The annual meeting of the American Society of Clinical Oncology ASCO, held May 29 – June 2, 2026, in Chicago, and recent approvals by the US Food and Drug Administration (FDA) have transformed the management of early-stage HER2-positive breast cancer. Trastuzumab deruxtecan (T-DXd, Enhertu®; Daiichi Sankyo and AstraZeneca) is now established as a foundational therapy in both the neoadjuvant and adjuvant settings. This article summarizes the key clinical trial data, regulatory actions, and practice-changing implications arising from DESTINY-Breast11, DESTINY-Breast05, and the latest guidelines.
Early Breast Cancer
Breast cancer remains the second most frequently diagnosed cancer globally and continues to be a leading cause of cancer-related mortality, with over two million new cases and more than 665,000 deaths reported worldwide in 2022.[1] In the United States alone, approximately 320,000 individuals are diagnosed each year, leading to more than 42,000 deaths annually.[2]
HER2 (human epidermal growth factor receptor 2) is a transmembrane tyrosine kinase receptor that promotes cell proliferation and survival. Overexpression of the HER2 protein, typically resulting from gene amplification, is found in about 20% of breast cancers and is associated with aggressive disease biology and poorer clinical outcomes.[3][4] Among patients with early-stage HER2-positive disease, nearly one-third are classified as high risk due to their increased likelihood of recurrence and less favorable prognosis.[5]
Treatment of HER2-positive early breast cancer occurs in two main settings: neoadjuvant (before surgery) and adjuvant (after surgery). While regional practices vary, the neoadjuvant standard of care in the U.S. generally involves multi-agent chemotherapy, including carboplatin, trastuzumab, pertuzumab, and a taxane.[6] Achieving a pathologic complete response (pCR) following neoadjuvant therapy is an established surrogate for improved long-term outcomes in this population.[7] However, between 39% and 66% of patients do not achieve pCR, leaving a substantial proportion at heightened risk of disease recurrence.[8][9][10][11][12]
In the adjuvant setting, even with additional post-surgical therapy for patients with residual disease, some individuals still develop invasive recurrences or succumb to their disease.[13] The prognosis worsens significantly for patients whose disease progresses to metastasis, with five-year survival rates falling from nearly 90% in early-stage disease to approximately 30% in the metastatic setting.[14] Therefore, optimizing adjuvant therapy is crucial to further reduce the risk of recurrence and improve the likelihood of cure in patients with residual disease after neoadjuvant treatment.[15][16]
Key Practice-Changing Data from ASCO 2026
Neoadjuvant Therapy: DESTINY-Breast11 (NCT05113251) was a global, randomized, open-label phase 3 trial comparing:
- Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca); 5.4 mg/kg monotherapy for 4 cycles followed by THP (taxane, trastuzumab, pertuzumab) for 4 cycles (T-DXd-THP)
- Versus in patients with high-risk (lymph node positive [N1-3] or with a primary tumor stage T3-4), locally advanced or inflammatory HER2-positive early-stage breast cancer, the standard-of-care regimen of four doses of doxorubicin/cyclophosphamide followed by THP (ddAC-THP);
The participating patients were randomized 1:1:1 to receive either eight cycles of trastuzumab deruxtecan as a monotherapy, four cycles of trastuzumab deruxtecan followed by four cycles of THP, or four cycles of ddAC followed by four cycles of THP. The primary endpoint of DESTINY-Breast11 is pCR (absence of invasive disease in the breast and lymph nodes) as assessed by blinded independent central review (BICR). Secondary endpoints include event-free survival, invasive disease-free survival, overall survival, pharmacokinetics, immunogenicity, and safety.
Among 927 patients with high-risk, early HER2-positive breast cancer, T-DXd-THP achieved a remarkable centrally assessed pCR rate of 67.3% (95% CI: 61.9–72.4), compared to 56.3% (95% CI: 50.6–61.8) for ddAC-THP (p=0.003).[17] These results represent an absolute improvement of 11 percentage points in pCR—a surrogate marker for long-term survival—while reducing exposure to anthracyclines and their attendant toxicities.
Secondary endpoints, including event-free survival (EFS) and overall survival (OS), remain immature and were not statistically controlled, but supportive evidence from the adjuvant setting strengthens the case for early T-DXd use.
Adjuvant Therapy: DESTINY-Breast05
DESTINY-Breast05 (NCT04622319) enrolled 1,635 adults with HER2-positive breast cancer and residual invasive disease after neoadjuvant therapy. Patients were randomized to receive either trastuzumab deruxtecan (T-DXd) or trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche) for up to 14 cycles.
