A phase 1/2, randomized, global trial to investigate efficacy and safety of EpCAM × 4-1BB bsAb (BNT314/GEN1059) in combination with pumitamig (BNT327; PD-L1 × VEGF-A bsAb) and chemotherapy in patients with metastatic colorectal cancer (mCRC).

TPS266 Background: Pumitamig (BNT327, PD-L1 × VEGF-A bsAb) and BNT314 (GEN1059/DuoBody-EpCAM×4-1BB) are investigational bispecific antibody (bsAb) immunomodulators. Pumitamig is designed to co-localize PD-1/PD-L1 checkpoint blockade with VEGF-A neutralization, thereby reducing immune suppression and promoting vascular normalization, immune-cell activation and tumor infiltration. In Phase 2 trials, pumitamig plus chemotherapy (chemo) showed encouraging efficacy results and a manageable safety profile in patients (pts) with various solid tumors (e.g. 1255MO ESMO2024; OA13.02 WCLC2025). BNT314 is hypothesized to promote immune responses through EpCAM-dependent activation of the co-stimulatory receptor 4-1BB (CD137). In preclinical studies, combining BNT314 with PD-1/PD-L1 blockade potentiated its effects on T-cell function and antitumor activity in models with low or high inherent immunogenicity (731 SITC2024; 6075 AACR2025). We evaluate pumitamig and BNT314 for the treatment of microsatellite stable or mismatch repair proficient (MSS/pMMR) mCRC, a tumor typically resistant to immunotherapy, based on the hypothesis that VEGF-A modulation enhances immune infiltration and 4-1BB activation boosts T-cell activity to overcome resistance. Methods: This Phase 1/2, randomized, three-part trial evaluates safety, efficacy and pharmacokinetics in pts with MSS/pMMR mCRC. Part A (Phase 1, safety run-in, dose escalation, BOIN design) recruits pts (second-line [2L] and beyond) to evaluate up to 5 dose levels (DL) of BNT314 (Q6W) plus pumitamig (Q2W). Two DL of BNT314 may be selected to be tested with a lower pumitamig dose. In part B (Phase 1, dose optimization), 2L pts (cohort 1) and first-line pts (cohort 2) are randomized 1:1 to receive one of two DL of BNT314 (Q6W) in combination with BNT327 (Q2W/Q3W) + standard of care (SoC) chemo. In Part C (Phase 2), 2L pts are randomized 1:1:1 to receive BNT314 (Q6W) + BNT327 (Q2W) + SoC chemo, bevacizumab (Q2W) + SoC chemo or BNT327 (Q2W) + SoC chemo. Pts in Part C will be stratified by v-Raf murine sarcoma viral oncogene homolog B (BRAF)/rat sarcoma virus (RAS) mutation status (RAS/BRAF wildtype vs RAS mutant vs BRAF mutant), and presence of liver metastases. Up to 482 pts will be enrolled in total. Key inclusion criteria are unresectable histologically confirmed adenocarcinoma of the colon or rectum, confirmed MSS/pMMR mCRC and known RAS status. Primary endpoints are safety (Part A & B), objective response rate (ORR) (Part B) and progression free survival (Part C) with key secondary endpoint being ORR in Part C. Overall survival is an exploratory endpoint (Parts A & B) and a secondary endpoint in Part C. The trial was initiated in Q3 2025; recruitment is ongoing in the US. Sites are planned in Europe, Asia-Pacific, and Australia. Clinical trial information: NCT07079631 .