Datroway (datopotamab deruxtecan-dlnk)

Late-phase ADCs include trastuzumab deruxtecan (targeting HER2 [human epidermal growth factor receptor 2]), datopotamab deruxtecan and sacituzumab govitecan (targeting TROP2 [trophoblast cell-surface antigen 2]), patritumab deruxtecan (targeting HER3), telisotuzumab vedotin (targeting c-MET [cellular-mesenchymal epithelial transition factor]), and sigvotatug vedotin (targeting IB6 [integrin beta-6]). Ongoing, biomarker-driven trials and combination strategies with immunotherapy or tyrosine kinase inhibitors hold the potential to further enhance the efficacy of ADCs. In this review, the authors highlight the current landscape and future directions of ADCs in NSCLC, emphasizing available results for compounds in late-stage clinical development and different disease settings.

TROPION-Lung14 will assess 1L osimertinib + Dato-DXd versus osimertinib alone in patients with EGFR-mutated LA/M NSCLC, potentially providing a new treatment option. ClinicalTrials.gov identifier: NCT06350097 (Registration Date: April 5, 2024).

Datopotamab deruxtecan represents a clinically meaningful therapeutic option based on the targeted delivery of cytotoxic chemotherapy for patients with endocrine-resistant HR-positive/HER2-negative breast cancer. Ongoing studies are required to define optimal treatment sequencing, combination strategies, and long-term safety outcomes.

Trastuzumab deruxtecan expanded therapeutic utility across HER2-low and HER2-ultralow disease, whereas sacituzumab govitecan and datopotamab deruxtecan provide later-line options. Ultimately, management of hormone receptor-positive/HER2-negative MBC requires dynamic integration of tumor biology, systemic therapy advances, and patient-defined goals of care. As therapeutic complexity increases, shared decision making and equitable access to evidence-based and supportive care services remain essential for delivering high-quality, individualized oncology care.

P1, N=145, Active, not recruiting, Daiichi Sankyo | Trial completion date: Apr 2026 --> Dec 2026

P3, N=644, Active, not recruiting, AstraZeneca | Trial completion date: Nov 2028 --> Dec 2026

P1/2, N=334, Recruiting, AstraZeneca | N=234 --> 334 | Trial completion date: Feb 2026 --> Dec 2028 | Trial primary completion date: Feb 2026 --> Dec 2028

DS-1062a, a TROP2-directed ADC delivering the camptothecin (CPT)-like topoisomerase I inhibitor deruxtecan (Dxd), demonstrated marked tumor regression in HNSCC and ESCA xenografts...These findings establish TROP2 as a therapeutically actionable target and reveal AUNIP as a genetic rheostat governing ADC and chemotherapy response. Co-targeting AUNIP represents a promising strategy to potentiate SSB-inducing therapies and improve outcomes in patients with squamous carcinomas of the upper aerodigestive tract.

P3, N=582, Recruiting, AstraZeneca | Trial completion date: May 2032 --> Aug 2031

P3, N=400, Recruiting, AstraZeneca

P1/2, N=66, Recruiting, Memorial Sloan Kettering Cancer Center

Exposure-safety analysis further supported that this approach may reduce the potential associated safety risks. These results support the recommended Dato-DXd dosing regimen (6 mg/kg Q3W with dose capping for patients ≥90 kg) and highlight its favorable benefit-risk profile in patients with HR+/HER2-breast cancer.