T-DXd plus pertuzumab delivers durable treatment exposure across response groups in DESTINY-Breast09
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Deep and durable responses with trastuzumab deruxtecan plus pertuzumab in HER2-positive breast cancer
Trastuzumab deruxtecan (ENHERTU; T-DXd) is a HER2-directed ADC co-developed by AstraZeneca and Daiichi Sankyo that has transformed the treatment landscape of HER2-positive metastatic breast cancer. In December 2025, the US FDA approved Trastuzumab deruxtecan in combination with pertuzumab for the first-line treatment of unresectable or metastatic HER2-positive breast cancer based on the positive Phase III DESTINY-Breast09 results. The approval was supported by Priority Review and Breakthrough Therapy Designation.
Following the US approval, regulatory decisions in the European Union, Japan, and China are anticipated in H2 2026, supporting further global expansion of ENHERTU in the frontline setting. In DESTINY-Breast09, T-DXd plus pertuzumab demonstrated a statistically significant and clinically meaningful progression-free survival benefit over the current standard-of-care regimen of taxane, trastuzumab, and pertuzumab, along with deep and durable responses and a manageable safety profile. These findings position the combination as a potential new first-line standard of care and reinforce the shift toward earlier use of antibody-drug conjugates in HER2-positive disease.
Key Efficacy Highlights:
|
Phase III DESTINY-Breast09 trial Data | ||||
|
Category |
Parameter |
Complete Response |
Partial Response |
Stable/Progressive Disease |
|
Efficacy |
Response Rate |
15.4% |
71.1% |
13.5% |
|
Median Time to Response |
8.4 months |
1.5 months |
— | |
|
Median Treatment Duration |
28.0 months |
22.2 months |
4.4 months | |
|
Median DOR, |
NC |
39.2 (34.8, NC) |
– | |
|
Median PFS, months (95% CI) |
NC |
40.7 (36.0, NC) |
13.0 (4.0, 25.7) | |
|
6-months PFS rate, % (95% CI) |
100 (100, 100) |
97.7 (95.0, 99.0) |
57.2 (41.2, 70.4) | |
|
12-months PFS rate, % (95% CI) |
94.8 (84.8, 98.3) |
89.8 (85.4, 92.9) |
51.9 (35.9, 65.7) | |
|
24-months PFS rate, % (95% CI) |
85.1 (72.2, 92.3) |
72.9 (66.6, 78.2) |
35.5 (21.1, 50.2) | |
|
Safety |
Grade ≥3 TRAE Rate |
0.30 |
0.30 |
0.57 |
|
Discontinuation Rate |
0.14 |
0.11 |
0.16 | |
|
Treatment-Related ILD/Pneumonitis Incidence |
12.1% (all Grade 1/2) |
11.9% (all Grade 1/2) |
12.2% (including 2 Grade 5 events) | |
|
Median Time to First ILD/Pneumonitis Onset |
484 days |
227 days |
99 days | |
|
PFS: Progression-Free Survival; DOR: Duration of Response; NC: not calculable; TRAEs: Treatment-Related Adverse Events; ILD: Interstitial Lung Disease | ||||
KOL insights
“DESTINY-Breast09 reinforces the paradigm shift toward using ADCs earlier in the treatment journey of metastatic HER2-positive breast cancer. While the impressive efficacy of trastuzumab deruxtecan plus pertuzumab supports its frontline potential, long-term treatment optimization, maintenance strategies, and sequencing after ADC exposure remain critical unanswered questions." – Expert Opinion
“The robust DESTINY-Breast09 results support a paradigm shift toward earlier ADC use, positioning trastuzumab deruxtecan plus pertuzumab as a strong contender to replace the current first-line standard in HER2-positive metastatic breast cancer.”– Expert Opinion
Conclusion-
Breast cancer remains the most common cancer in women in the United States, accounting for 306,791 cases in 2025, with HER2-positive disease accounting for 46,019 cases and representing a high-risk subset with evolving treatment needs.
Landmark advances such as trastuzumab (HERCEPTIN) and pertuzumab (PERJETA) established the backbone of modern neoadjuvant and first-line regimens, with subcutaneous formulations further improving convenience and access. Further, approval of trastuzumab deruxtecan (ENHERTU) has intensified the competitive HER2 landscape, accelerating the shift toward ADC-based regimens as potential next-generation standards of care. In the Phase III DESTINY-Breast09 study, ENHERTU plus pertuzumab demonstrated deep and durable responses with a meaningful proportion of patients achieving complete or deep partial responses, reinforcing a clear qualitative shift toward more profound and sustained tumor control in HER2-positive breast cancer.
Executive Summary
AstraZeneca and Daiichi Sankyo’s trastuzumab deruxtecan (ENHERTU) plus pertuzumab demonstrated a statistically significant and meaningful improvement in progression-free survival versus the current standard first-line regimen in HER2-positive metastatic breast cancer, with a manageable safety profile, supporting its December 2025 US approval in this setting. Regulatory progress is further reinforced by EMA validation of the Type II Variation application for first-line use, with additional approvals expected across the EU, Japan, and China in H2 2026, underscoring its potential to redefine frontline treatment standards.