Background
Phase III, randomised, open-label, international trial; N=644. Previously untreated, locally recurrent inoperable or metastatic TNBC for whom immunotherapy was not an option (~70% of mTNBC). Datopotamab deruxtecan (Dato-DXd) = TROP2-directed ADC with topoisomerase-I-inhibitor (DXd) payload. Stratified by geography, disease-free interval, PD-L1 status.
Results
Interventions and follow up: Arm A: Dato-DXd 6 mg/kg IV q3w (n=323)
Arm B: Investigator's choice chemotherapy (n=321)
Primary endpoint: Dual — PFS (BICR, RECIST v1.1) and OS
mFollow up: NR in abstract
Results: PFS: 10.8 vs 5.6 mo; HR 0.57 (99% CI 0.44–0.73); P<.0001
OS: 23.7 vs 18.7 mo; HR 0.79 (95.01% CI 0.64–0.98); P=.029
ORR: NR in abstract
Arm B: Investigator's choice chemotherapy (n=321)
Primary endpoint: Dual — PFS (BICR, RECIST v1.1) and OS
mFollow up: NR in abstract
Results: PFS: 10.8 vs 5.6 mo; HR 0.57 (99% CI 0.44–0.73); P<.0001
OS: 23.7 vs 18.7 mo; HR 0.79 (95.01% CI 0.64–0.98); P=.029
ORR: NR in abstract
Adverse events
Grade ≥3 TRAEs: 33% vs 29%
Discontinuation (TRAE): 4% vs 7%
Treatment-related deaths: 0 vs 0
Of note: stomatitis, nausea, ocular surface events, ILD are established Dato-DXd toxicities (rates NR in abstract)
Discontinuation (TRAE): 4% vs 7%
Treatment-related deaths: 0 vs 0
Of note: stomatitis, nausea, ocular surface events, ILD are established Dato-DXd toxicities (rates NR in abstract)
Conclusions
First phase III trial to show a significant PFS and OS benefit for a TROP2 ADC over chemotherapy in first-line, immunotherapy-ineligible advanced TNBC. ~5-month median OS gain establishes Dato-DXd as a new first-line option for this large, underserved population.
Key Limitations
Open-label design. Restricted to IO-ineligible patients — does not inform PD-L1+ patients eligible for pembrolizumab-chemo. OS crossed its boundary at a borderline P=.029. Comparator was single-agent chemotherapy; rising use of pembrolizumab and ADCs in early-stage TNBC may shift the applicable population. No head-to-head data vs sacituzumab govitecan; TROP2 ADC sequencing unresolved.
Clinical Context
Prior 1L standard for IO-ineligible mTNBC was single-agent chemotherapy. Dato-DXd is FDA approved in pretreated HR+/HER2− MBC and EGFR-mutant NSCLC; not yet approved for 1L TNBC (regulatory review anticipated). Complements sacituzumab govitecan (ASCENT; 2L+ approval) and pembrolizumab-chemo for PD-L1 CPS≥10 (KEYNOTE-355).