In HR+ cohort, for ENHERTU (N=331), median overall survival (months)=23.90 (95% Cl 20.80-24.80), Confirmed Objective Response Rate=52.90% (95% Cl 47.30-58.40), Complete Response rate=36.00%, Partial Response rate= 49.50%, median Duration of Response (months)=10.70 (95% Cl 8.50-13.70); for Chemotherapy (N=163), median overall survival (months)=17.50 (95% Cl 15.20-24.80), Confirmed Objective Response Rate=16.60% (95% Cl 11.20-23.20), Complete Response rate=0.60%, Partial Response rate= 16.00%, median Duration of Response (months)=6.80 (95% Cl 6.50-9.90). In HR+ and HR- cohort, for ENHERTU (N=373), median Progression-Free Survival (mFPS)=9.90 months (95% Cl 9.00-11.30), median overall survival (months) = 23.40 (95% Cl 20.00-24.80), Confirmed Objective Response Rate = 52.30% (95% Cl 47.10-57.40), Complete Response rate=35.00%, Partial Response rate= 49.10%, median Duration of Response(months)=10.70 (95% Cl 8.50-13.20); for Chemotherapy (N=184), median Progression-Free Survival (mFPS)=5.40 months(95% Cl 4.20-6.80), median overall survival (months)=16.80(95% Cl 14.50-20.00), Confirmed Objective Response Rate=16.30% (95% Cl 11.30-22.50), Complete Response rate=11.00%, Partial Response rate= 15.20%, median Duration of Response(months)=6.80 (95% Cl 6.00-9.90).

The median patient age was 54 years. Approximately 50% of patients were treated with 0-1 prior lines of therapy in the metastatic setting, and 50% were treated with 2 prior treatment regimens. At baseline, 16.50% of patients in the T-DXd group and 14.80% of those in the T-DM1 group had brain metastases. At a median follow-up of 15.90 months, T-DXd significantly improved PFS by 72% compared with T-DM1 across all patient subgroups. Findings were consistent irrespective of hormone receptor status, prior treatment with pertuzumab, number of prior lines of therapy, presence or absence of visceral disease, and presence or absence of brain metastases. The overall response rate (ORR) in the overall study cohort was 79.70% and 34.20% in the T-DXd and T-DM1 groups, respectively, representing an absolute improvement in ORR of 45% with T-DXd Findings were consistent across all patient subgroups, with the absolute improvement in ORR associated with T-DXd relative to T-DM1 ranging from 39% to 52%.

In the trastuzumab deruxtecan group (N=119), confirmed disease control rate=86.00% (95% Cl 78.00-91.00%), median Duration of Response (mDOR)=11.30 months (95% Cl 5.60-not estimable), median overall survival (mOS)=12.50 months (95% Cl 9.60-14.30), estimated overall survival was 80.00% at 6 months and 52.00% at 12 months, median progression-free survival (mPFS)=5.60 months (95% CI, 4.30-6.90), estimated progression-free survival=43.00% at 6 months and 30.00% at 12 months In the chemotherapy group (N=56), confirmed disease control rate=62.00% (95% Cl 49.00-75.00%), median Duration of Response (mDOR)=3.90 months (95% Cl 3.0-4.9), median overall survival (mOS)=8.40 months (95% Cl 6.90-10.70), estimated overall survival was 66.00% at 6 months and 29.00% at 12 months, median progression-free survival (mPFS)=3.50 months (95% CI, 2.00-4.30), estimated progression-free survival=21.00% at 6 months and 0.00% at 12 months.

Disease-control rate was 97.30% (95% CI, 93.80-99.10), Median Duration of Response (months)=14.80 (95% CI, 13.80-16.90), clinical-benefit rate was 76.10% (95% CI, 69.30-82.10), median duration of progression-free survival was 16.40 months (95% CI, 12.70-not reached), estimated overall survival was 93.90% (95% CI, 89.30-96.60) at 6 months and 86.20% (95% CI, 79.80-90.70) at 12 months.

In the ITT population (n=15 patients), intracranial response rate by RANO-BM was 73.33% (95% CI 48.10-89.10%) (11/15 patients; 2 patients in complete remission (13.33%); 9 patients in partial remission (60.00%)). In the per protocol population (PP;n=14 patients), the response rate was 78.57% (95% CI 49.20-95.30%) (11/14). Two patients had stable disease for 6 months and one patient had stable disease at first restaging and progressed after four cycles of trastuzumab deruxtecan. Clinical benefit rate was 13/14 (92.86%; 95% CI 66.10-99.80%) in the PP population.

In patients with extracranial metastases at baseline (n=13), a partial response by RECIST 11 was observed in 5/13 (27.8%; 95% CI 13.9-68.4%) patients, with the remainder having stable disease. None of the patients progressing on trastuzumab deruxtecan had extracranial progression as the first site of progressive disease In patients with measurable extracranial disease at baseline (n=8), a partial remission was observed in 5/8 (62.50%; 95% CI 24.50-91.50%) patients, with the remainder having stable disease.

The antitumor activity of DS-8201a was evaluated in various patient-derived xenograft models with different HER2 expression levels. Each cell suspension or tumor fragment was inoculated subcutaneously into specific pathogen-free female nude mice.The tumor-bearing mice were randomized into treatment and control groups based on the tumor volumes, and dosing was initiated on day 0. In this group, 3 mg/kg or 10 mg/kg DS-8201a was i.v. respectively to the tumor-bearing mice.

The antitumor activity of DS-8201a was evaluated in various patient-derived xenograft models with different HER2 expression levels. Each cell suspension or tumor fragment was inoculated subcutaneously into specific pathogen-free female nude mice.The tumor-bearing mice were randomized into treatment and control groups based on the tumor volumes, and dosing was initiated on day 0. In this group, 10 mg/kg DS-8201a was i.v. to the tumor-bearing mice.

The antitumor activity of DS-8201a was evaluated in various patient-derived xenograft models with different HER2 expression levels. Each cell suspension or tumor fragment was inoculated subcutaneously into specific pathogen-free female nude mice.The tumor-bearing mice were randomized into treatment and control groups based on the tumor volumes, and dosing was initiated on day 0. In this group, 10 mg/kg DS-8201a was i.v. to the tumor-bearing mice.

The antitumor activity of DS-8201a was evaluated in various patient-derived xenograft models with different HER2 expression levels. Each cell suspension or tumor fragment was inoculated subcutaneously into specific pathogen-free female nude mice.The tumor-bearing mice were randomized into treatment and control groups based on the tumor volumes, and dosing was initiated on day 0. In this group, 10 mg/kg DS-8201a was i.v. to the tumor-bearing mice.

