Drug Update · Oncology

FDA Approves T-DXd for HER2+ EBC: 67.3% pCR in DESTINY-Breast11

July 13, 2026

Primary endpoint

Pathological complete response (pCR; ypT0/is ypN0)

pCR T-DXd-THP

67.3% [1]

pCR ddAC-THP

56.3% [1]

Neoadjuvant dose (approved)

ENHERTU 5.4 mg/kg every 3 weeks for 4 cycles followed by THP for 4 cycles [2][12]

Clinical Perspective

Medical oncologists treating adult patients with HER2-positive (IHC 3+ or ISH+) Stage II or III breast cancer should note that the FDA label now includes ENHERTU followed by THP as a neoadjuvant option for this population ^[2]^[3]. The DESTINY-Breast11 data support a higher pCR rate with T-DXd-THP versus ddAC-THP and lower rates of some high-grade toxicities, while showing similar low rates of adjudicated ILD/pneumonitis across arms ^[1]. Will the observed pCR improvement translate into a definitive long-term event-free survival or overall survival benefit with longer follow-up?

Dr. Meera Pillai · Oncology

The FDA approved ENHERTU (trastuzumab deruxtecan) for the neoadjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) Stage II or III breast cancer on May 15, 2026, based on DESTINY-Breast11 data showing a pathological complete response (pCR) of 67.3% with trastuzumab deruxtecan followed by paclitaxel, trastuzumab, and pertuzumab (T-DXd-THP) versus 56.3% with dose-dense doxorubicin + cyclophosphamide followed by THP (ddAC-THP) ^[2]^[1]. The approval and labeling specify ENHERTU 5.4 mg/kg every 3 weeks for 4 cycles followed by THP for 4 cycles in the neoadjuvant setting ^[2]^[3]. Clinicians should consult current prescribing information for full dosing guidance.

Clinical Context

Trastuzumab deruxtecan (ENHERTU; T-DXd) is a HER2-directed antibody and topoisomerase I inhibitor conjugate; the antibody component targets HER2 and the payload (DXd) is a membrane-permeable topoisomerase I inhibitor released after intracellular linker cleavage ^[3]. DESTINY-Breast11 tested T-DXd alone or T-DXd followed by paclitaxel + trastuzumab + pertuzumab (T-DXd-THP) against a comparator regimen of ddAC followed by THP in high‑risk HER2-positive early breast cancer; the publication notes that neoadjuvant standard-of-care for HER2-positive early-stage breast cancer is trastuzumab + pertuzumab with polychemotherapy ^[1]. The ENHERTU label and the DESTINY-Breast11 report informed the FDA’s neoadjuvant indication and recommended neoadjuvant/post-neoadjuvant dosing in the label ^[2]^[3].

Key Findings

DESTINY-Breast11 showed that T-DXd-THP achieved a pathological complete response rate of 67.3% versus 56.3% with ddAC-THP (treatment difference 11.2%; 95% CI 4.0% to 18.3%; P = 0.003) in the intent-to-treat population ^[1].
The single-agent T-DXd arm had a pCR rate of 43.0% (n = 123) reported in the trial ^[1].
The pCR benefit with T-DXd-THP was observed in both hormone receptor–positive and hormone receptor–negative subgroups: HR-positive 61.4% versus 52.3% (ΔpCR 9.1%; 95% CI 0.2% to 17.9%) and HR-negative 83.1% versus 67.1% (ΔpCR 16.1%; 95% CI 3.0% to 28.8%) ^[1].
Event-free survival (EFS) data were immature (maturity 4.5%); median EFS hazard ratio for T-DXd-THP versus ddAC-THP was 0.56 (95% CI 0.26 to 1.17) ^[1].
The FDA-approved neoadjuvant regimen is ENHERTU 5.4 mg/kg every 3 weeks for 4 cycles followed by THP for 4 cycles, as specified in the prescribing information ^[2]^[3].
Clinicians should consult current prescribing information for full dosing guidance.

