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The TROP2-directed antibody-drug conjugate Dato-DXd delayed progression by about two months compared with chemotherapy, but patients did not live longer, which stalled its approval in breast cancer.
Open-label phase 3 trial of 732 patients with hormone-receptor-positive, HER2-negative metastatic breast cancer after one or two lines of chemotherapy, randomised to datopotamab deruxtecan (Dato-DXd, 6 mg/kg) or investigator's choice chemotherapy (eribulin, vinorelbine, capecitabine or gemcitabine). Dual primary endpoints were PFS by blinded review and overall survival.
PFS was improved (6.9 vs 4.9 months, HR 0.63) with fewer high-grade adverse events, but the final overall survival analysis showed no difference. The trial is a cautionary example that a TROP2 ADC can beat chemotherapy on PFS in an unselected population without changing survival.
For hormone-receptor-positive metastatic breast cancer that has already had chemotherapy, Dato-DXd controls the disease for longer with fewer severe side effects than chemotherapy, but does not help patients live longer, so it is not a standard option here. The result is a reminder that progression-free survival is a surrogate; regulators and clinicians should wait for survival data before adopting an ADC in a setting where later therapies are effective.
Shares Binghe Xu, TROPION-Breast01, Aditya Bardia, Datopotamab deruxtecan.
Shares TROPION-Breast02, ADC sequencing, TROP2, Datopotamab deruxtecan.
Shares Seock-Ah Im, Binghe Xu, Payload-class switching as the rule for ADC sequencing, ADC sequencing.
Shares Carlos Barrios, Seock-Ah Im, Daiichi Sankyo, Progression-free survival (PFS).
Shares Seock-Ah Im, Binghe Xu, Payload-class switching as the rule for ADC sequencing, Daiichi Sankyo.
Shares TROPION-Breast02, ADC sequencing, TROP2, Datopotamab deruxtecan.
Shares Payload-class switching as the rule for ADC sequencing, ADC sequencing, Biomarkers are not validated or standardised, Topoisomerase-I inhibitors (and ADC payloads).
Shares TROP2 PET to choose and sequence TROP2 ADCs, Datopotamab deruxtecan, Daiichi Sankyo, Topoisomerase-I inhibitors (and ADC payloads).