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

Jianwei Zhang; Sifan Qi; Huabin Hu; Xiaosheng He; Liang Huang; Jiaming Zhou; Hui Wang; Xiaojian Wu; Liang Kang; Meijin Huang; Zhen He; Huaiming Wang; Dianke Chen; Xiaohui Zhai; Xiaoyu Xie; Jiayu Ling; Yan Zhang; Jiancong Hu; Shanshan Li; Zehua Wu; Tao Yang; Runkai Cai; Yue Cai; Lixing Zhong; Weiwei Li; Lishuo Shi; Chao Wang; Yan Huang; Yandong Zhao; Wuteng Cao; Ge Qin; Yanhong Deng

doi:10.1016/j.medj.2026.101141

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

Med. 2026 May 13:101141. doi: 10.1016/j.medj.2026.101141. Online ahead of print.

Authors

Jianwei Zhang¹, Sifan Qi², Huabin Hu¹, Xiaosheng He³, Liang Huang³, Jiaming Zhou³, Hui Wang³, Xiaojian Wu³, Liang Kang³, Meijin Huang³, Zhen He³, Huaiming Wang³, Dianke Chen¹, Xiaohui Zhai¹, Xiaoyu Xie¹, Jiayu Ling¹, Yan Zhang¹, Jiancong Hu⁴, Shanshan Li¹, Zehua Wu¹, Tao Yang⁴, Runkai Cai², Yue Cai¹, Lixing Zhong¹, Weiwei Li¹, Lishuo Shi⁵, Chao Wang⁶, Yan Huang⁶, Yandong Zhao⁶, Wuteng Cao⁷, Ge Qin¹, Yanhong Deng⁸

Affiliations

¹ Department of Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
² Department of Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
³ Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
⁴ Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Endoscopy Center, The Sixth Affiliated Hospital of Sun Yat-sen University, Yuancun Erheng Road, Guangzhou, China.
⁵ Clinical Research Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
⁶ Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
⁷ Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Radiology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
⁸ Department of Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; The State Key Laboratory of Oncology in South China, Guangzhou, China. Electronic address: dengyanh@mail.sysu.edu.cn.

PMID: 42134324
DOI: 10.1016/j.medj.2026.101141

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).

Keywords: cadonilimab; immunotherapy; locally advanced colorectal cancer; mFOLFOXIRI; neoadjuvant therapy; proficient mismatch repair; translation to patients.

Associated data

ClinicalTrials.gov/NCT05571644