Safety & Tolerability

Grade ≥3 adverse events: T-DXd 22.6% (n = 64); T-DXd-THP 37.5% (n = 120); ddAC-THP 55.8% (n = 174) ^[1].
Serious adverse events: T-DXd 10.2% (n = 29); T-DXd-THP 10.6% (n = 34); ddAC-THP 20.2% (n = 63) ^[1].
All-grade left-ventricular dysfunction: T-DXd 0.7% (n = 2); T-DXd-THP 1.3% (n = 4); ddAC-THP 6.1% (n = 19) ^[1].
All-grade adjudicated drug‑related interstitial lung disease/pneumonitis: T-DXd 4.9% (n = 14); T-DXd-THP 4.4% (n = 14); ddAC-THP 5.1% (n = 16) ^[1].
Treatment-related deaths: three events reported (T-DXd-THP 0.3% [n = 1]; ddAC-THP 0.6% [n = 2]) ^[1].

Study Design

DESTINY-Breast11 was a randomized, open-label, phase III trial conducted at 147 sites in 18 countries, enrolling adults with high‑risk HER2‑positive early breast cancer and randomizing them 1:1:1 to T-DXd (×8 cycles), T-DXd-THP (4 + 4 cycles), or ddAC-THP (4 + 4 cycles); the primary endpoint was pathological complete response (ypT0/is ypN0) in the intent-to-treat population ^[1]. Enrollment was 286 (T-DXd), 321 (T-DXd-THP), and 320 (ddAC-THP) patients; the T-DXd-alone arm enrollment closed early on recommendation of the Independent Data Monitoring Committee ^[1]. Details on dosing, administration, and boxed warnings (including ILD/pneumonitis and embryo‑fetal toxicity) are in the ENHERTU prescribing information ^[2]^[3].

FAQ

Q1 What is ENHERTU (ENHERTU) approved for?

ENHERTU (trastuzumab deruxtecan) is approved as neoadjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) Stage II or III breast cancer, to be given as ENHERTU followed by a taxane, trastuzumab, and pertuzumab (THP). The label also includes adjuvant and multiple metastatic indications; the neoadjuvant approval followed the DESTINY-Breast11 trial showing a higher pCR with T-DXd-THP versus ddAC-THP.

Q2 How does ENHERTU work?

ENHERTU is a HER2-directed antibody-drug conjugate: a humanized anti-HER2 IgG1 linked to a topoisomerase I inhibitor payload (DXd). After HER2 binding and internalization, the linker is cleaved intracellularly, releasing DXd which induces DNA damage and apoptotic cell death in tumor cells.

Q3 What is the recommended neoadjuvant dose of ENHERTU?

The prescribing information specifies ENHERTU 5.4 mg/kg administered intravenously every 3 weeks for 4 cycles as the neoadjuvant component, followed by THP for 4 cycles; post-neoadjuvant dosing and other regimens are described in the label. Clinicians should consult current prescribing information for complete dosing guidance.

Q4 What are the most common or important side effects?

In DESTINY-Breast11, rates of grade ≥3 adverse events were lower with T-DXd (22.6%) and T-DXd-THP (37.5%) than with ddAC-THP (55.8%); serious adverse events were 10.2%, 10.6%, and 20.2% respectively. All-grade adjudicated drug-related ILD/pneumonitis rates were reported as 4.9% (T-DXd), 4.4% (T-DXd-THP), and 5.1% (ddAC-THP). Left-ventricular dysfunction occurred at rates of 0.7%, 1.3%, and 6.1% respectively. The ENHERTU label includes a boxed warning for interstitial lung disease/pneumonitis and embryo-fetal toxicity and lists common adverse reactions and recommended monitoring.

Clinicians should consult current prescribing information for complete dosing guidance.

FDA Approves T-DXd for HER2+ EBC: 67.3% pCR in DESTINY-Breast11

FDA Approves T-DXd for HER2+ EBC: 67.3% pCR in DESTINY-Breast11

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

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