI
Cycle Day 1
HP
Invited Discussant LBA1
for all patients
ctDNA
pCR
T-DXd for 4
X 14 cycles
Baseline tumor-informed
detectable
cycles
Surgery
ultrasensitive ctDNA for
(at C2D1)
RCB2/3
all patients
RD
ACx4-T-DM1x
Plasma samples for serial ctDNA testing
14 cycles
RCB1
"
"
T-DM1 X 14 cycles
Baseline
C2d1
(week 0)
(week 3)
Side adapted from Bia Sequi/Ada Waks
BERLIN AUDITORIUM - HUB 27
[Slide 1]
PREOPERATIVE/ADJUVANT THERAPY
See BINV-M 1 of 10 for Considerations for Those Receiving Preoperative/Adjuvant Systemic Therapy.
HR-Positive or -Negative and HER2-Positive9
Preferred:
Preoperative or adjuvant setting:
TCHP (Docetaxel/Carboplatin + Trastuzumab + Pertuzumab)
Adjuvant setting:
TCH (Docetaxel/Carboplatin + Trastuzumab)
If no residual disease after preoperative therapy or no preoperative therapy: Complete up to 1 year of HER2-targeted therapy with Trastuzumabh
(category 1) + Pertuzumab. If node positive at initial staging, Pertuzumab + Trastuzumab (category 1)
If residual disease after preoperative therapy:
Ado-trastuzumab emtansine (category 1) alone. If Ado-trastuzumab emtansine discontinued for toxicity, then Trastuzumab (category 1)
+ Pertuzumab to complete 1 year of therapy. If node positive at initial staging, Pertuzumab + Trastuzumab (category 1)J
Fam-trastuzumab deruxtecan-nxki (category 1) for those with high risk of recurrence defined as inoperable cancer (cT4, N0-3, M0 or cT1-3, N2-3,
M0) at presentation prior to neoadjuvant therapy or operable cancer (cT1-3, N0-1, M0) with axillary node-positive disease (ypN1-3) following
preoperative therapy.
[Slide 1]
Primary endpoint: IDFSᵃ
T-DXd
T-DM1
n= 818
n= 817
Patients with events, n (%)
51 (6.2)
102 (12.5)
3-year IDFS, % (95% CI)
92.4 (89.7-94.4)
83.7 (80.2-86.7)
HR (95 % CI)
0.47 (0.34-0.66)
1.0
P value
<0.0001b
Invasive Disease-Free Survival
0.8
Д8.7%
0.6
T-DXd (n = 818)
T-DM1 (n = 817)
Censor
0.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54
Time, months
Number at Risk:
T-DXd 818 788 781 776 771 768 758 753 731 684 634 544 440 380 370 275 218 212 129 92 90 46 14 14 0 0 0 0
T-DM1 817 781 769 760 745 734 719 708 687 632 599 527 417 355 337 233 186 177 120 84 79 38 14 13 4 1 1 0
53% reduction in the risk of invasive disease recurrence or death for T-DXd compared with T-DM1
HR, hazard ratio; IDFS, invasive disease-free survival; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan
Efficacy stopping boundary, P 0.0183.
MDFS is defined as the time from randomization until the date of first occurrence of one of the following events: recurrence of ipsilateral invasive breast tumor, recurrence of ipsilateral locoregional invasive breast cancer, contralateral invasive breast
cancer, a distant disease recurrence, or death from any cause. Two-sided Pvalue from stratified log-rank test. Hazard ratio and 95% CI from stratified Cox proportional hazards model with stratification factor of operative status at disease
presentation
Dr Charles E Geyer Jr
Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.
BERLIN
DESTINY-Breast05
ESMO
congress
DESTINY-Breast 05 — Trastuzumab deruxtecan (T-DXd, Enhertu) vs. T-DM1 (Kadcyla)
DESTINY-Breast 05 is a phase 3, global, randomized, open-label trial evaluating T-DXd (Enhertu) vs. T-DM1 (Kadcyla) in adult patients with high-risk HER2-positive early breast cancer who have residual invasive disease following neoadjuvant therapy. The trial demonstrated a statistically significant and clinically meaningful improvement in invasive disease-free survival over T-DM1 (HR 0.47; 95% CI 0.34–0.66; P<0.0001). On May 15, 2026 — via FDA Project Orbis concurrent review — the FDA approved Enhertu in the adjuvant residual-disease setting (DB-05) and in the neoadjuvant setting for Stage II/III disease (DB-11), bringing T-DXd into the HER2+ curative-intent continuum. The FDA approval adds T-DXd as a new adjuvant option; T-DM1 retains its KATHERINE-based residual-disease indication on label. Investigators including Shanu Modi (MSK) describe T-DXd as a potential new standard of care in early-stage disease given its head-to-head superiority over T-DM1.
Enhertu (fam-trastuzumab deruxtecan-nxki) — approved May 15, 2026 — As adjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) breast cancer who have residual invasive disease following neoadjuvant trastuzumab (with or without pertuzumab) and taxane-based treatment.
Dosing: 5.4 mg/kg IV every 3 weeks for 14 cycles. Black-box warning: interstitial lung disease / pneumonitis and embryo-fetal toxicity.
✅ FDA-approved: DESTINY-Breast 05 adds T-DXd (Enhertu) as a new adjuvant option for adult patients with HER2-positive (IHC 3+ or ISH+) early breast cancer with residual invasive disease following neoadjuvant trastuzumab (±pertuzumab) plus taxane therapy. T-DM1 (Kadcyla) retains its existing KATHERINE-based indication on label; T-DXd does not formally replace it, but did demonstrate head-to-head superiority on iDFS in DB-05 and is positioned by investigators as a potential new standard of care. ✅ Companion approval: Via DESTINY-Breast 11 (same May 15, 2026 FDA action under Project Orbis), T-DXd → THP is also approved in the neoadjuvant setting for Stage II/III HER2+ disease. Together the two indications extend T-DXd across the HER2+ curative-intent continuum.
Study Design
Trial Methodology & Results
Study Design
Phase 3, randomized, open-label, multicenter, global trial; 1,635 patients randomized 1:1 to 14 cycles of either T-DXd or T-DM1.
Population
Adult patients with centrally confirmed HER2-positive (IHC 3+ or ISH+) early breast cancer with residual invasive disease in the breast and/or axillary nodes after neoadjuvant chemotherapy plus HER2-directed therapy — a high-risk-of-recurrence population.
Interventions
Intravenous T-DXd at 5.4 mg/kg every 3 weeks for 14 cycles versus intravenous T-DM1 at 3.6 mg/kg every 3 weeks for 14 cycles.
Median iDFS was NOT REACHED in both arms at interim analysis. T-DXd reduced the risk of invasive disease recurrence or death by 53% — HR 0.47 (95% CI 0.34–0.66; P<0.0001). The 3-year iDFS rate was 92.4% (T-DXd) vs. 83.7% (T-DM1). Distant disease recurrence risk fell 51% and brain metastasis risk fell 36% with T-DXd.
✓ iDFS HR 0.47 — 53% reduction in invasive recurrence/death
OS data was immature at the interim analysis (2.9% data maturity). OS hazard ratio was 0.61 (95% CI 0.34–1.10), 3-year OS 97.4% (T-DXd) vs. 95.7% (T-DM1). Final OS analysis pending.
