The Most Effective First-Line Treatment for HER2-Positive Breast Cancer: A 13.8-Month Gain

📢 Update With the NEJM Publication

DESTINY-Breast09 full results were published on October 29, 2025 in the New England Journal of Medicine(DOI: 10.1056/NEJMoa2508668).

T-DXd + pertuzumab demonstrated, in first-line treatment of metastatic HER2-positive breast cancer, significant superiority over the standard THP regimen and emerged as a candidate for the new standard of care.

A Study That Attracted Major Interest at ASCO 2025

Breast canceris diagnosed in 2.3 million new cases each year, making it the world's second most common cancer after lung cancer. Approximately 15–20% of cases show HER2 overexpression, defining this subtype.

Previously known for its aggressive course, this subtype has seen dramatic improvements thanks to targeted therapies. However, at diagnosis, 5–10% of patients still have metastatic disease , and long-term control remains difficult for this group.

DESTINY-Breast09 was presented at ASCO 2025 and has now been published in NEJM, providing evidence that could change the paradigm in HER2-positive advanced disease.

Study Design: DESTINY-Breast09

This phase 3, multicenter, randomized study enrolled previously untreated patients with metastatic disease: 1157 HER2-positive patients were included. Participants were randomized 1:1:1 to three arms:

1. T-DXd + pertuzumab
2. T-DXd + placebo (still blinded)
3. THP: a taxane (docetaxel or paclitaxel) + trastuzumab + pertuzumab (standard arm)

The primary endpoint was progression-free survival (PFS) . Assessments were performed through independent central review (BICR).

T-DXd + Pertuzumab: A 13.8-Month PFS Gain

• Median follow-up: 29.0 months
• T-DXd + P arm: mPFS = 40.7 months (95% CI: 36.5–NC)
• THP arm: mPFS = 26.9 months (95% CI: 21.8–NC)
• Risk reduction: 44%
• HR: 0.56 (95% CI: 0.44–0.71, p < 0.00001)

Response rate (ORR): 85.1% vs 78.6%
Complete response rate: 15.1% vs 8.5%
Duration of response (DoR): 39.2 months vs 26.4 months

This represents one of the longest progression-free survival outcomes reported to date in metastatic HER2-positive breast cancer.

Safety Profile and Points Requiring Attention

• Rate of Grade ≥3 adverse events: 63.5% (T-DXd + P) vs 62.3% (THP)
• Most common toxicities: neutropenia, hypokalemia, anemia
• ILD / pneumonitis: 12.1% (T-DXd + P) vs 1.0% (THP)
• 2 patients died from ILD (grade 5)

No new safety signal was identified, but close monitoring is recommended because of the risk of interstitial lung disease.

Clinical Practice and Unanswered Questions

How Necessary Is Prolonged Combination Therapy?

In DESTINY-Breast09, patients received T-DXd + P for approximately 3.5 years , whereas the conventional THP regimen used maintenance therapy after only 4–6 months of chemotherapy. This difference raises new questions about quality of life, toxicity and financial burden .

How Should T-DXd Be Sequenced?

The earlier DESTINY-Breast03 study showed that T-DXd could provide, even in the second line, 28.8 months of mPFS . This raises the following questions:

• Should T-DXd be preferred in the first line for every patient?
• Might sequencing after THP be more suitable for some patients?
• Should the T-DXd + P combination be used only for induction , followed by a switch to trastuzumab + pertuzumab maintenance?

Conclusion: A Change in the Treatment Paradigm Is Approaching

DESTINY-Breast09has provided the strongest evidence supporting first-line T-DXd + pertuzumab. In HER2-positive metastatic breast cancer, this combination is emerging as a candidate for the new standard of care .

Nevertheless, more data are needed on long-term safety, quality of life and sequencing strategies .