Eligible patients had DLL3-expressing (≥1% tumor cells), progressive advanced solid tumors refractory to ≥1 prior therapy, ECOG 0-1, and adequate organ function. Key exclusions included active infections, recent cardiovascular events, prior PBD-based drugs, uncontrolled comorbidities, pregnancy/breastfeeding, or other malignancies within 3 years (except specified exceptions). CNS metastases required stability post-treatment.

Efficacy endpoints included objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) assessed per RECIST v1.1 up to 35.2 months. Pharmacokinetic analysis measured rovalpituzumab tesirine serum concentrations during Cycle 1, with anti-therapeutic antibodies (ATA) evaluated at Day 1 and 42 days post-last dose.

Eligible participants must have previously received ≥1 rovalpituzumab tesirine dose in a parent study. Retreatment candidates (Arm A) required initial treatment tolerance, prior clinical benefit (stable disease or better), ≥12-week progression-free interval post-treatment, ECOG 0-1, adequate organ function, and stable CNS metastases if applicable. Exclusion criteria prohibited enrollment of subjects without prior rovalpituzumab tesirine study participation.

Eligible participants must be ≥18 years with chemotherapy-naïve extensive-stage SCLC showing ≥75% DLL3 expression, ECOG 0-1, adequate organ function, and stable CNS metastases if present, excluding those with prior SCLC treatments, significant comorbidities, recent cardiovascular events, active infections, pregnancy, other malignancies within 3 years, or PBD-based drug exposure.

The study evaluates dose-limiting toxicities (DLTs) within 21 days post-dose and treatment-emergent adverse events (TEAEs) through 30 days after treatment in Phase 1a, along with Grade >2 lab abnormalities and 4-year progression-free survival (PFS) as key safety endpoints for DLL3-expressing SCLC patients receiving rovalpituzumab tesirine monotherapy or combination therapy.

Secondary endpoints include 12-week ECG parameter changes (RR, PR, QRS, waveform), QTcF-plasma concentration correlation, arrhythmia events stratified by QTcF changes, safety monitoring through 30 days post-treatment, efficacy outcomes (ORR, DOR, PFS, OS, CBR) assessed up to 24 months, and pharmacokinetic analysis (Cmax, AUC) during treatment cycles.

Eligible participants were &ge;18 years with progressive SCLC after 1-2 prior platinum regimens (ECOG 0-1), adequate organ function, controlled CNS metastases, and proper contraception, excluding those with active CNS disease, uncontrolled cardiac conditions, recent anticancer therapies (<14-21 days), QTcF >450/470ms, HIV/Hepatitis, or hypersensitivity to drug components.

Eligible participants were adults with DLL3-positive (&ge;1% tumor staining) SCLC progressing after &ge;2 prior regimens (including platinum), having measurable disease, ECOG 0-1, and adequate organ function, while excluding those with active infections, recent cardiovascular events, uncontrolled comorbidities, concurrent corticosteroids >20mg/day, other malignancies within 3 years, or prior PBD exposure unless undergoing protocol-specified retreatment.

Eligible participants had DLL3-expressing SCLC progressing after &ge;2 prior regimens (including platinum), ECOG 0-1, measurable disease, and stable CNS metastases if present, while excluding those with recent cardiovascular events, active infections, other malignancies within 3 years, prior PBD exposure, or hypersensitivity to study drug components.

Key efficacy measures included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR) per RECIST v1.1, along with quality-of-life assessments via EORTC QLQ-C15-PAL and QLQ-LC13 questionnaires, all monitored over approximately 32 months to evaluate treatment impact on disease progression and patient-reported outcomes.

Key eligibility requires ECOG 0-2 (0-1 for combinations), adequate organ function, and disease-specific prior therapy profiles. Notable exclusions include: recent immunosuppressants (14-day washout), active autoimmune/inflammatory conditions, uncontrolled CNS metastases, CYP3A modifiers for venetoclax arm, and prior PBD exposure for SCLC cohort. The study incorporates rigorous safety monitoring through 90-day follow-up after last dose (up to 24 months total), with special attention to immune-related AE risks and drug-specific toxicities.

This multi-part phase 1 study evaluates budigalimab (anti-PD-1) across three treatment settings: monotherapy dose escalation (Part 1), combination with rovalpituzumab tesirine in SCLC (Part 2), and combination with venetoclax in NSCLC (Part 3). Primary objectives include determining MTD/RP2D through DLT evaluation (≤33% incidence threshold), characterizing PK parameters (t1/2, Cmax, Tmax, AUC), and assessing safety profiles over 6-month dose-finding periods. Pharmacokinetic sampling continues for 12 weeks post-dose.

Secondary objectives assess antitumor activity through RECIST v1.1-defined endpoints (ORR, CBR, PFS, DOR) with 30-day post-treatment follow-up. Combination arms include additional PK analyses for co-administered agents (rovalpituzumab tesirine/venetoclax). The study employs a traditional 3+3 design for dose escalation, with expansion cohorts requiring measurable disease and specific prior therapy exposure (e.g., PD-1/PD-L1 naïve status for SCLC cohort, 1 prior PD-1/L1-containing regimen for NSCLC cohort).

Median age of all randomized patients (N=748) was 64 years; 78.00% had TNM stage IV disease. At futility analysis of the subset with DLL3-high tumors, the hazard ratio for OS was 1.07 (95% confidence interval: 0.84-1.36) favoring the placebo arm,with median OS of 8.50 and 9.80 months in the Rova-T and placebo arms,respectively; futility criteria were met. Rova-T significantly improved PFS versus placebo by investigator assessment (4.00 versus 1.40 mo,hazard ratio=0.48, p < 0.001).

The recommended phase II dose (RP2D) was 0.30 mg/kg every 6 weeks (q6w) for two cycles. At the RP2D, grade 3/4 adverse events included anemia (17.00%), thrombocytopenia (15.00%), and elevated aspartate aminotransferase (8.00%). Responses were confirmed in 15/145 patients (10.34%) treated at 0.30 mg/kg, including 9/69 patients (13.04%) with NEC/NET. Rova-T at 0.30 mg/kg q6w had manageable toxicity, with antitumor activity observed in patients with NEC/NET, melanoma, MTC, and glioblastoma.

In pooled patients with NEC/NET expressing a high level of DLL3 (50% DLL3-positive tumor cells), the ORR was 17.14% (6/35) and 34.29% (12/35) had a BOR (all PRs). In those with NEC/NET expressing a low level of DLL3 (1-49% DLL3-positive tumor cells), the ORR was 8.82% (3/34) and the BOR rate was 14.70% (5/34) (all PRs). The median PFS values for pooled patients with NEC/NET expressing high and low levels of DLL3 were 4.30 months (95% CI, 2.7-6.1) and 3.30 months (95% CI, 2.40-4.80), respectively. The median OS values for patients expressing high and low levels of DLL3 were 7.40 months (95% CI, 5.60-13.10) and 7.10 months (95% CI, 4.30-9.90), respectively.

Progressive small-cell lung cancer (SCLC) who had previously been treated with at least one prior line of platinum-containing chemotherapy were enrolled if they were naive to PD-1/PD-L1targeting agents, had ECOG performance status 0-1, measurable disease per RECIST v1.1 or disease evaluable by tumor antigen assessment, and adequate bone marrow, cardiac, hepatic, and renal functions.