The antitumor activity of DS-8201a and trastuzumab were evaluated in various mice xenograft models with different HER2 expression levels; CFPAC-1 (low-expression). Each cell suspension or tumor fragment was inoculated subcutaneously into specific pathogen-free female nude mice.The tumor-bearing mice were randomized into treatment and control groups based on the tumor volumes, and dosing was initiated on day 0. In this group, 1 mg/kg DS-8201a or 10 mg/kg trastuzumab was i.v. to the tumor-bearing mice.

The antitumor activity of DS-8201a was evaluated in various mice xenograft models with different HER2 expression levels; GCIY (negative). Each cell suspension or tumor fragment was inoculated subcutaneously into specific pathogen-free female nude mice.The tumor-bearing mice were randomized into treatment and control groups based on the tumor volumes, and dosing was initiated on day 0. In this group, 10 mg/kg DS-8201a or Anti-HER2 ADC(same drug-linker as DS-8201a and DAR=3.4) was i.v. to the tumor-bearing mice.

The in vivo antitumor activity of DS-8201a was evaluated in a HER2-positive NCI-N87 xenograft model. Each cell suspension or tumor fragment was inoculated subcutaneously into specific pathogen-free female nude mice. The tumor-bearing mice were randomized into treatment and control groups based on the tumor volumes, and dosing was initiated on day 0 In this group, 0.25 mg/kg DS-8201a was iv to the tumor-bearing mice.

The antitumor activity of DS-8201a was evaluated in various mice xenograft models with different HER2 expression levels; JIMT-1 (moderate positive). Each cell suspension or tumor fragment was inoculated subcutaneously into specific pathogen-free female nude mice.The tumor-bearing mice were randomized into treatment and control groups based on the tumor volumes, and dosing was initiated on day 0. In this group, 10 mg/kg DS-8201a or Anti-HER2 ADC(same drug-linker as DS-8201a and DAR=3.4) was i.v. to the tumor-bearing mice.

The antitumor activity of DS-8201a was evaluated in various mice xenograft models with different HER2 expression levels; Capan-1 (weak positive). Each cell suspension or tumor fragment was inoculated subcutaneously into specific pathogen-free female nude mice.The tumor-bearing mice were randomized into treatment and control groups based on the tumor volumes, and dosing was initiated on day 0. In this group, 10 mg/kg DS-8201a or Anti-HER2 ADC(same drug-linker as DS-8201a and DAR=3.4) was i.v. to the tumor-bearing mice.

The in vivo antitumor activity of DS-8201a was evaluated in a HER2-positive NCI-N87 xenograft model. Each cell suspension or tumor fragment was inoculated subcutaneously into specific pathogen-free female nude mice. The tumor-bearing mice were randomized into treatment and control groups based on the tumor volumes, and dosing was initiated on day 0 In this group, 0.5 mg/kg DS-8201a was iv to the tumor-bearing mice.

The in vivo antitumor activity of DS-8201a was evaluated in a HER2-positive NCI-N87 xenograft model. Each cell suspension or tumor fragment was inoculated subcutaneously into specific pathogen-free female nude mice.The tumor-bearing mice were randomized into treatment and control groups based on the tumor volumes, and dosing was initiated on day 0. In this group, 1 mg/kg DS-8201a was i.v. to the tumor-bearing mice.

The antitumor activity of DS-8201a was evaluated in various mice xenograft models with different HER2 expression levels; KPL-4 (strong positive). Each cell suspension or tumor fragment was inoculated subcutaneously into specific pathogen-free female nude mice.The tumor-bearing mice were randomized into treatment and control groups based on the tumor volumes, and dosing was initiated on day 0. In this group, 10 mg/kg DS-8201a or Anti-HER2 ADC(same drug-linker as DS-8201a and DAR=3.4) was i.v. to the tumor-bearing mice.

The in vivo antitumor activity of DS-8201a was evaluated in a HER2-positive NCI-N87 xenograft model. Each cell suspension or tumor fragment was inoculated subcutaneously into specific pathogen-free female nude mice.The tumor-bearing mice were randomized into treatment and control groups based on the tumor volumes, and dosing was initiated on day 0. In this group, 2 mg/kg DS-8201a was i.v. to the tumor-bearing mice.

The in vivo antitumor activity of DS-8201a was evaluated in a HER2-positive NCI-N87 xenograft model. Each cell suspension or tumor fragment was inoculated subcutaneously into specific pathogen-free female nude mice.The tumor-bearing mice were randomized into treatment and control groups based on the tumor volumes, and dosing was initiated on day 0. In this group, 4 mg/kg DS-8201a was i.v. to the tumor-bearing mice.

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).

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

Eligibility requires relapsed/progressed advanced solid tumors with mandatory TROP2 biomarker testing (no minimum threshold), age ≥18, ECOG 0-1, LVEF ≥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 ≥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×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 (≤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 (≥18 years) must have advanced/metastatic NSCLC without EGFR/ALK alterations (KRAS mutations permitted), with cohort-specific prior therapy requirements (treatment-naïve to ≤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 ≥18 years with histologically confirmed non-squamous NSCLC (symptomatic BM allowed), measurable intracranial disease (≥10mm), ECOG PS≤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≥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 (≥18) with stage IIIB-IV NSCLC (with/without actionable mutations), life expectancy ≥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 ≤1, life expectancy ≥3 months, stable treated brain metastases, and adequate organ function, with reproductive safeguards (contraception for 7 months post-treatment).

Eligibility requires adults (≥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.

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.

In dose escalation phase, pts with metastatic or unresectable non-small cell lung cancer (NSCLC) with EGFR activating mutation after disease progression during/after EGFR TKI therapy; In Dose Expansion phase, pts with metastatic or unresectable NSCLC with EGFR activating mutation or squamous or non-squamous NSCLC with disease progression during/after systemic treatment for locally advanced or metastatic disease.

Eligibility requires locally advanced/metastatic NSCLC (RECIST v1.1 measurable lesions, ECOG 0-1). Dose escalation mandates EGFR TKI resistance (Jackman criteria), while expansion cohorts specify prior therapies (e.g., platinum-based regimens, KRAS-G12C inhibitors in Cohort 5). Exclusions include ILD, uncontrolled CVD, active infections, recent cytotoxic therapy, or contraindications like QT prolongation. Cohort-specific exclusions apply (e.g., EGFR mutations in Cohort 2, leptomeningeal disease in Cohort 4).

The study evaluates dose-limiting toxicities (DLTs) over 21 days in the dose-escalation phase and adverse event summaries over approximately 36 months. Efficacy measures include ORR (using RECIST v1.1 via BICR) during dose expansion. Pharmacokinetic endpoints-Cmax, AUCinf, and AUC (last)-for HER3-DXd, total anti-HER3, and MAAA-1181a are assessed across cycles with intensive blood sampling (pre-dose to Day 15).

