Investigational Drug
Datopotamab deruxtecan
HealthScout AI Analysis
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Overview
Datopotamab deruxtecan (Dato‑DXd; DS‑1062; US brand name Datroway) is a TROP2‑directed antibody–drug conjugate (ADC) developed by Daiichi Sankyo and AstraZeneca. In the United States, it is FDA‑approved for: - Unresectable or metastatic HR‑positive/HER2‑negative breast cancer after prior endocrine therapy and chemotherapy (January 17, 2025). (fda.gov) - Locally advanced or metastatic EGFR‑mutated NSCLC after prior EGFR‑directed therapy and platinum chemotherapy (accelerated approval, June 23, 2025). (fda.gov)
Large phase 3 trials have reported improved progression‑free survival vs chemotherapy in HR+/HER2− breast cancer (TROPION‑Breast01) and in previously treated NSCLC overall (TROPION‑Lung01), with the clearest benefit in nonsquamous NSCLC; overall survival in Lung01 did not reach statistical significance in the all‑comers population. (ascopubs.org)
Mechanism of action
Dato‑DXd is a humanized anti‑TROP2 IgG1 linked via a cleavable tetrapeptide linker to a membrane‑permeable topoisomerase I inhibitor payload (DXd); the average drug–antibody ratio is ~4. Upon TROP2 binding and internalization, lysosomal cleavage releases DXd, causing DNA damage and apoptosis. Preclinical studies also show “bystander” killing of adjacent low‑TROP2 tumor cells. (pubmed.ncbi.nlm.nih.gov)
Dosing used in pivotal trials and in US labeling is 6 mg/kg IV every 3 weeks (capped at 540 mg for ≥90 kg). (pubmed.ncbi.nlm.nih.gov)
Efficacy
Breast cancer (HR+/HER2−, previously treated) - TROPION‑Breast01 (phase 3, n≈732): Dato‑DXd significantly improved PFS vs investigator’s‑choice single‑agent chemotherapy (BICR HR 0.63; 95% CI 0.52–0.76; median 6.9 vs 4.9 months). Confirmed ORR 36.4% vs 22.9%. OS was immature at the primary analysis (HR 0.84; 95% CI 0.62–1.14). These data supported the US approval. (ascopubs.org)
NSCLC (previously treated, all histologies) - TROPION‑Lung01 (phase 3, n=604): PFS benefit vs docetaxel (median 4.4 vs 3.7 months; HR 0.75; P=0.004); OS not statistically significant in the overall population (median 12.9 vs 11.8 months; HR 0.94; P=0.53). Benefit was most pronounced in nonsquamous NSCLC. (pubmed.ncbi.nlm.nih.gov)
NSCLC (nonsquamous subgroup from Lung01; descriptive) - Nonsquamous subgroup showed higher activity: ORR 31.2% vs 12.8% with docetaxel; median PFS 5.5 vs 3.6 months; OS 14.6 vs 12.3 months (HR 0.84). OS did not meet significance in the overall study. (iaslc.org)
EGFR‑mutated NSCLC (post‑EGFR TKI and platinum) - Pooled analysis (TROPION‑Lung05 phase 2 + Lung01 subset; n≈117): confirmed ORR 42.7% (95% CI 33.6–52.2), median DOR 7.0 months, median PFS 5.8 months, median OS 15.6 months. These data supported the US accelerated approval. (daiichisankyo.us)
Early‑phase breast cancer cohorts - TROPION‑PanTumor01 (phase 1): in heavily pretreated HR+/HER2− and TNBC cohorts, BICR ORR 26.8% and 31.8%, with median PFS 8.3 and 4.4 months, respectively. (ascopubs.org)
Safety
Class‑consistent risks include stomatitis/oral mucositis, nausea, ocular events, alopecia, and interstitial lung disease (ILD)/pneumonitis.
