Drug Update · Pharmacology

FDA Approves ENHERTU for Early HER2-Positive Breast Cancer: 67.3% pCR

August 28, 2026

Neoadjuvant pCR ENHERTU

67.3% (N=321) in DESTINY-Breast11 [6]

Neoadjuvant pCR comparator

56.3% (N=320) ddAC followed by THP [6]

Treatment difference

11.2% (95% CI 3.9, 18.3); p=0.003 [6]

Label effective date

2026-05-15 [6]

Recommended neoadjuvant dose

ENHERTU 5.4 mg/kg IV every 3 weeks for 4 cycles followed by THP [6]

Clinical Perspective

This label update affects oncologists, breast cancer specialists, oncology pharmacists, and advanced practice providers managing adult patients with Stage II–III HER2-positive breast cancer who are candidates for neoadjuvant therapy; the FDA labeling now includes ENHERTU followed by THP as a neoadjuvant option based on pCR improvement in DESTINY-Breast11 ^[2]. The DESTINY-Breast11 data support use of ENHERTU to increase pathologic complete response rates when sequenced with THP compared to ddAC followed by THP, and clinicians will need to counsel patients about ILD risk, neutropenia, and embryo-fetal toxicity per the label ^[2]^[1]. What remains to be defined is whether the pCR improvement will translate into longer-term invasive disease-free survival or overall survival in this population?

Dr. Pooja Sinha, MBBS, MD (General Medicine), MRCP · General Medicine

ENHERTU (fam-trastuzumab deruxtecan-nxki) received a label update effective 2026-05-15 that includes an indication for neoadjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) Stage II or III breast cancer, given as ENHERTU followed by a taxane, trastuzumab, and pertuzumab (THP). The approval decision references DESTINY-Breast11, in which ENHERTU followed by THP achieved a pathological complete response (pCR) rate of 67.3% versus 56.3% with ddAC followed by THP (treatment difference 11.2%; 95% CI 3.9, 18.3; p=0.003) ^[2].

Clinical Context

ENHERTU is a HER2-directed antibody-drug conjugate (fam-trastuzumab deruxtecan-nxki) composed of a humanized anti-HER2 IgG1 linked to a topoisomerase I inhibitor payload (DXd); following HER2 binding and internalization, the linker is cleaved and DXd is released intracellularly to cause DNA damage and apoptotic cell death ^[2]. The updated U.S. prescribing information lists multiple HER2-related breast cancer indications including neoadjuvant and adjuvant settings, first-line metastatic combination use with pertuzumab, monotherapy for unresectable or metastatic HER2-positive disease, HER2-low/ultralow metastatic disease, and select non-breast HER2 indications; the neoadjuvant indication specifically covers Stage II or III HER2-positive disease to be followed by THP ^[2]. The manufacturer name is ENHERTU (fam-trastuzumab deruxtecan-nxki); full prescribing information and label details are provided by the FDA ^[2]^[1].

Key Findings

DESTINY-Breast11 demonstrated that ENHERTU 5.4 mg/kg given once every 3 weeks for 4 cycles followed by THP for 4 cycles achieved a centrally assessed pathological complete response (pCR) rate of 67.3% (N=321) versus 56.3% (N=320) for ddAC followed by THP; treatment difference 11.2% (95% CI 3.9, 18.3); p=0.003 ^[2].
Clinicians should consult current prescribing information for full dosing guidance.
The DESTINY-Breast11 trial enrolled 927 adult patients with HER2-positive, high-risk early-stage breast cancer and used centrally assessed pCR (ypT0/Tis ypN0) following surgery as the major efficacy outcome; the study supported the neoadjuvant approval and is cited in the labeling update effective 2026-05-15 ^[2].