Secondary outcomes include pharmacokinetics (Cmax, Tmax, AUC[0-21]) during dose escalation and efficacy metrics (ORR, DCR, DOR, TTR, PFS, OS) monitored over ~36 months. Dose expansion tracks similar endpoints over ~60 months, including NSCLC-SAQ symptom severity scores and PRO-CTCAE analyses to assess symptom progression. ADA status and PK parameters are also evaluated in specific cohorts.

Exclusion criteria include small cell or mixed histology NSCLC, active interstitial lung disease, uncontrolled respiratory conditions, symptomatic brain/spinal cord metastases, or inadequate washout periods (e.g., <14 days for chemo, <28 days for major surgery). Prior HER3 antibodies, topoisomerase I inhibitors, or ADCs containing such inhibitors are prohibited. Unresolved toxicities (>Grade 1), active secondary malignancies (except certain cured cancers), uncontrolled cardiovascular disease, or active HBV/HCV/HIV infections also exclude participation. Chronic systemic corticosteroids >10 mg prednisone/day or leptomeningeal disease are additional exclusions.

The primary objective is to assess Objective Response Rate (ORR) by BICR per RECIST v1.1, defined as the proportion of participants achieving confirmed CR (disappearance of all target lesions) or PR (≥30% decrease in sum of diameters) from screening until progression, death, or study discontinuation (up to ~21 months). Secondary endpoints include Duration of Response (time from first confirmed response to progression/death), Progression-Free Survival (time from treatment start to PD/death), ORR by investigator, Disease Control Rate (CR+PR+SD), Time to Tumor Response, and Best Percentage Change in Sum of Diameters of measurable tumors. Overall Survival will track from treatment start to death (up to ~45 months). Safety will be evaluated through Treatment-Emergent AEs, SAEs, and AESIs from baseline to Day 47 post-last dose.

Eligible participants must be ≥18 years with histologically confirmed advanced/metastatic NSCLC progressing after osimertinib and platinum-based chemotherapy, harboring EGFR exon 19 or L858R mutations, and having ≥1 measurable lesion per RECIST v1.1. Required tumor tissue includes fresh biopsy or archival specimen obtained within 3 months post-progression. ECOG 0-1 and adequate organ function (platelets ≥100K/mm ³, hemoglobin ≥9 g/dL, ANC ≥1500/mm ³, creatinine clearance ≥30 mL/min, and liver function within specified limits) are mandatory.

Eligible patients must have HER3-positive advanced/metastatic breast cancer, ECOG 0-1, LVEF ≥50%, and measurable disease (RECIST 1.1). Dose expansion requires prior taxane therapy (except TNBC cohort), while TNBC patients need HR-/HER2- status and 1-2 prior lines. Exclusions include prior HER3/ADC treatment (e.g., exatecan-based), severe cardiac/pulmonary disease, or corrected QT prolongation (>450ms males, >470ms females).

In DE/DF, U3-1402 was administered intravenously (IV) Q2W or Q3W at doses ranging from 1.6 to 8.0 mg/kg. Patients had HER3-expressing advanced/unresectable disease refractory/intolerant to standard treatment or for which no standard treatment was available. In the expansion part, U3-1402 was administered IV Q3W to patients with HER3-high (4.8 or 6.4 mg/kg) or HER3-low (6.4 mg/kg) HR+/HER2- MBC or with HER3-high triple-negative breast cancer (TNBC; 6.4 mg/kg).

The primary safety and efficacy endpoints include the incidence of Treatment-emergent Adverse Events (TEAEs) up to 28 days post-last dose and Best Overall Response (CR, PR, or SD per RECIST 1.1) assessed via blinded independent review. ORR is defined as confirmed CR/PR, while SD indicates neither sufficient shrinkage nor progression (≥20% increase).

Clinical assessments span from baseline through treatment and follow-up, evaluating pathological, molecular (CelTIL/HER3/Ki67), and QoL outcomes. Safety monitoring includes AEs, lab abnormalities, and protocol compliance until 30 days post-surgery. The study emphasizes strict eligibility around treatment history and comorbidities to ensure patient suitability for neoadjuvant therapy and surgery.

The primary endpoint is pCRBL rate (ypT0/is ypN0) at surgery, indicating complete absence of invasive carcinoma in the breast and lymph nodes. Secondary endpoints include Residual Cancer Burden (RCB) categories, pCRB (breast-only response), tumor ORR per RECIST v1.1, iDFS at 3/5 years (covering recurrence types), CelTIL score changes, HER3/ERBB3 expression, Ki67 changes, Quality of Life via EORTC-BR45/QLQ-C30, and safety with AE monitoring per NCI CTCAE v5.0.

Inclusion criteria: Untreated, non-metastatic ER+/PgR+/HER2- breast adenocarcinoma with Ki67≥20% or high genomic risk, ECOG 0-1, chemotherapy/surgery eligibility, tumor sample availability, adequate organ function, and LVEF≥50%. Exclusion criteria: Metastatic/bilateral cancer, prior treatments (chemo/radiation/anti-HER3/topoisomerase inhibitors), excisional biopsy, cardiac/pulmonary diseases, other malignancies (exceptions apply), uncontrolled systemic conditions, infections (HIV/hepatitis), hypersensitivity to drug components, high anthracycline exposure, ILD history, unresolved toxicities (>grade 1), neuropathy, chronic steroids (>10mg prednisone), corneal disease, pregnancy, or hydroxychloroquine use within 14 days.

Eligible patients must have prior T-DXd progression, HER2+/HER2-low breast cancer, measurable lesions, and adequate organ function. Exclusions include ILD, uncontrolled systemic diseases, active brain metastases, unresolved toxicities, significant cardiovascular disorders, active HBV/HCV, pregnancy, or prior anti-HER3 therapy. Contraception and washout periods per protocol are mandatory.

Eligible participants must have HER2+ locally advanced or metastatic breast cancer, meet specific HIV/HBV/HCV and ECOG criteria, and have prior anti-HER2 therapy history (varying by study arm). Exclusion criteria include uncontrolled cardiovascular/pulmonary disease, active infections, prior HER2-targeted TKIs (Arm 3), and certain malignancies or neurological conditions.

Eligible participants have locally advanced TNBC/HR-low+/HER2- breast cancer (AJCC stages cT1c-T4/N0-N2), controlled HBV/HCV, ECOG 0-1, and LVEF ≥50%/LLN. Exclusions include prior anti-PD-1/L1/HER3 therapy, active malignancies, CNS metastases, ILD, uncontrolled infections, or cardiovascular/corneal disease. Metastatic (M1) or cN3 disease is excluded.