- The primary endpoint, 3-year IDFS, was 92.4% (95% CI: 89.7–94.4) for T-DXd versus 83.7% (95% CI: 80.2–86.7) for T-DM1 (HR 0.47, 95% CI: 0.34–0.66; p<0.0001).[18]
- The 3-year DFS rates were 92.3% and 83.5%, respectively (HR, 0.47; 95% CI, 0.34–0.66; p<0.0001).
These data conclusively establish T-DXd as a superior adjuvant option for patients with residual disease and high risk of recurrence, with a substantial reduction in invasive recurrence or death.
FDA Approvals and Regulatory Context
On May 15, 2026, the FDA granted two new early-stage indications for trastuzumab deruxtecan:[19]
- Neoadjuvant Setting: T-DXd followed by THP for adult patients with HER2-positive (IHC 3+ or ISH+) stage II or III breast cancer, as determined by an FDA-authorized test.
- Adjuvant Setting: T-DXd monotherapy for adult patients with HER2-positive breast cancer with residual invasive disease after neoadjuvant trastuzumab (with or without pertuzumab) and taxane-based therapy.
The FDA also approved two companion diagnostic devices for HER2 testing. These actions, reviewed under Project Orbis in collaboration with multiple international regulatory agencies, position T-DXd as a foundational therapy across early and metastatic HER2-positive breast cancer.
Safety and Monitoring
While T-DXd is highly effective, safety monitoring is critical. Interstitial lung disease (ILD) remains the most significant risk, with rates of adjudicated drug-related ILD/pneumonitis of 4.4% (DESTINY-Breast11, neoadjuvant) and 10% (DESTINY-Breast05, adjuvant, all grades), with <1% grade ≥3 in both settings. Fatal ILD cases were rare but underscore the need for proactive surveillance, prompt evaluation of new respiratory symptoms, and multidisciplinary management.[18][19]
Other common adverse reactions (≥20%) include hematologic (decreased white blood cell, neutrophil, and hemoglobin counts), gastrointestinal (nausea, diarrhea, vomiting, constipation), and hepatic (increased transaminases). The prescribing information includes a boxed warning for ILD/pneumonitis and embryo-fetal toxicity, and guidance for neutropenia and left ventricular dysfunction.[19]
Practice-Changing Implications
- Neoadjuvant: For high-risk, early-stage HER2-positive breast cancer, T-DXd-THP is now a preferred regimen, offering the highest reported pCR rates and a favorable tolerability profile compared to anthracycline-containing regimens.[17]
- Adjuvant: For patients with residual invasive disease after standard neoadjuvant therapy, T-DXd replaces T-DM1 as the new standard, with unmatched efficacy in reducing invasive recurrences and death.[18]
- Guidelines: The National Comprehensive Cancer Network (NCCN) now lists T-DXd as a Category 1 recommended adjuvant treatment for high-risk, HER2-positive patients with residual disease after preoperative therapy.[20]
- Patient Selection: Careful assessment of risk, HER2 status, and comorbidities is essential. T-DXd’s benefit is clearest in high-risk and residual disease populations.
- Survivorship and Toxicity Management: Proactive ILD monitoring and rapid intervention are essential components of care.
New Standards
The integration of trastuzumab deruxtecan into early-stage HER2-positive breast cancer management marks a transformative advance in the field. ASCO 2026 and regulatory approvals have set new standards, with trastuzumab deruxtecan delivering unprecedented efficacy in both neoadjuvant and adjuvant settings. Ongoing vigilance for ILD, careful patient selection, and multidisciplinary collaboration will be crucial to fully realizing the benefits of these practice-changing therapies.
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Clinical trials
Trastuzumab Deruxtecan (T-DXd) Alone or in Sequence With THP, Versus Standard Treatment (ddAC-THP), in HER2-positive Early Breast Cancer – ClinicalTrials.gov ID NCT05113251
A Study of Trastuzumab Deruxtecan (T-DXd) Versus Trastuzumab Emtansine (T-DM1) in High-risk HER2-positive Participants With Residual Invasive Breast Cancer Following Neoadjuvant Therapy (DESTINY-Breast05) – ClinicalTrials.gov ID NCT04622319
Highlights of Prescribing Information
Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]
Trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche)[Prescribing Information]
References
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This article was first published in ADC Review | Journal of Antibody-drug Conjugates on June 23, 2026/
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