Eligible participants are ≥18 years with inoperable/metastatic HR+/HER2-negative breast cancer, progressed on 1-2 prior chemotherapy lines, and eligible for ICC options. Key criteria: ECOG PS 0-1, ≥1 measurable lesion (RECIST 1.1), stable brain metastases (if applicable), adequate organ function (hematologic, hepatic, renal, LVEF ≥50%), and washout periods (3 weeks for prior therapies, 4 weeks for radiotherapy). FFPE tumor samples and 12-week life expectancy are required.

The primary endpoints include Progression-Free Survival (PFS) assessed by BICR per RECIST 1.1 from randomization until progression or death (21-month timeframe), analyzed via hazard ratio for all randomized participants regardless of treatment discontinuation or additional therapies. Overall Survival (OS) is measured from randomization to death (44-month timeframe), with hazard ratio analysis similarly inclusive of all randomized participants.

Secondary endpoints encompass Objective Response Rate (ORR; confirmed CR/PR per RECIST 1.1), Duration of Response (DoR; time from first response to progression/death), Investigator-assessed PFS, Disease Control Rate (DCR; CR/PR/SD at 12 weeks), Time to First/Second Subsequent Therapy (TFST/TSST), PFS2 (time to second progression/death), and PROs (TTD in pain, physical functioning, GHS/QoL via EORTC QLQ-C30). Pharmacokinetics (Dato-DXd plasma concentrations) and immunogenicity (ADA testing) are also evaluated.

Eligible participants are ≥18 years with locally recurrent/metastatic TNBC (ER/PR/HER2-negative), no prior metastatic chemotherapy, and ineligible for PD-1/PD-L1 inhibitors. Key criteria: ECOG PS 0-1, ≥1 measurable lesion (RECIST 1.1), stable brain metastases (if applicable), adequate organ function (hematologic, hepatic, renal), and washout periods (3-6 weeks for prior therapies). Required: FFPE tumor sample (≤3 months old), 12-week life expectancy, and contraception compliance. Exclusion: active HBV, recent transfusions/G-CSF, or pregnancy. Informed consent and optional genetic research consent are mandatory.

The primary endpoints include Progression-Free Survival (PFS), defined as time from randomization to BICR-assessed progression per RECIST 1.1 or death (26-month timeframe), analyzed via hazard ratio (HR) for all randomized participants, with censoring for missed visits. Overall Survival (OS) measures time from randomization to death (42-month timeframe), analyzed by HR. Both endpoints include all randomized participants regardless of treatment discontinuation or additional therapies.

Secondary endpoints include Objective Response Rate (ORR; confirmed CR/PR per RECIST 1.1), Duration of Response (DoR; time from first response to progression/death), Investigator-assessed PFS, Disease Control Rate (DCR; CR/PR/SD at 12 weeks), and Time to Deterioration (TTD) in pain, physical functioning, breast/arm symptoms, and GHS/QoL (EORTC scales). Additional endpoints: Time to First/Second Subsequent Therapy (TFST/TSST), PFS2 (second progression/death), pharmacokinetics (Dato-DXd plasma concentrations), immunogenicity (ADA testing), and safety (AEs per CTCAE v5.0). All analyses use HR or odds ratios and include all randomized participants.

Eligible participants are ≥18 years with residual invasive TNBC post-neoadjuvant therapy (anthracycline/taxane ± platinum/pembrolizumab), ECOG PS 0-1, and no relapse. Key requirements: FFPE tumor sample from residual disease, LVEF ≥50%, no adjuvant therapy, and adequate organ function. Exclusion: germline BRCA mutations. Radiotherapy must be completed ≤6 weeks pre-randomization (or surgery ≤16 weeks if no radiotherapy).

A Phase 3 Open-label, Randomised Study of Datopotamab Deruxtecan (DatoDXd) With or Without Durvalumab Versus Investigator's Choice of Therapy in Patients With Stage I-III Triple-negative Breast Cancer Who Have Residual Invasive Disease in the Breast and/or Axillary Lymph Nodes at Surgical Resection Following Neoadjuvant Systemic Therapy (TROPION-Breast03)

The primary endpoints include Progression-Free Survival (PFS), defined as time from randomization to BICR-assessed progression per RECIST 1.1 or death (26-month timeframe), analyzed via hazard ratio (HR) for all randomized participants, with censoring for missed visits. Overall Survival (OS) measures time from randomization to death (42-month timeframe), analyzed by HR. Both endpoints include all randomized participants regardless of treatment discontinuation or additional therapies.

Patient-reported outcomes assess time to deterioration (TTD) in physical function (PROMIS SF-8c), GHS/QoL (EORTC IL172), and fatigue (PROMIS SF-7a) over 24-36 months, analyzed via HR and mean score differences. Pharmacokinetics (Dato-DXd plasma concentrations) and immunogenicity (ADA titres) are evaluated at specific cycle timepoints. Safety/tolerability (AEs per CTCAE v5.0) is monitored until 90 days post-treatment. All analyses maintain intent-to-treat principles.