An Open-label Randomized Phase 2 Study to Evaluate Safety and Efficacy of Patritumab Deruxtecan Plus Pembrolizumab Administered Either Before or After Carboplatin/Paclitaxel Plus Pembrolizumab Compared With Pembrolizumab in Combination With Chemotherapy Followed by Surgery and Adjuvant Pembrolizumab for High-Risk Early-Stage Triple-Negative or Hormone Receptor-Low Positive/Human Epidermal Growth Factor Receptor-2 Negative Breast Cancer (HERTHENA-Breast03)

Eligible patients are adults (≥18y) with untreated, non-metastatic HR+/HER2- or TNBC (ASCO-CAP criteria), measurable lesions (≥1cm), Ki67≥10%, LVEF≥50%, and adequate organ function. Exclusions include prior HER3/topoisomerase I inhibitor therapy, cardiac/pulmonary disorders, unresolved grade≥2 toxicity, QT prolongation, active infections, or concurrent malignancies (exceptions: cured cancers in past 3 years).

Eligible adults (≥18y) with HER2- (Parts A/B: 1-5 prior chemo lines, endocrine/CDK4/6i-refractory HR+) or HER2+ MBC (Part Z: ≥2 anti-HER2 therapies including trastuzumab deruxtecan) must have measurable disease, ECOG 0-1, and adequate organ function. Key exclusions: prior HER3-targeted therapy, unresolved Grade>1 toxicity (except alopecia), active brain metastases/ILD, LVEF<50%, or severe cardiovascular/pulmonary conditions. HER2+ cohorts prohibit other exatecan ADCs (non-trastuzumab deruxtecan).

Exclusion criteria include curative-intent resectable disease, interstitial lung disease, uncontrolled systemic illnesses, active brain metastases, inadequate washout periods for prior therapies, cardiovascular risks (QT prolongation, LVEF <50%, recent MI), active HBV/HCV/HIV infections, pregnancy/breastfeeding, hypersensitivity to study drugs, and concurrent experimental treatments. Participants must not have unresolved grade ≥2 toxicities (except alopecia) or other primary malignancies within 3 years (exceptions: cured non-melanoma skin cancer or in-situ lesions). Legal or psychological barriers to protocol compliance also disqualify.

The primary outcome is the investigator-assessed objective response rate (ORR), defined as the proportion of participants achieving complete response (CR) or partial response (PR), measured over an average of 8 months during treatment. Secondary outcomes include duration of response (DOR), progression-free survival (PFS), and clinical benefit ratio (CBR), all assessed by investigators and central review over up to 42 months. Safety endpoints cover adverse events, lab abnormalities, ECG changes, and quality of life measures via EORTC QLQ-C30 and ECOG performance status. Additional efficacy metrics include overall survival (OS) and central-review ORR.

Eligible participants are adults with histologically confirmed HER2-negative, hormone receptor-positive (HR+), unresectable locally advanced or metastatic breast cancer who progressed after CDK4/6 inhibitor therapy with endocrine treatment. Key requirements include accessible tumor biopsy sites, measurable lesions, ECOG PS 0-1, life expectancy ≥12 weeks, adequate organ function, and compliance with contraception protocols. Prior treatments may include anthracyclines, taxanes, PI3K/mTOR/AKT inhibitors, or PARP inhibitors, but only one line of chemotherapy for advanced disease is permitted.

Eligibility requires ≥18y/o patients with advanced/metastatic disease progression after prior therapies (1-3 lines depending on tumor type), ECOG 0-1. Exclusions include HER2+ gastric cancer, active ILD, recent malignancies (except cured carcinomas), prior HER3/TOP1-ADC treatment, and metastatic irinotecan exposure. Tumor tissue confirmation and biomarker status (e.g., HPV, HER2) are mandated per protocol-specific thresholds.

This study evaluates HER3-DXd monotherapy efficacy in various cancer cohorts (excluding prostate cancer) with primary endpoints including confirmed objective response rate (ORR) per RECIST v1.1 and PSA reduction ≥50% (prostate cohort only), assessed over 27 months. ORR combines complete (CR) and partial response (PR) rates, while prostate-specific outcomes focus on biochemical markers.

Safety and efficacy assessments cover all cohorts, tracking treatment-emergent adverse events (graded via NCI-CTCAE v5.0), duration of response (DoR), clinical benefit rate (CR+PR+SD≥183d), and pharmacokinetics (Cmax, Tmax, AUC). The prostate cohort adds PCWG3-based radiographic PFS, time to first skeletal event, and subsequent therapy metrics over 27 months, with intensive PK sampling during cycles 1-8.

Eligible participants (≥18y/o, ECOG 0-1) must have progressed on ≥2 prior lines including fluoropyrimidine/irinotecan/anti-EGFR/VEGF therapies, with measurable lesions and adequate organ function. Key exclusions: active ILD, uncontrolled cardiovascular disease, untreated CNS metastases, unresolved CTCAE Grade ≥2 toxicities, prior HER3/exatecan-ADC exposure, or HIV/HBV/HCV viremia outside protocol-permitted thresholds. Tumor tissue requirements mandate pretreatment biopsy unless recent archival samples exist.

The study evaluates U3-1402 in advanced/metastatic colorectal cancer, assessing primary endpoints including blinded independent central review (BICR)-confirmed ORR (CR+PR per RECIST v1.1) and investigator-assessed efficacy outcomes (ORR, DoR, DCR) over 27 months, with tumor response metrics capturing both radiographic and clinical progression events.

Secondary objectives include safety profiling (TEAEs, lab abnormalities), pharmacokinetics (Cmax, Tmax, AUClast), and immunogenicity (ADA incidence), with intensive PK sampling during cycles 1-8. Disease control parameters (PFS by BICR/investigator, OS) and biomarker analyses (HER3 expression) are tracked alongside protocol-defined washout periods for prior therapies.

Key inclusion criteria involve unresectable/metastatic colorectal cancer, biliary tract cancer (BTC), or hepatocellular carcinoma (HCC), with prior therapy and recovery from treatment side effects. Exclusion criteria cover interstitial lung disease (ILD), severe respiratory compromise, leptomeningeal disease, corneal disease, uncontrolled cardiovascular/cerebrovascular conditions, or active systemic infections, ensuring patient safety in the study.

The primary endpoints include Dose-Limiting Toxicity (DLT) evaluated over 21 days in the dose-escalation phase, Adverse Events (AEs) monitored over approximately 45 months, and participants discontinuing treatment due to AEs. Additionally, Objective Response Rate (ORR) per RECIST 1.1 via Blinded Independent Central Review (BICR) will assess Complete Response (CR) or Partial Response (PR) rates. All endpoints aim to evaluate safety and efficacy.

