Phase 2/3 trial of pumitamig (PD-L1 × VEGF-A bsAb) plus chemotherapy versus bevacizumab plus chemotherapy in previously untreated, unresectable, or metastatic colorectal cancer (ROSETTA CRC-203).

Abstract

TPS3672 Background: Microsatellite-stable/mismatch repair-proficient metastatic colorectal cancer (mCRC) demonstrated limited benefit from immune checkpoint inhibition and is treated with first-line standard chemotherapy with/without biologic agents, such as anti-VEGF or anti-EGFR therapy. Pumitamig (BNT327/BMS986545) is an investigational bispecific antibody engineered to simultaneously target both PD-L1 and VEGF-A within the tumor and tumor microenvironment, a dual mechanism intended to enhance antitumor immunity and inhibit angiogenesis. Pumitamig plus chemotherapy has shown encouraging efficacy and manageable safety in patients (pts) with solid tumors (Cheng Y, et al. J Thorac Oncol 2025;20[suppl 1]. Abstract 301P; Schmid P, et al. SABCS 2025. Abstract PS1-13-25). This phase 2/3 trial aims to investigate the safety and efficacy of pumitamig and establish if it improves clinical outcomes when added to chemotherapy versus current standard of care in pts with previously untreated mCRC. Methods: ROSETTA CRC-203 is a global, randomized, blinded phase 2/3 study. Pts aged ≥ 18 years, with ECOG PS 0-1, with previously untreated, unresectable, or mCRC, no microsatellite instability-high/mismatch repair-deficient biomarkers, no BRAF V600E mutation and measurable disease per RECIST v1.1 are eligible. Key exclusion criteria include untreated central nervous system metastases, significant cardiovascular disease, recent or active malignancy, and prior systemic therapy with checkpoint inhibitors or chemotherapy. Pts in the Phase 2 dose-optimization part of the study will be randomized 1:1:1 to receive pumitamig low or pumitamig high dose + FOLFOX (Q2W)/FOLFIRI (Q2W) or bevacizumab + FOLFOX (Q2W)/FOLFIRI (Q2W). The primary endpoint is objective response rate (ORR) by RECIST v1.1 per investigator assessment, with progression-free survival (PFS), and duration of response (DOR) as secondary endpoints. In phase 3, eligible pts will be randomized 1:1 to receive pumitamig at the recommended phase 3 dose + FOLFOX (Q2W)/FOLFIRI (Q2W)/CAPOX (Q3W) or bevacizumab + FOLFOX (Q2W)/FOLFIRI (Q2W)/CAPOX (Q3W), until disease progression or unacceptable toxicity. The primary endpoint is PFS by RECIST v1.1 per blinded independent central review. Overall survival, ORR, and DOR are secondary endpoints. Safety will be monitored throughout the study according to CTCAE v5.0. Recruitment is ongoing. ClinicalTrials.gov ID: NCT07221357. Clinical trial information: NCT07221357 .