Eligible participants have PD-L1+ (CPS ≥10) locally recurrent/metastatic TNBC per ASCO-CAP guidelines, ECOG PS 0-1, and measurable disease (RECIST 1.1). Key requirements: FFPE tumor sample (≤3 months old), no prior metastatic therapy (except completed curative treatment ≥6 months prior for recurrent cases), and eligibility for ICC (paclitaxel/nab-paclitaxel/gemcitabine-carboplatin). Adequate organ function and contraception use are mandatory.

A Phase III, Open-label, Randomised Study of Datopotamab Deruxtecan (Dato-DXd) With or Without Durvalumab Compared With Investigator's Choice of Chemotherapy (Paclitaxel, Nab-paclitaxel or Gemcitabine + Carboplatin) in Combination With Pembrolizumab in Patients With PD-L1 Positive Locally Recurrent Inoperable or Metastatic Triple-negative Breast Cancer (TROPION-Breast05)

The primary endpoint is Progression-Free Survival (PFS), defined as time from randomization to BICR-assessed progression per RECIST 1.1 or death (33-month timeframe), analyzed via hazard ratio (HR) for all randomized participants. Censoring applies if progression/death follows ≥2 missed visits. Secondary efficacy measures include Overall Survival (OS; 64-month follow-up), Objective Response Rate (ORR), Duration of Response (DoR), and Clinical Benefit Rate at 24 weeks (CBR-24), all assessed per RECIST 1.1 by BICR/investigator.

Patient-reported outcomes evaluate Time to Deterioration (TTD) in breast/arm symptoms (EORTC IL116), pain (EORTC IL199), physical function (PROMIS SF8c), and GHS/QoL (EORTC IL172). Additional endpoints include Time to First/Second Subsequent Therapy (TFST/TSST), PFS2 (second progression/death), pharmacokinetics (Dato-DXd plasma concentrations), immunogenicity (ADA testing), and safety (AEs). All time-to-event endpoints use HR analysis with follow-up to 64 months.

A Phase III, Open-label, Randomised Study of Neoadjuvant Datopotamab Deruxtecan (Dato-DXd) Plus Durvalumab Followed by Adjuvant Durvalumab With or Without Chemotherapy Versus Neoadjuvant Pembrolizumab Plus Chemotherapy Followed by Adjuvant Pembrolizumab With or Without Chemotherapy for the Treatment of Adult Patients With Previously Untreated Triple-Negative or Hormone Receptor-low/HER2-negative Breast Cancer (D926QC00001; TROPION-Breast04)

The primary endpoints include pathologic complete response (pCR) rate assessed at definitive surgery (ypT0/Tis ypN0) and event-free survival (EFS) measuring time from randomization to disease progression/recurrence/second primary cancer/death (68-month follow-up), both analyzed via between-arm difference (pCR) or hazard ratio (EFS) for all randomized participants regardless of treatment discontinuation.

Key secondary endpoints comprise overall survival (OS; 82-month follow-up), distant disease-free survival (DDFS; 68-month follow-up), patient-reported outcomes (breast/arm symptoms, physical function, fatigue, QoL via EORTC/PROMIS scales), pharmacokinetics (Dato-DXd plasma concentrations), immunogenicity (ADA), and safety (AEs per CTCAE v5.0), analyzed through hazard ratios or mean score differences.

Eligible patients are adults (&ge;18) with triple-negative breast cancer (ER/PR <10%, HER2-negative), measurable brain metastases (RANO-BM) not requiring immediate local therapy, KPS &ge;70%, and adequate organ function. Prior PD-1/PD-L1 or TROP-2 inhibitors are allowed. Required washout periods: &ge;3 weeks for chemotherapy/surgery, &ge;4 weeks for chest radiation/antibody therapies.

Eligibility requires relapsed/progressed advanced solid tumors with mandatory TROP2 biomarker testing (no minimum threshold), age &ge;18, ECOG 0-1, LVEF &ge;50%, adequate organ function, and no prior TROP2/deruxtecan ADC therapy. Disease-specific criteria apply for NSCLC, TNBC, HR+/HER2-low breast cancer (prior T-DXd required), SCLC, ovarian, prostate, and other cancers, with contraception mandates and &ge;3-month life expectancy. The sub-study assesses oral mucositis/stomatitis via daily patient-reported outcomes.

A Phase III, Randomised, Open-label, Global Study of Adjuvant Datopotamab Deruxtecan (Dato-DXd) in Combination With Rilvegostomig or Rilvegostomig Monotherapy Versus Standard of Care, Following Complete Tumour Resection, in Participants With Stage I Adenocarcinoma Non-small Cell Lung Cancer Who Are ctDNA-positive or Have High-risk Pathological Features (TROPION-Lung12)

Key inclusion criteria cover histologically confirmed EGFR-mutant adenocarcinoma NSCLC (locally advanced/metastatic), progression on first-line osimertinib, measurable disease per RECIST 1.1, mandatory biopsy feasibility, adequate coagulation parameters (INR/aPTT <1.5&times;ULN), and ECOG 0-1 status, while permitting prior adjuvant/neoadjuvant therapy if completed >6 months pre-recurrence.