Secondary endpoints include Duration of Response (DOR) and Progression-Free Survival (PFS) using RECIST 1.1 criteria (assessed by BICR), measuring time to progressive disease (PD) or death. Overall Survival (OS) tracks time from treatment initiation until death. Pharmacokinetic endpoints include maximum plasma concentration (Cmax) and trough concentration (Ctrough) of patritumab deruxtecan, measured at designated time points over ~45 months. These metrics evaluate treatment efficacy and drug exposure.

Eligibility requires untreated Stage IV NSCLC (squamous/nonsquamous) with archived tumor tissue. Exclusions include prior systemic therapy for metastatic disease, uncontrolled CNS metastases, active autoimmune/immunodeficiency conditions, recent major surgery/radiotherapy (>30Gy to lungs), live vaccines (excluding licensed COVID-19 vaccines), or severe irAEs from prior immunotherapy. GI/liver dysfunction affecting drug absorption and unresolved prior treatment toxicities (>CTCAE Grade 1) also preclude enrollment.

Exclusion criteria include small-cell histology, active ILD/pneumonitis, untreated brain metastases, unresolved Grade ≥2 toxicities, uncontrolled cardiovascular disease (QTcF >450 ms, LVEF ≤45%, recent MI), strong CYP3A4 inducers, recent radiation/immunotherapy, prior malignancies (exceptions: non-melanoma skin cancer, curatively treated early-stage tumors), and poorly controlled HIV. Concomitant conditions jeopardizing protocol compliance also exclude participation.

The study evaluates dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) during dose escalation, classified per NCI-CTCAE v5.0. Objective response rate (ORR) is assessed in dose expansion phases, defined as confirmed CR or PR by RECIST v1.1 via blinded independent central review (BICR). Additional endpoints include duration of response (DoR), clinical benefit rate (CBR), disease control rate (DCR), time to response (TTR), progression-free survival (PFS), overall survival (OS), immunogenicity (ADA assessment), and pharmacokinetic parameters (Cmax, Tmax, AUC).

Key inclusion criteria for dose escalation and second-line expansion include confirmed EGFR exon 19del/L858R mutations, prior osimertinib treatment (≥6 weeks) with progression. First-line expansion requires untreated EGFR-mutant NSCLC eligible for osimertinib. All participants must have measurable disease per RECIST v1.1, adequate organ function, and provide tumor tissue (pre-/on-treatment biopsies for certain cohorts).

Inclusion criteria require signed consent, age ≥18, confirmed EGFRm NSCLC with progression post EGFR TKI (including osimertinib) and platinum-based chemotherapy, ECOG PS 0-1, adequate organ function, and contraception compliance. For resupply, continued treatment benefit and safety reporting are mandatory. Exclusion criteria include participation in Daiichi Sankyo ADC trials, small cell histology, active/past ILD, severe respiratory compromise, unresolved toxicities (Grade >1), uncontrolled cardiovascular disease, active HBV/HCV/HIV, HER3-DXd hypersensitivity, pregnancy, clinically significant infections, or corneal disease.

Eligible patients must have stage IV NSCLC (squamous/non-squamous), ECOG 0-1, available tumor tissue, and controlled HIV/HBV if applicable. Key exclusions include small cell histology, EGFR/ALK/ROS1 alterations (squamous), active CNS metastases, uncontrolled cardiovascular disease (recent MI, NYHA 3-4 CHF), prior topoisomerase I inhibitors/anti-HER3 ADCs, recent radiotherapy/vaccines, concurrent HBV/HCV, immunosuppressive therapy, or active autoimmune disease/infections requiring treatment. Washout periods for prior therapies and adequate recovery from major surgery are required.

Key exclusions include small cell/mixed histology, active ILD, uncontrolled respiratory conditions, symptomatic brain/spinal metastases, prior HER3 antibodies/topoisomerase I ADCs, other systemic therapies beyond EGFR TKIs in metastatic setting, active HBV/HCV/HIV, or secondary malignancies (excluding cured non-melanoma skin/cervical cancers). Chronic steroids >10 mg prednisone/day or leptomeningeal disease are excluded. Cardiovascular instability and clinically significant corneal disease also preclude participation.

The primary endpoint is Progression-Free Survival (PFS) per BICR, measured from randomization to first documented disease progression or death (up to ~49 months). Secondary efficacy outcomes include Overall Survival (OS), PFS by investigator/local practice, Objective Response Rate (CR+PR), Duration of Response (time from first response to progression/death), and Clinical/Disease Control Rates (CR+PR±SD). Intracranial PFS will be assessed by BICR per CNS-RECIST in patients with baseline CNS lesions. Patient-reported outcomes include NSCLC symptom burden (NSCLC-SAQ), QoL (EORTC-QLQ-C30, EQ-5D-5L), and treatment tolerability (PGI scales). Safety will evaluate TEAEs (CTCAE v5.0) and immunogenicity (ADA incidence).

Eligible patients must be ≥18 years with confirmed metastatic/locally advanced non-squamous EGFR-mutant NSCLC (exon 19del/L858R) progressing after 1-2 prior EGFR TKIs (including 3rd-gen TKI). Prior neoadjuvant/adjuvant therapy is allowed if recurrence occurred >12 months post-treatment. Patients must have ≥1 measurable lesion per RECIST v1.1, ECOG 0-1, and adequate organ function (platelets ≥100K/mm ³, ANC ≥1500/mm ³, Hb ≥9 g/dL, CrCl ≥45 mL/min, liver enzymes ≤3×ULN). Archival/fresh tumor tissue is required.

Eligible participants include adults (≥18) with locally advanced/metastatic NRG1 fusion-positive solid tumors, measurable lesions per RECIST v1.1, ECOG PS 0-1, and adequate organ function. Key exclusions involve interstitial lung disease, uncontrolled cardiovascular conditions, active hepatitis B/C, unresolved prior toxicities, certain recent treatments, and other active malignancies.

Eligible participants are adults (≥18) with histologically confirmed ES-SCLC, measurable per RECIST 1.1, progressing after ≥1 platinum-based systemic therapy (≥2 cycles). Key exclusions: prior B7-H3/ADC (exatecan-based) therapy, active CNS metastases, uncontrolled cardiovascular/respiratory disease, ILD, unresolved toxicities (>Grade 1), active infections (HBV/HCV/HIV), or immunosuppressive steroid use (>10 mg/day prednisone equivalent). Live vaccines within 30 days or pregnancy also preclude enrollment.

