Neoadjuvant mFOLFOXIRI with or without cadonilimab versus mFOLFOX6 in locally advanced colorectal cancer: A randomized phase 2 trial (OPTICAL-2)

Clinical Snapshot

Key Findings

• P Value: p = 0.046 (statistically significant)

• Effect Size: Odds ratio 3.4 for mFOLFOXIRI plus cadonilimab versus mFOLFOX6

• Primary Outcome: Pathological complete response: 26.8% (mFOLFOXIRI + cadonilimab) vs 14.6% (mFOLFOXIRI) vs 9.8% (mFOLFOX6)

• Nnt Or Sensitivity: Number needed to treat = 6 (based on 17% absolute risk reduction in pCR rate)

• Confidence Interval: 95% CI 1.04-13.24

Clinical Application

Requires access to cadonilimab (PD-1/CTLA-4 dual checkpoint inhibitor) and expertise in managing immunotherapy-related adverse events Cadonilimab not currently TGA-approved. mFOLFOXIRI available but not standard neoadjuvant care. Would require PBS consideration and NCCN/ESMO guideline updates before routine implementation Patients with pMMR/MSS locally advanced colorectal cancer suitable for neoadjuvant therapy

Abstract

BACKGROUND: The efficacy of neoadjuvant chemotherapy combined with dual immune checkpoint blockade in proficient mismatch repair/microsatellite-stable (pMMR/MSS) locally advanced colorectal cancer (LACRC) remains uncertain. METHODS: In this open-label, randomized phase 2 trial (ClinicalTrials.gov: NCT05571644), eligible patients were randomly assigned (1:1:1) to receive 6 cycles of neoadjuvant mFOLFOXIRI plus cadonilimab, mFOLFOXIRI, or mFOLFOX6, followed by surgery and adjuvant chemotherapy. The primary endpoint was pathological complete response (pCR) in the intention-to-treat population. Secondary endpoints included major pathological response (MPR), safety, locoregional recurrence, disease-free survival, and overall survival. FINDINGS: Between July 2023 and August 2024, 123 patients were randomly assigned (41 per group). Neoadjuvant mFOLFOXIRI plus cadonilimab significantly improved pCR compared with mFOLFOX6 (26.8% versus 9.8%; odds ratio [OR], 3.4; 95% confidence interval [CI], 1.04 to 13.24; p = 0.046), whereas mFOLFOXIRI alone did not (14.6% versus 9.8%; OR, 1.6; 95% CI, 0.4 to 6.7; p = 0.50). MPR rates were 68.3%, 46.3%, and 43.9%, respectively, and were significantly higher with mFOLFOXIRI plus cadonilimab than with mFOLFOX6 (p = 0.026). Downstaging to ypStage 0-I occurred in 66%, 45%, and 41% of patients in the three groups, respectively, and was significantly higher in the mFOLFOXIRI plus cadonilimab group (p = 0.027). Grade ≥3 adverse events were manageable, with liver enzyme elevation and neutropenia being the most common. CONCLUSIONS: Neoadjuvant mFOLFOXIRI plus cadonilimab significantly improved pCR compared with mFOLFOX6 in LACRC, with a manageable safety profile, supporting further investigation. FUNDING: This work was funded by the National Science Fund for Distinguished Young Scholars (82425045) and the National Natural Science Foundation of China (82272800).

References

1. 1.Zhang, J., Qi, S., Hu, H., He, X., Huang, L., Zhou, J., Wang, H., Wu, X., Kang, L., Huang, M., He, Z., Wang, H., Chen, D., Zhai, X., Xie, X., Ling, J., Zhang, Y., Hu, J., Li, S., Wu, Z., Yang, T., Cai, R., Cai, Y., Zhong, L., Li, W., Shi, L., Wang, C., Huang, Y., Zhao, Y., Cao, W., Qin, G., & Deng, Y. (2026). Neoadjuvant mFOLFOXIRI with or without cadonilimab versus mFOLFOX6 in locally advanced colorectal cancer: A randomized phase 2 trial (OPTICAL-2). Med (New York, N.Y.). https://doi.org/10.1016/j.medj.2026.101141