- Breast (TROPION‑Breast01): grade ≥3 treatment‑related AEs were lower with Dato‑DXd vs chemo (20.8% vs 44.7%). Additional safety analyses reported stomatitis/oral mucositis in 56%, ocular events in 40%, and adjudicated drug‑related ILD in 3% (mostly low grade). (ascopubs.org)
- NSCLC (TROPION‑Lung01): stomatitis ~47% and nausea ~34% with Dato‑DXd; grade ≥3 TRAEs 26% vs 42% with docetaxel; pneumonitis/ILD ~4%. No late safety signals with extended follow‑up. (ascopost.com)
- Stomatitis management and incidence across trials are detailed in a peer‑reviewed review and show mostly grade 1–2 events with early onset; implementation of prophylaxis/management guidelines reduced frequency and severity. (academic.oup.com)
- Pooled ILD analysis across breast and lung trials reported adjudicated drug‑related ILD in ~5% (mostly grade 1–2), with rare grade ≥3 events; careful monitoring is recommended. US labeling includes boxed/serious warnings for ILD/pneumonitis, ocular adverse reactions, and stomatitis. (ovid.com)
Further reading
- Journal of Clinical Oncology (phase 3): TROPION‑Breast01 primary results (HR+/HER2− breast) — Bardia et al., 2025. https://ascopubs.org/doi/10.1200/JCO.24.00920 (ascopubs.org)
- Journal of Clinical Oncology (phase 3): TROPION‑Lung01 primary paper (previously treated NSCLC). https://pubmed.ncbi.nlm.nih.gov/39250535/ (pubmed.ncbi.nlm.nih.gov)
- FDA approval (breast, Jan 17, 2025) — Datroway (datopotamab deruxtecan-dlnk). https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-datopotamab-deruxtecan-dlnk-unresectable-or-metastatic-hr-positive-her2-negative-breast (fda.gov)
- FDA accelerated approval (EGFR‑mutated NSCLC, Jun 23, 2025). https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-datopotamab-deruxtecan-dlnk-egfr-mutated-non-small-cell-lung-cancer (fda.gov)
- Preclinical mechanism paper (AACR, Molecular Cancer Therapeutics, 2021). https://pubmed.ncbi.nlm.nih.gov/34413126/ (pubmed.ncbi.nlm.nih.gov)
- Toxicity management and stomatitis review (The Oncologist, 2025). https://pmc.ncbi.nlm.nih.gov/articles/PMC11942793/ (pmc.ncbi.nlm.nih.gov)
Notes: - Some subgroup and pooled‑analysis data are descriptive and not powered for formal OS comparisons; consult the cited full texts/abstracts for methodology and limitations. (iaslc.org)
Last updated: Oct 2025
Active trials using Datopotamab deruxtecan
Found 12 active trials using this drug:
HealthScout AI summary: Adults with unresectable locally advanced or metastatic urothelial carcinoma who progressed during or after first-line enfortumab vedotin plus pembrolizumab are randomized to datopotamab deruxtecan (TROP2-directed antibody–drug conjugate with a topoisomerase I inhibitor payload) plus cisplatin/carboplatin versus gemcitabine plus platinum. Includes cisplatin-eligible and -ineligible patients (carboplatin used when cisplatin-ineligible); excludes prior TROP2 ADCs and non-urothelial variants like small cell, adenocarcinoma, and urachal.
ClinicalTrials.gov ID: NCT07129993
HealthScout AI summary: Adults with locally advanced/metastatic NSCLC enrolled by biomarker and line: first-line AGA-negative with PD-L1 ≥50% get rilvegostomig (PD‑1/TIGIT bispecific) ± ramucirumab, first-line AGA-negative with PD-L1 1–49% get rilvegostomig + ramucirumab, and second-line AGA-positive nonsquamous post–targeted therapy get datopotamab deruxtecan (TROP2 ADC) + ramucirumab ± rilvegostomig. Designed to assess safety and antitumor activity across these combinations, excluding patients with active autoimmune disease, uncontrolled comorbidities, or unstable CNS disease.
ClinicalTrials.gov ID: NCT07098338
HealthScout AI summary: This trial enrolls adults with unresectable or metastatic HER2-negative (HER2-low or HER2-0) breast cancer who have progressed on prior ADC therapy, including those with stable or treated CNS metastases. Patients are randomized to receive either trastuzumab deruxtecan (an anti-HER2 ADC) or datopotamab deruxtecan (an investigational anti-TROP2 ADC), with crossover permitted at progression.
ClinicalTrials.gov ID: NCT06533826
HealthScout AI summary: Eligible patients are adults with advanced or metastatic non-squamous EGFR-mutated NSCLC who have progressed after prior osimertinib; the trial compares Dato-DXd (a TROP2-targeted antibody-drug conjugate) alone or with osimertinib versus standard platinum-based doublet chemotherapy. Patients with uncontrolled comorbidities or active/untreated CNS metastases are excluded.