Secondary endpoints include progression-free survival (PFS), duration of response (DoR), overall survival (OS), time to response (TTR), and disease control rate (DCR) assessed up to 36 months by BICR/investigator. Pharmacokinetic evaluations (Cmax, Tmax, Ctrough, AUC, T1/2) track I-DXd, anti-B7-H3 antibody, and MAAA-1181a levels; immunogenicity assesses treatment-emergent antidrug antibodies (ADAs).

Eligible participants are adults (≥18) with histologically confirmed ES-SCLC, measurable per RECIST 1.1, progressing after ≥1 platinum-based systemic therapy (≥2 cycles). Key exclusions: prior B7-H3/ADC (exatecan-based) therapy, active CNS metastases, uncontrolled cardiovascular/respiratory disease, ILD, unresolved toxicities (>Grade 1), active infections (HBV/HCV/HIV), or immunosuppressive steroid use (>10 mg/day prednisone equivalent). Live vaccines within 30 days or pregnancy also preclude enrollment.

Secondary endpoints include progression-free survival (PFS), duration of response (DoR), overall survival (OS), time to response (TTR), and disease control rate (DCR) assessed up to 36 months by BICR/investigator. Pharmacokinetic evaluations (Cmax, Tmax, Ctrough, AUC, T1/2) track I-DXd, anti-B7-H3 antibody, and MAAA-1181a levels; immunogenicity assesses treatment-emergent antidrug antibodies (ADAs).

Eligible participants are adults (≥18) with histologically confirmed ES-SCLC, measurable per RECIST 1.1, progressing after ≥1 platinum-based systemic therapy (≥2 cycles). Key exclusions: prior B7-H3/ADC (exatecan-based) therapy, active CNS metastases, uncontrolled cardiovascular/respiratory disease, ILD, unresolved toxicities (>Grade 1), active infections (HBV/HCV/HIV), or immunosuppressive steroid use (>10 mg/day prednisone equivalent). Live vaccines within 30 days or pregnancy also preclude enrollment.

Secondary endpoints include progression-free survival (PFS), duration of response (DoR), overall survival (OS), time to response (TTR), and disease control rate (DCR) assessed up to 36 months by BICR/investigator. Pharmacokinetic evaluations (Cmax, Tmax, Ctrough, AUC, T1/2) track I-DXd, anti-B7-H3 antibody, and MAAA-1181a levels; immunogenicity assesses treatment-emergent antidrug antibodies (ADAs).

Eligible participants are adults (≥18) with histologically confirmed ES-SCLC, measurable per RECIST 1.1, progressing after ≥1 platinum-based systemic therapy (≥2 cycles). Key exclusions: prior B7-H3/ADC (exatecan-based) therapy, active CNS metastases, uncontrolled cardiovascular/respiratory disease, ILD, unresolved toxicities (>Grade 1), active infections (HBV/HCV/HIV), or immunosuppressive steroid use (>10 mg/day prednisone equivalent). Live vaccines within 30 days or pregnancy also preclude enrollment.

Secondary endpoints include progression-free survival (PFS), duration of response (DoR), overall survival (OS), time to response (TTR), and disease control rate (DCR) assessed up to 36 months by BICR/investigator. Pharmacokinetic evaluations (Cmax, Tmax, Ctrough, AUC, T1/2) track I-DXd, anti-B7-H3 antibody, and MAAA-1181a levels; immunogenicity assesses treatment-emergent antidrug antibodies (ADAs).

Eligibility requires locally advanced/metastatic esophageal SCC (1L setting), controlled HIV/HBV/HCV if applicable. Exclusions: prior systemic therapy for metastatic disease, high-risk tumor invasion (aorta/respiratory tract), uncontrolled effusions, corneal disease, or prior PD- (L)1/CTLA-4 treatment. HIV+ candidates with Kaposi's sarcoma are excluded.

Phase IB tracks Dose-Limiting Toxicities (DLTs) including Grade 3/4 hematologic/nonhematologic AEs (e.g., thrombocytopenia, febrile neutropenia) or treatment-related discontinuations (21-day window). Safety endpoints also cover AE incidence (28 months) and intervention discontinuation rates (25 months). Phase II measures ORR (73 months) per RECIST 1.1 via blinded central review.

Eligible participants (≥18 years) require histologically confirmed unresectable/metastatic ESCC, progression post-platinum+ICI therapy (≤1 prior line), ≥1 measurable lesion (RECIST v1.1), and ECOG 0-1. Exclusions: prior B7-H3/topoisomerase inhibitors, adenosquamous subtype, high-risk tumor invasion (aorta/respiratory tract), active brain metastases, recent thromboembolic events (6 months), or clinically significant ILD/pulmonary disease. Chronic steroids (>10 mg/day prednisone-equivalent) are excluded except for inhalers/topicals.

Primary efficacy endpoints include Overall Survival (OS) and Progression-Free Survival (PFS), both measured from randomization to death or disease progression (up to 54 months) by BICR per RECIST v1.1. Secondary outcomes are Objective Response Rate (ORR), Duration of Response (DoR), and Disease Control Rate (DCR). Patient-reported outcomes assess EORTC QLQ-C30/OES18 changes, while safety tracks TEAEs, AESIs, and ADA incidence over 54 months.

Eligible participants require histologically confirmed Stage IV squamous NSCLC with progression post anti-PD- (L)1 + platinum therapy. HIV/HBV/HCV-infected patients may enroll with controlled viral loads. Exclusions include small cell histology, uncontrolled cardiovascular/pulmonary disease, active CNS metastases, autoimmune/ILD conditions, dual HBV/HCV infection, transplant history, or recent major surgery complications.

Eligible participants require histologically confirmed Stage IV NSCLC (non-small cell) with no prior systemic treatment for metastatic disease. Key exclusions: small cell histology, active CNS metastases, uncontrolled autoimmune/infectious conditions, recent major surgery (<3 weeks), prior immunotherapy discontinuation due to severe irAEs, and active HBV/HCV infections unless properly controlled. Screening requirements include tumor tissue submission and completion within specified windows (35 days for Part A, 28 days for Part B).

Eligible participants include Stage IV nonsquamous NSCLC patients (EGFR/ALK/ROS1-negative) with RECIST 1.1-measurable disease, ECOG 0-1, and adequate organ function. Exclusions cover comorbidities like uncontrolled infections, recent radiotherapy, active malignancies, CNS metastases, autoimmune/ILDs, and prior transplant/HIV/Kaposi's sarcoma, ensuring protocol safety alignment.

Eligible participants must have extensive-stage SCLC post-platinum therapy, archival/fresh tissue availability, and controlled HIV if applicable. Key exclusions cover active infections, uncontrolled cardiovascular/neurologic conditions, prior transplants, untreated brain metastases, recent radiotherapy, immunosuppressive therapy, and malignancies requiring active treatment within 3 years. Specific restrictions apply to Part 1, including recent anticancer therapies and corneal disease.

