147TiP BNT326-02: A phase Ib/II trial of BNT326/YL202 (HER3 ADC) with pumitamig (PD-L1 × VEGF-A bsAb) in non-small cell lung cancer (NSCLC)

Background: Pumitamig (BNT327) is an investigational anti-PD-L1 x VEGF-A bispecific antibody designed to restore effector T-cell function through PD-L1 binding, while colocalizing VEGF-A neutralization to the tumor microenvironment.BNT326/YL202 is an investigational HER3-targeted ADC consisting of an anti-HER3 IgG1 monoclonal antibody linked to 8 molecules of a novel topoisomerase I inhibitor via a tripeptide linker.HER3 surface overexpression is common in lung cancer.Preclinical in vivo models showed superior tumor growth inhibition with this combination versus either treatment alone (Hamilton E, AACR 2025, #648).Based on promising clinical data for HER3-targeted ADCs and pumitamig in lung cancer, the trial will assess the combination's safety and efficacy in molecularly defined lung cancer subgroups.Trial design: This global phase Ib/II, open-label trial (NCT07111520) evaluates safety, optimal combination dose, PK, and preliminary anti-tumor efficacy of BNT326 with pumitamig in previously treated or treatment-nave advanced/metastatic NSCLC.Patients (18 years) must have an ECOG PS 1 and non-squamous or squamous NSCLC.Part 1: Dose-escalation using a 3+3 design in 2L+ NSCLC (Actionable Genomic Alteration AGA+/-).Three dose levels (DL1, DL2, DL3 optional) of BNT326 and a fixed dose of pumitamig will be evaluated.Primary endpoint: safety, including doselimiting toxicities, to determine RP2D.Part 2a: Cohort A: previously treated, cohort B: treatment-nave, each with two arms (DL1, DL2).Primary endpoints: safety and overall response rate (ORR).Part 2b: Primary endpoint: ORR.Cohort C: EGFRmutated (m)/wildtype (WT), any PD-L1 expression, with 1 prior therapy.Randomized 1:1:1 to BNT326 (DL1 or DL2) with pumitamig or BNT326 alone (DL2).Stratification: EGFRm/WT, squamous/non-squamous, prior immunotherapy (IO)+chemo/IO/chemo.Cohort D: AGA-negative, treatment-nave.Stratification: squamous/non-squamous, liver/brain metastasis y/n.D1: PD-L1 50%, randomized 1:1:1 to BNT326 (DL2) with pumitamig, pembrolizumab, or pumitamig alone.D2: PD-L1 <50%, randomized 1:1 to BNT326 (DL2) with pumitamig or pembrolizumab + chemotherapy.Enrollment is ongoing globally.