ClinicalTrials.gov ID: NCT06417814
HealthScout AI summary: This trial enrolls treatment-naïve adults with stage IIIB/IIIC or IV nonsquamous NSCLC harboring EGFR Ex19del or L858R mutations, randomizing them to receive either standard osimertinib or osimertinib combined with datopotamab deruxtecan, a TROP2-directed antibody-drug conjugate. Key exclusions include prior EGFR TKI or TROP2 therapy and significant interstitial lung or cardiac disease.
ClinicalTrials.gov ID: NCT06350097
HealthScout AI summary: This trial enrolls adults with previously untreated, locally advanced or metastatic non-squamous NSCLC, high PD-L1 expression (TC ≥ 50%), and no EGFR/ALK/ROS1 alterations, randomizing to either datopotamab deruxtecan (a TROP2-directed ADC) plus rilvegostomig (a bispecific PD-1/TIGIT antibody), rilvegostomig alone, or pembrolizumab monotherapy as first-line therapy. Eligible patients must have ECOG 0-1 and no prior systemic therapy for advanced disease.
ClinicalTrials.gov ID: NCT06357533
HealthScout AI summary: This trial enrolls adults with HER2-negative metastatic breast cancer (ER-positive or triple-negative) with brain metastases or any HER2-negative subtype with leptomeningeal disease, who receive datopotamab deruxtecan, an anti-TROP2 antibody-drug conjugate delivering a topoisomerase I inhibitor. All participants must have CNS involvement, good performance status, and no major comorbidities; the drug is given IV every 3 weeks.
ClinicalTrials.gov ID: NCT06176261
HealthScout AI summary: This trial enrolls patients with PD-L1 positive (CPS ≥10) locally recurrent inoperable or metastatic triple-negative breast cancer, who have not received prior systemic therapy for advanced disease, to compare datopotamab deruxtecan (a TROP2-directed antibody-drug conjugate) with or without durvalumab (a PD-L1 inhibitor) versus investigator’s choice of chemotherapy plus pembrolizumab.
ClinicalTrials.gov ID: NCT06103864
HealthScout AI summary: Eligible patients are adults with previously untreated, advanced or metastatic non-squamous NSCLC, PD-L1 TPS <50%, and no actionable genomic alterations. The trial compares pembrolizumab plus platinum/pemetrexed versus combinations including datopotamab deruxtecan (a TROP2-directed antibody-drug conjugate) with pembrolizumab, with or without platinum chemotherapy.
ClinicalTrials.gov ID: NCT05555732
HealthScout AI summary: Adults with advanced/metastatic solid tumors (endometrial, gastric, mCRPC, ovarian, colorectal, urothelial, biliary) receive datopotamab deruxtecan (anti‑TROP2 antibody–drug conjugate delivering a topoisomerase I inhibitor) as monotherapy or combined with agents such as capecitabine/5‑FU, bevacizumab ± platinum, prednisone (mCRPC), platinum in urothelial cancer, or bispecific PD‑1/CTLA‑4 (volrustomig) or PD‑1/TIGIT (rilvegostomig) immunotherapies. Key exclusions include active/untreated CNS disease, prior TROP2- or deruxtecan-based ADCs, significant ILD/pneumonitis history, and uncontrolled infections/comorbidities.
ClinicalTrials.gov ID: NCT05489211
HealthScout AI summary: This trial enrolls adults with advanced or metastatic solid tumors—including breast, ovarian, prostate, pancreatic (HRR-mutated), IDH1/2-mutant glioma, and other selected solid cancers—who have progressive disease and good performance status, testing the selective PARP1 inhibitor AZD9574 as monotherapy or in combination with temozolomide, trastuzumab deruxtecan, or datopotamab deruxtecan. Eligibility may require specific genetic or molecular features depending on tumor type and study module.
ClinicalTrials.gov ID: NCT05417594
HealthScout AI summary: This trial enrolls adults with previously untreated advanced or metastatic non-squamous NSCLC, high PD-L1 expression (TPS ≥50%), and no EGFR, ALK, or ROS1 alterations, randomizing them to pembrolizumab alone or in combination with datopotamab deruxtecan, a TROP2-directed antibody-drug conjugate delivering a topoisomerase I inhibitor. Prior immune checkpoint inhibitor or TROP2-targeted therapy is not allowed.
ClinicalTrials.gov ID: NCT05215340
