INCA033890-303: A randomized, double-blind, phase 3 study of FOLFOX and bevacizumab with or without INCA33890 in the first-line treatment of metastatic microsatellite-stable colorectal cancer.

Abstract

TPS3683 Background: Immune checkpoint inhibitors have demonstrated limited efficacy in the treatment of microsatellite stable colorectal cancer (MSS CRC), especially when the liver is involved. Transforming growth factor β (TGFβ) signaling within the tumor microenvironment suppresses T-cell proliferation and effector function, contributing to an immune-excluded phenotype. Although clinical targeting of the TGFβ pathway has been previously attempted, these approaches have been hampered by limited efficacy and significant toxicity. INCA33890 is a first-in-class bispecific antibody targeting both TGFβ receptor 2 (TGFβR2) and programmed cell death protein 1 (PD-1). This molecule is designed to inhibit TGFβR2 and PD-1 signaling specifically in PD-1–positive cells, sparing PD-1–negative cells from TGFβ inhibition. In the phase 1 INCA 33890-101 study (NCT05836324), INCA33890 demonstrated a manageable safety profile and durable single-agent activity in patients with refractory MSS CRC, including in patients with active liver metastases. The monotherapy objective response rate (ORR) was 15.2% overall (n = 105), including 12.0% in patients with liver metastases (n = 75) and 23.3% (n = 30) in patients without liver metastases. Methods: The multicenter, global, phase 3 INCA033890-303 study (NCT07284849) activated in December 2025 and is planned to open at 225 sites across 23 countries. The primary objective of this study is to evaluate the efficacy of INCA33890 versus intravenous placebo, each in combination with FOLFOX and bevacizumab, as first-line treatment for patients with previously untreated, histologically confirmed, unresectable metastatic MSS CRC. Prior neoadjuvant or adjuvant therapy is allowed provided there was no recurrence within 12 months of treatment completion. Key exclusion criteria include microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) status, BRAF V600E mutation, untreated or progressing brain metastases, and active autoimmune disease requiring systemic immunosuppression. Approximately 700 patients will be randomized 1:1 to receive intravenous INCA33890 or placebo, each in combination with FOLFOX and bevacizumab. Randomization will be stratified by tumor sidedness, the presence of liver metastases, and programmed death-ligand 1 (PD-L1) score. The primary endpoint is progression-free survival as assessed by investigators. The key secondary endpoint is overall survival. Additional secondary endpoints are ORR, safety and tolerability, duration of response, and patient-reported outcomes. Trial enrollment is ongoing. Clinical trial information: NCT07284849 .