Eligible participants must have DLL3-expressing malignancies: SCLC post-platinum therapy, relapsed/refractory NEPC, or other neuroendocrine tumors failing standard therapy. Key exclusions cover active CNS metastases, uncontrolled effusions, recent cardiovascular events (6 months), active hepatitis/HIV, transplants, immunosuppressive therapy (prednisone >10mg/day), interstitial lung disease, and investigational drug use within 3 weeks/5 half-lives. Autoimmune conditions and unresolved toxicities from prior treatments are prohibited.

Safety endpoints include the percentage of participants experiencing adverse events (AEs) and discontinuing due to AEs, graded per NCI CTCAE v5.0 and ASTCT criteria, monitored for up to 4 years. Dose-limiting toxicities (DLTs) following HPN328 treatment (mono/combination) are tracked alongside comprehensive pharmacokinetic parameters (Cmax, Tmax, AUCt/inf, t½, CL, Vss, AC) for gocatamig, atezolizumab, and I-DXd in serum/plasma under single dose and steady state conditions.

Efficacy outcomes focus on tumor response using RECIST v1.1 (PCWG3-modified for NEPC), including ORR, EC-ORR (extra-cranial), BOR, PFS, EC-PFS, OS, DOR, and EC-DOR - all evaluated over 4 years. Immunogenicity is assessed via anti-drug antibody (ADA) incidence against gocatamig, atezolizumab, and I-DXd at designated timepoints. Response criteria incorporate target lesion measurements (≥30% decrease for PR, ≥20% increase for PD with 5mm threshold) and new lesion appearance.

Eligible participants must have metastatic prostate adenocarcinoma progressing on ADT with 1-2 prior ARPI therapies (PARPi allowed if indicated), stable ECOG 0-1, and bone therapy stability. Exclusions cover ILD, uncontrolled cardiovascular/metabolic conditions, prior mCRPC taxanes, active CNS metastases, steroids >10mg/day, recent radiotherapy, autoimmune/transplant history, and other malignancies requiring treatment within 3 years.

Primary safety outcomes include DLTs (Grade 4 toxicities, significant Grade 3 events, treatment delays/discontinuations), AEs, and treatment discontinuations due to AEs in both efficacy (54 months) and safety lead-in phases (21 days), with PSA response rate additionally tracked in the efficacy phase. DLT criteria cover hematologic/nonhematologic toxicities, liver injuries, febrile neutropenia, and dose interruptions.

Key efficacy measures per PCWG-modified RECIST 1.1 include ORR (CR/PR), rPFS (radiological progression/death), OS, DOR (response maintenance), TFST (subsequent therapy initiation), time to PSA progression (≥25% increase + ≥2ng/mL threshold), and TTPP (pain progression per BPI-SF/AQA), all monitored for up to 54 months with Kaplan-Meier analyses.

Eligible participants must have ECOG 0-1, measurable lesions per RECIST 1.1 (excluding irradiated sites without progression), adequate organ function, and specified advanced/metastatic cancers (e.g., HNSCC, ESCC, NSCLC, SCLC, CRPC). Key exclusions include prior B7-H3/I-DXd treatment, ADC-related toxicities, multiple malignancies (exceptions apply), uncontrolled cardiovascular/pulmonary disease, active infections, and conditions compromising safety or study integrity per investigator assessment. ESCC Cohort 4 requires progression post-platinum/ICI with ≤1 prior line of systemic therapy.

Eligibility requires ECOG 0-1, measurable lesions (RECIST v1.1), progression after standard therapy, and tumor-specific criteria (e.g., prior ICI/platinum for HNSCC; ≤3 lines for endometrial cancer; HER2-low status for breast cancer). Key exclusions: prior B7-H3/I-DXd treatment, ADC-related toxicities, untreated brain metastases, inadequate washout periods. Disease-specific mandates include biopsy availability (archival/tfresh), Child-Pugh A for HCC, and targeted therapy for actionable mutations.

The primary efficacy endpoint is Objective Response Rate (ORR) assessed by investigator per RECIST v1.1 (complete/partial response confirmed) until progression/death (up to 57 months). Safety outcomes include dose-limiting toxicities (Grade ≥3 non-disease-related events in Cycle 1) and treatment-emergent adverse events (TEAEs) monitored from consent until 47 days post-treatment, graded via NCI-CTCAE v5.0 in the HCC cohort.

Secondary endpoints encompass incidence of TEAEs, serious AEs (SAEs), and adverse events of special interest (AESIs) through follow-up, alongside efficacy measures: Duration of Response (DoR), Progression-Free Survival (PFS), Disease Control Rate (DCR), and Overall Survival (OS). Pharmacokinetics (Cmax, Tmax, t1/2, Ctrough, AUC) and immunogenicity (ADA incidence) are evaluated via noncompartmental analysis during 21-day cycles up to 57 months.

PDX studies CTG-2093, CTG-0166, CTG-0820, and CTG-1061 studies were performed by Champions Oncology, Inc. Models were established by inoculating tumor fragments derived from patients with small cell lung cancer (SCLC), nonsmall cell lung cancer (NSCLC), head and neck cancer, and bladder cancer, respectively, which were maintained in host mice, subcutaneously into female Hsd: Athymic Nude-Foxn1nu mice.Group assignment was carried out when the tumor volume reached approximately 100 to 300 mm³. The tumor-bearing mice were treated with DS-7300a or relevant controls intravenously on days 0 and 14.

Eligible participants are adults (≥18 years) with advanced/metastatic HER2-expressing solid tumors (IHC 1+/2+/3+ or HER2 mutations) who failed or are intolerant to standard therapy. Key inclusion criteria: ECOG 0-1, adequate organ function, measurable lesions per RECIST 1.1, and washout from prior therapies. Exclusion criteria include uncontrolled brain metastases, cardiovascular disease, significant pulmonary conditions, prior topoisomerase I inhibitor-ADCs, active infections (HIV/HBV/HCV), pregnancy, and unresolved toxicity >Grade 1 from prior treatments.

The pharmacokinetics (PK) of GQ1005 will be assessed via maximum concentration (Cmax), time to peak concentration (Tmax), and area under the curve (AUC). Antitumor efficacy measures include overall response rate (ORR), duration of response (DOR), disease control rate (DCR), time-to-response (TTR), progression-free survival (PFS), and overall survival (OS), all evaluated per RECIST 1.1. Immunogenicity will be assessed by anti-drug antibody (ADA) formation.