Eligible participants must have histologically confirmed advanced/metastatic NSCLC with documented negative/unknown status for actionable EGFR/ALK alterations (non-squamous) or meeting specific testing criteria (squamous), allowing KRAS mutations or non-actionable genomic variants, with prior therapy limits (&le;2 lines for dose escalation; immunotherapy-naive status for expansion cohorts), mandatory biopsy compliance, available archival tissue for biomarker analysis, adequate baseline organ function, and ineligibility for curative resection/chemoradiation.

Secondary endpoints include objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS) assessed over ~30 months, alongside pharmacokinetic parameters (Cmax, Tmax, AUC) of Dato-DXd components measured through serial plasma sampling during 21-day treatment cycles, with immunogenicity monitoring for anti-drug antibodies against Dato-DXd and pembrolizumab.

Eligible participants (&ge;18 years) must have advanced/metastatic NSCLC without EGFR/ALK alterations (KRAS mutations permitted), with cohort-specific prior therapy requirements (treatment-na&iuml;ve to &le;2 prior lines), measurable disease per RECIST 1.1, ECOG 0-1, adequate organ function, mandatory biopsy compliance, and PD-L1 testing for Cohorts 5-14 using validated assays.

Eligibility requires &ge;18 years with histologically confirmed non-squamous NSCLC (symptomatic BM allowed), measurable intracranial disease (&ge;10mm), ECOG PS&le;2, and biomarker-defined subgroups (AGA/non-AGA). Prior therapy mandates include platinum/immunotherapy for non-AGA patients and targeted therapy sequences for AGA patients, with stringent organ function requirements (LVEF&ge;50%, hematologic/hepatic parameters) and reproductive safeguards (contraception for 4-7 months post-treatment). Archival/metastatic tumor tissue and washout periods for prior treatments are mandatory.

The study evaluates intracranial efficacy (ORR-IC per RANO-BM criteria) and extracranial/systemic response (ORR-EC/bicompartmental ORR per RECIST v1.1) over an average 8-month period, alongside comprehensive assessments including PFS, CBR, DCR, TTR, DoR, tumor burden changes, OS, safety (CTCAE v5.0), and patient-reported outcomes (QoL via QLQ-C30/BN20, neurofunction via NANO scale).

Eligibility requires adults (&ge;18) with stage IIIB-IV NSCLC (with/without actionable mutations), life expectancy &ge;3 months, prior therapy per genomic status (platinum/immunotherapy for non-AGA; targeted therapy sequences for AGA including osimertinib for EGFR+), measurable disease (RECIST v1.1), ECOG PS 0-1, adequate organ function, and reproductive safeguards (contraception for 4-7 months post-treatment), with mandatory tumor tissue submission (fresh or archival within 2 years) for biomarker analysis.

Secondary endpoints include investigator-assessed PFS, ORR (CR/PR rate), DOR (response duration), DCR (disease control), TTR (response timing), TTD (symptom worsening), safety profiles (TEAEs), pharmacokinetics (Cmax/Tmax/AUC of DS-1062a/anti-TROP2/MAAA-1181a), and immunogenicity (ADA incidence), offering comprehensive therapeutic evaluation across efficacy, safety, and drug exposure parameters.

Eligible participants must have advanced NSCLC refractory to 1-3 prior lines (including platinum/immunotherapy for non-mutated cases or targeted therapy+platinum for mutated cases), measurable disease (RECIST v1.1), ECOG &le;1, life expectancy &ge;3 months, stable treated brain metastases, and adequate organ function, with reproductive safeguards (contraception for 7 months post-treatment).

Eligibility requires adults (&ge;18) with measurable disease (RECIST v1.1), ECOG PS 0-1, and tumor sample availability, with protocol-specific criteria: Sub-Protocol A for HER2-low metastatic breast cancer (1-2 prior chemotherapy lines), Sub-Protocol B for trastuzumab-refractory gastric/GEJ adenocarcinoma, and Sub-Protocol C for NSCLC (platinum/immunotherapy for non-AGA; targeted therapy sequences for AGA). Key exclusions include prior EZH2 inhibitor use, uncontrolled CNS metastases, active infections, CYP3A inducer use, and prior topoisomerase I/TROP2-targeted therapy exposure.

A phase 3 open-label, randomised study of datopotamab deruxtecan (DatoDXd) with or without durvalumab versus investigator's choice of therapy in patients with stage i-2i triple-negative breast cancer who have residual invasive disease in the breast and/or axillary lymph nodes at surgical resection following neoadjuvant systemic therapy (TROPION-Breast03).

A phase 3, randomised, open-label, multicentre, global study of datopotamab deruxtecan (Dato-DXd) in combination with durvalumab and carboplatin versus pembrolizumab in combination with platinum-based chemotherapy for the first-line treatment of patients with locally advanced or metastatic NSCLC without actionable genomic alterations (D926NC00001; AVANZAR).

Dato-DXd was intravenously administered at 10 mg/kg to NCI-N87 xenograft model mice. When the tumor volume reached approximately 150-300 mm³,the tumor-bearing mice were assigned to the vehicle control group,the treatment groups and the satellite sampling groups,and Dato-DXd or other test substances were administered intravenously once on day 0.