Safety & Tolerability

Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported; monitor for cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in patients with Grade 2 or higher ILD/pneumonitis ^[1].
Embryo-fetal toxicity: exposure during pregnancy can cause embryo-fetal harm; advise patients on the need for effective contraception ^[1].
Neutropenia: a decrease in neutrophil count was reported in 30% of patients and Grade 3 or 4 events occurred in 16% of patients in a cohort of 234 patients; median time to first onset was 1.4 months (range: 0.3 to 18.2). Febrile neutropenia was reported in 1.7% of patients ^[1].
Left ventricular dysfunction: LVEF decreases have been observed; LVEF assessment is recommended prior to initiation and periodically during treatment, and management may include interruption or discontinuation ^[1].
The most common adverse reactions (≥20%) included nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough, and thrombocytopenia ^[1].

Study Design

DESTINY-Breast11 was a randomized, three-arm, open-label, multicenter, global study that enrolled 927 adult patients with HER2-positive, high-risk early-stage breast cancer and randomized patients 1:1:1 to neoadjuvant regimens including ENHERTU followed by THP or comparator ddAC followed by THP; the major efficacy outcome was centrally assessed pathological complete response (pCR) defined as ypT0/Tis ypN0 following surgery ^[2]. The ENHERTU neoadjuvant regimen evaluated ENHERTU 5.4 mg/kg every 3 weeks for 4 cycles followed by THP for 4 cycles, and the trial demonstrated a statistically significant improvement in pCR for the ENHERTU arm versus ddAC followed by THP ^[2]. Clinicians should consult current prescribing information for full dosing guidance. Label effective date (most recent revision) is 2026-05-15 ^[2].

FAQ

Q1 What is ENHERTU approved for?

ENHERTU (fam-trastuzumab deruxtecan-nxki) is indicated in the U.S. for multiple HER2-related breast cancer settings. Relevant to the recent label update, ENHERTU followed by a taxane, trastuzumab, and pertuzumab (THP) is indicated as neoadjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) Stage II or III breast cancer. The prescribing information lists additional metastatic and adjuvant indications and notes accelerated approvals for some indications where applicable.

Q2 How does ENHERTU work?

ENHERTU is a HER2-directed antibody-drug conjugate comprised of a humanized anti-HER2 IgG1 linked to a topoisomerase I inhibitor payload (DXd). After binding HER2 on tumor cells, ENHERTU is internalized and the linker is cleaved by lysosomal enzymes, releasing the membrane-permeable DXd which causes DNA damage and apoptotic cell death.

Q3 What is the recommended dose of ENHERTU for the neoadjuvant indication?

For the neoadjuvant indication studied in DESTINY-Breast11, ENHERTU is administered at 5.4 mg/kg as an intravenous infusion once every 3 weeks for 4 cycles followed by THP for 4 cycles; post-neoadjuvant adjuvant ENHERTU dosing and other indication-specific dosing are provided in the full prescribing information. Clinicians should consult current prescribing information for complete dosing guidance.

Q4 What are the side effects clinicians must counsel patients about?

The label identifies interstitial lung disease (ILD) and pneumonitis, including fatal cases, as boxed warnings and advises monitoring and permanent discontinuation for Grade 2 or higher ILD/pneumonitis. Other labeled risks include embryo-fetal toxicity, neutropenia including Grade 3/4 events and febrile neutropenia, and left ventricular dysfunction. The most common adverse reactions (≥20%) include nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough, and thrombocytopenia. Clinicians should consult current prescribing information for complete dosing guidance.

FDA Approves ENHERTU for Early HER2-Positive Breast Cancer: 67.3% pCR

Direct Clinical Takeaway & Evidence Summary

FDA Approves ENHERTU for Early HER2-Positive Breast Cancer: 67.3% pCR

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

Get weekly clinical updates for Pharmacology in your inbox.

Related Clinical Updates

FDA Approves Ensitrelvir (XOCOVA) for COVID-19 Post-Exposure: 67% Lower Symptomatic Infection in SCORPIO-PEP

FDA Lists Multiple 2025–2026 Biosimilar Approvals, Including Rituximab and Insulin Aspart

FDA Announces Major Steps to Implement Real-Time Clinical Trials (Apr 28, 2026)

Verified HCP Portal