Eligible participants are adults (≥18 years) with advanced/metastatic HER2-expressing solid tumors (IHC 1+/2+/3+ or HER2 mutations) who failed or are intolerant to standard therapy. Key inclusion criteria: ECOG 0-1, adequate organ function, measurable lesions per RECIST 1.1, and washout from prior therapies. Exclusion criteria include uncontrolled brain metastases, cardiovascular disease, significant pulmonary conditions, prior topoisomerase I inhibitor-ADCs, active infections (HIV/HBV/HCV), pregnancy, and unresolved toxicity >Grade 1 from prior treatments.

The pharmacokinetics (PK) of GQ1005 will be assessed via maximum concentration (Cmax), time to peak concentration (Tmax), and area under the curve (AUC). Antitumor efficacy measures include overall response rate (ORR), duration of response (DOR), disease control rate (DCR), time-to-response (TTR), progression-free survival (PFS), and overall survival (OS), all evaluated per RECIST 1.1. Immunogenicity will be assessed by anti-drug antibody (ADA) formation.

Eligible patients must have HER2-expressing (IHC≥1+ or NSCLC mutations) advanced solid tumors (ECOG 0-1, life expectancy ≥12 weeks), measurable disease (RECIST 1.1), adequate organ function, and no prior topoisomerase I inhibitor ADCs. Key exclusions include active CNS metastases, uncontrolled comorbidities, unresolved treatment toxicities (>CTCAE v5.0 grade 1), or severe hypersensitivity to HER2 therapies/ADC components.

As of August 20, 2024, ten patients had been enrolled (n=4 breast cancer, n=2 NSCLC, n=2 biliary tract cancer, n=1 colorectal cancer, and n=1 salivary gland cancer) (table 1). Patients received JSKN033 at doses of 1.1 mg/kg (n=1), 2.3 mg/kg (n=1), 4.5 mg/kg (n=3), 5.6 mg/kg (n=3), and 6.7 mg/kg (n=2). The most common treatment-related adverse event (TRAE) was mild to moderate injection site reactions (Grade 1-2). No Grade 3 or higher TRAEs or serious adverse events were observed, and no TRAEs led to treatment discontinuation.

This study enrolls patients with histologically confirmed advanced/metastatic solid tumors (Part 1) or HER2-overexpressing breast cancer (Cohort A) and gastric/GEJ adenocarcinoma (Cohort B) (Part 2) who failed prior HER2-targeted therapies. Key requirements include: signed informed consent; LVEF ≥50%; ECOG PS 0-1; life expectancy ≥3 months; adequate hematologic (ANC ≥1.5×10⁹/L, platelets ≥100×10⁹/L, Hb ≥90g/L), hepatic (bilirubin ≤1.5×ULN, AST/ALT ≤3×ULN [≤5×ULN if liver mets]), renal (creatinine ≤1.5×ULN or CrCl ≥60mL/min), and coagulation (INR/PT/APTT ≤1.5×ULN) parameters; measurable lesions (required in Part 2, preferred in Part 1); recovery from prior treatment toxicities (CTCAE v5.0 ≤1); and use of effective contraception. Female participants require negative pregnancy testing within 7 days prior to enrollment.

The study evaluates dose-limiting toxicity (DLT) per NCI CTCAE v5.0 during Cycle 1 (21 days), with maximum tolerated dose (MTD) defined as the highest dose where ≤1 of 3 patients experience DLT within this observation window. Treatment-related adverse events (AEs) and serious adverse events (SAEs) will be monitored for up to 3 years using NCI CTCAE v5.0 criteria, while the recommended Phase II dose (RP2D) will be determined based on Cycle 1 (21-day) safety data.

The study will assess pharmacokinetic (PK) parameters including peak plasma concentration (Cmax), time to peak concentration (Tmax), area under the curve (AUC), half-life (t1/2), and apparent clearance (CL/F) from Cycle 1 to Cycle 10 (21-day cycles). Immunogenicity will be evaluated through anti-drug antibody (ADA) formation up to 18 months. Efficacy measures include objective response rate (ORR), progression-free survival (PFS), and duration of response (DoR) assessed up to 18 months, with overall survival (OS) monitored for up to 3 years. All PK and safety data will be collected during the 21-day treatment cycles.

This clinical trial will evaluate efficacy and safety outcomes over a 24-month period. The primary efficacy endpoint is objective response rate (ORR), defined as the proportion of patients achieving complete response (CR) or partial response (PR) per investigator assessment using RECIST v1.1 criteria. Safety monitoring will include comprehensive evaluation of all adverse events (AEs) and serious adverse events (SAEs), with severity graded according to NCI CTCAE version 5.0 standards throughout the study duration. Both ORR and AE/SAE data will be systematically collected and analyzed to assess the treatment's clinical benefit-risk profile.

Eligible patients (aged 18-75, ECOG 0-1) must have advanced solid tumors, measurable lesions per RECIST 1.1, and ≥12-week life expectancy. Exclusions include recent major surgery (within 4 weeks), active CNS metastases, prior malignancies (5 years), steroid use (within 2 weeks), pregnancy/lactation, or conditions compromising study integrity. Contraception is required during and post-treatment.

The primary objectives are to assess DLT (within 21 days of first cycle), determine MTD/RDEs, and monitor AE incidence throughout the trial. Secondary efficacy endpoints include ORR (CR + PR per RECIST 1.1), PFS (time from first dose to PD/death), DoR (response duration from CR/PR to PD), and OS (time from first dose to death), evaluated over 60 months.

Eligible patients were aged ≥18 (≥20 in Japan) with ECOG 0-1 and advanced/metastatic GIST resistant/intolerant to imatinib ± post-IM therapy (cohort-dependent). Key requirements included measurable disease (RECIST v1.1), adequate organ function, LVEF ≥50%, and tumor biopsy consent. Exclusions encompassed unresolved toxicities (NCI CTCAE >Gr 1), active CNS metastases, QTcF >470 ms, ILD, uncontrolled infections, and pregnancy/lactation, among others.

The study assessed dose-limiting toxicities (DLTs) during Cycle 1 (21 days), including hematologic (e.g., Gr 4 neutropenia >7 days, Gr ≥3 febrile neutropenia) and non-hematologic (Gr ≥3 TEAEs, excluding certain exceptions). Additionally, TEAEs were evaluated using NCI CTCAE v5.0, and efficacy outcomes (ORR, DCR, DOR, PFS) were monitored for up to 5 years post-treatment per RECIST v1.1.

Pharmacokinetic analysis evaluated AUClast, AUCtau, Cmax, Tmax, Ctrough, and t1/2 for DS-6157a, total anti-GPR20 antibody, and MAAA-1181a using noncompartmental methods, with blood sampling across multiple 21-day cycles. Immunogenicity (anti-drug antibodies) and efficacy (BOR, PFS) were also assessed, with responses classified based on RECIST v1.1 criteria (CR, PR, SD, PD).