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Advancements in Treatment Selection and Sequencing in HER2-Positive Metastatic Breast Cancer: Insights from ASCO 2025 - Episode 4

DESTINY-Breast09: Could T-DXd ± Pertuzumab Redefine First-Line HER2+ mBC Treatment?

Panelists discuss how the DESTINY-Breast09 trial results showing significant progression-free survival benefit with trastuzumab deruxtecan plus pertuzumab versus standard therapy may shift first-line treatment standards for specific patient populations.

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DESTINY-Breast09 Trial Results

The DESTINY-Breast09 trial presented highly anticipated results at ASCO 2025, comparing trastuzumab deruxtecan (T-DXd) plus pertuzumab against the standard CLEOPATRA regimen in first-line HER2-positive metastatic breast cancer (mBC). The study enrolled patients with at least 6 months disease-free interval from prior therapy, excluding rapid progressors, with roughly equal distribution between de novo and recurrent disease. The T-DXd combination demonstrated impressive progression-free survival of 40.7 months versus 26.9 months for the control arm.

The trial design used indefinite T-DXd treatment rather than induction-maintenance approach, representing a different strategy from current practice patterns. Safety data showed expected T-DXd toxicities including 12% interstitial lung disease (ILD) rate, mostly grade 1 to 2, though 2 fatal cases (0.5%) occurred. The overall survival data remains immature, and progression-free survival-2 data showed trends favoring the experimental arm, though many patients remain on therapy.

Key questions emerge regarding optimal patient selection and treatment sequencing if T-DXd moves to first-line use. The data suggests particular benefit for patients with recent recurrence, high visceral disease burden, or brain metastases. However, the induction-maintenance paradigm preferred by many oncologists wasn't tested in this trial design, leaving questions about whether T-DXd could be used with planned treatment breaks and potential rechallenge strategies.

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