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A newer antibody-drug conjugate, trastuzumab deruxtecan, kept HER2-positive metastatic breast cancer under control roughly four times longer than the previous standard, T-DM1, and later lengthened survival.
Open-label phase 3 trial of 524 patients with HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, randomised 1:1 to trastuzumab deruxtecan (T-DXd, 5.4 mg/kg) or trastuzumab emtansine (T-DM1). Primary endpoint was progression-free survival by blinded independent central review.
At the interim analysis, 12-month PFS was 75.8% vs 34.1% (HR 0.28). The 2023 update reported median PFS 28.8 vs 6.8 months and a significant overall survival benefit (HR 0.64). It moved T-DXd into the second line and is the clearest head-to-head demonstration that ADC design (payload, drug-to-antibody ratio, bystander effect) determines clinical outcome.
For HER2-positive metastatic breast cancer that has progressed after trastuzumab and a taxane, trastuzumab deruxtecan is now the standard second-line treatment and T-DM1 has moved later in the sequence. The benefit is large enough that ADC design, not just the target, is understood to be what matters. Patients need lung monitoring because of the risk of pneumonitis.
Shares Yeon Hee Park, Sung-Bae Kim, Seock-Ah Im, Binghe Xu.
Shares Seock-Ah Im, Binghe Xu, Payload-class switching as the rule for ADC sequencing, ADC sequencing.
Shares Drug-to-antibody ratio (DAR), Interstitial lung disease (ILD) / pneumonitis, Payload (ADC), Trastuzumab deruxtecan.
Shares Seock-Ah Im, Giuseppe Curigliano, Interstitial lung disease (ILD) / pneumonitis, Daiichi Sankyo.
Shares Payload-class switching as the rule for ADC sequencing, ADC sequencing, Payload (ADC), Acquired resistance to every therapy.
Shares Sara A. Hurvitz, Javier Cortés, Payload (ADC), Progression-free survival (PFS).
Shares Javier Cortés, ADC sequencing, Daiichi Sankyo, Progression-free survival (PFS).
Shares Interstitial lung disease (ILD) / pneumonitis, Daiichi Sankyo, Trastuzumab deruxtecan, Topoisomerase-I inhibitors (and ADC payloads).