Background
Comprehensive clinical overview of 5 TROP2-directed ADCs in NSCLC development: datopotamab deruxtecan (Dato-DXd), sacituzumab govitecan, sacituzumab tirumotecan (MK-2870), DB-1305, SHR-A1921. Reviews mechanisms, linker chemistry, payload attributes, and clinical trial data.
Interventions and follow up
Design: Clinical overview of TROP2-targeted ADCs in NSCLC
Primary endpoint: Synthesis of efficacy and safety evidence
mFollow up: Not applicable
Primary endpoint: Synthesis of efficacy and safety evidence
mFollow up: Not applicable
Results
ORR: 25–50% across agents
mPFS: 4–7 months
mOS: 10–20+ months (depending on agent, line of therapy, prior treatment)
Linker/payload: cleavable linkers allow systemic payload release (broader bystander effect); non-cleavable more selective; topoisomerase inhibitors show higher response but greater myelosuppression risk
mPFS: 4–7 months
mOS: 10–20+ months (depending on agent, line of therapy, prior treatment)
Linker/payload: cleavable linkers allow systemic payload release (broader bystander effect); non-cleavable more selective; topoisomerase inhibitors show higher response but greater myelosuppression risk
Adverse events
Mucosal: mucositis 10–40% (grades 1–3, occasionally grade 4)
Hematologic: myelosuppression (neutropenia, anemia) 10–30% (grade 3+)
GI: diarrhea 10–25%
Infusion: reactions 5–10%, manageable
Management: proactive dental care, G-CSF, anti-diarrheal reduce discontinuation
Hematologic: myelosuppression (neutropenia, anemia) 10–30% (grade 3+)
GI: diarrhea 10–25%
Infusion: reactions 5–10%, manageable
Management: proactive dental care, G-CSF, anti-diarrheal reduce discontinuation
Conclusions
TROP2 ADCs offer multiple mechanisms and efficacy profiles; unique linker/payload characteristics inform mechanism of action, dosing, and management. Sequential use of multiple ADCs and combination with immunotherapy/chemotherapy show promise but require further study to define optimal integration.
Key Limitations
Narrative review, not a primary trial — no head-to-head data. Several agents (DB-1305, SHR-A1921, sacituzumab tirumotecan) are early-phase/investigational with immature efficacy data. Aggregated ranges span heterogeneous populations and lines. No validated TROP2 biomarker threshold for patient selection. Cross-trial efficacy comparison is hypothesis-generating only.
Clinical Context
Datopotamab deruxtecan is FDA-approved for EGFR-mutant NSCLC after prior therapy; other TROP2 ADCs remain investigational in NSCLC. ESMO/ASCO have not issued dedicated TROP2-ADC NSCLC guidance. This overview frames the emerging class and informs sequencing decisions pending mature randomized data.