Eligibility requires unresectable/metastatic gastrointestinal cancers (PDAC, CCA/GBC, colorectal, gastric/GEJ/EAC) with prior therapy and ≥3-month life expectancy; exclusions include active ILD/pneumonitis, uncontrolled cardiovascular disease, progressing malignancies, untreated CNS metastases, autoimmune disease requiring recent treatment, or major surgery complications. HIV+ candidates must have controlled viral loads without Kaposi's sarcoma/Castleman's disease history.

Safety assessments include incidence of adverse events (AEs) over 14 months and treatment discontinuations due to AEs within 12 months. Key secondary endpoints are duration of response (DOR), progression-free survival (PFS), and overall survival (OS)-all tracked up to 49 months-with disease progression defined as ≥20% tumor growth plus ≥5 mm absolute increase or new lesions by RECIST 1.1 via BICR.

Key inclusion criteria: age ≥18, ECOG PS 0-1, preserved LVEF (≥50%), adequate organ function, and contraception compliance. Exclusion criteria: prior CDH6/ADC therapy (exatecan-based), active CNS metastases (unless stable post-treatment), multiple primary malignancies (unless disease-free ≥3 years), significant cardiac history (e.g., MI within 6 months, CHF NYHA II-IV), uncontrolled infections, or active pulmonary diseases. Tumor tissue archival is mandatory.

The study evaluates dose-limiting toxicities (DLTs) occurring within 21 days in Cycle 1, treatment-emergent adverse events (TEAEs) up to 40 days post-treatment, and objective response rate (ORR) per RECIST v1.1 with assessments spanning up to 52 months. ORR is defined as the proportion of participants achieving complete response (CR) or partial response (PR).

Pharmacokinetic analyses for R-DXd and metabolites include AUC (21d), AUClast, Cmax, Ctrough, and Tmax across multiple cycles (21-day duration). Efficacy endpoints include ORR (investigator-assessed), duration of response (DoR), disease control rate (DCR), clinical benefit rate (CBR), time to response (TTR), progression-free survival (PFS), and anti-drug antibody (ADA) assessment up to 52 months. DCR and CBR further incorporate stable disease (SD) criteria lasting ≥180 days.

Eligible participants must have Stage IV squamous NSCLC, prior progression on anti-PD- (L)1 and platinum chemotherapy, controlled HIV/HBV/HCV if applicable, while exclusions involve uncontrolled cardiovascular/pulmonary disease, active infections, CNS metastases, autoimmune disorders requiring recent treatment, concurrent malignancies, prior transplants, or unresolved surgery complications.

The primary objectives include assessing Objective Response Rate (ORR) as the percentage of participants achieving Complete Response (CR) or Partial Response (PR) per RECIST 1.1, evaluated by Blinded Independent Central Review (BICR), along with the reporting of adverse events (AEs) and treatment discontinuations due to AEs over an 84-month timeframe.

Key secondary endpoints encompass Duration of Response (DOR), defined as the time from first documented CR/PR to progression or death, Progression-Free Survival (PFS) measured from randomization to disease progression or death, and Overall Survival (OS), calculated as the time from randomization to death from any cause, all assessed per RECIST 1.1 by BICR.

Key inclusion requires Stage IV nonsquamous NSCLC (EGFR-/ALK-/ROS1-) post anti-PDL1/platinum failure with measurable disease, adequate organ function, and controlled infections (HIV/HBV/HCV), while exclusions involve recent radiotherapy, uncontrolled comorbidities, active infections/CNS metastases, immune disorders, transplant history, or unresolved surgical issues, maintaining rigorous patient selection criteria.

Eligible participants were adults with platinum-resistant high-grade ovarian, peritoneal, or fallopian tube cancer (1-3 prior lines, including bevacizumab) having measurable lesions and adequate organ function. Key exclusions included active ILD, uncontrolled cardiovascular disease, prior CDH6/exatecan-derivative therapy, HIV/HBV/HCV infections (unless controlled), and pregnancy. Phase 3 participants had to qualify for investigator-choice chemotherapy.

Secondary endpoints included ORR via Investigator assessment (up to 30 months), Duration of Response (DoR, up to 40 months), Disease Control Rate (DCR, up to 40 months), Overall Survival (OS, up to 40 months), and safety metrics including Treatment-emergent Adverse Events (TEAEs). Pharmacokinetic parameters (Cmax, Tmax, AUC, t1/2) and immunogenicity (ADA) were analyzed alongside biomarker correlations (CDH6, CA-125) and quality-of-life assessments.

Eligible participants must be ≥18 years old with measurable disease (RECIST 1.1), ECOG 0-1, and progression post-systemic therapy. Cohort-specific criteria apply (e.g., prior PD-1/VEGF-TKI for ccRCC, ≥1 line for endometrial/cervical cancer). Key exclusions include active brain metastases, recent thromboembolic events, unresolved toxicities (>Grade 1), ILD/pneumonitis history, prior CDH6/exatecan ADC exposure, or uncontrolled infections (HIV/HBV/HCV).

The primary outcomes include Objective Response Rate (ORR) assessed by investigators (excluding ccRCC cohort), defined as the proportion of patients achieving confirmed complete or partial response per RECIST 1.1. For the ccRCC cohort, Disease Control Rate (DCR) is the main endpoint, counting patients with confirmed responses or stable disease lasting ≥5 weeks. Additionally, safety metrics (TEAEs, SAEs, AESIs) across all cohorts will be monitored up to 32 months.

Secondary endpoints include Progression-Free Survival (PFS), Duration of Response (DoR), and Time to Response (TTR), all evaluated per RECIST 1.1. ORR and DCR are also secondary measures for specific cohorts (ccRCC or non-ccRCC). Pharmacokinetic analysis of R-DXd (Cmax) and anti-drug antibody (ADA) incidence will be assessed periodically up to 32 months.