Regorafenib plus sintilimab as a salvage treatment for microsatellite stable metastatic colorectal cancer: a single-arm, open-label, phase II clinical trial

Rui Liu (), Zhi Ji, Xia Wang, Lila Zhu, Jiaqi Xin, Lijun Ma, Jiayu Zhang, Shaohua Ge, Le Zhang, Yuchong Yang, Tao Ning, Ming Bai, Jingjing Duan, Feixue Wang, Yansha Sun, Hongli Li (), Ting Deng (), Yi Ba () and Jihui Hao ()
Additional contact information
Rui Liu: Tianjin Key Laboratory of Digestive Cancer
Zhi Ji: Tianjin Key Laboratory of Digestive Cancer
Xia Wang: Tianjin Key Laboratory of Digestive Cancer
Lila Zhu: Tianjin Key Laboratory of Digestive Cancer
Jiaqi Xin: Tianjin Key Laboratory of Digestive Cancer
Lijun Ma: Tianjin Key Laboratory of Digestive Cancer
Jiayu Zhang: Tianjin Key Laboratory of Digestive Cancer
Shaohua Ge: Tianjin Key Laboratory of Digestive Cancer
Le Zhang: Tianjin Key Laboratory of Digestive Cancer
Yuchong Yang: Tianjin Key Laboratory of Digestive Cancer
Tao Ning: Tianjin Key Laboratory of Digestive Cancer
Ming Bai: Tianjin Key Laboratory of Digestive Cancer
Jingjing Duan: Tianjin Key Laboratory of Digestive Cancer
Feixue Wang: Tianjin Key Laboratory of Digestive Cancer
Yansha Sun: Tianjin Key Laboratory of Digestive Cancer
Hongli Li: Tianjin Key Laboratory of Digestive Cancer
Ting Deng: Tianjin Key Laboratory of Digestive Cancer
Yi Ba: Tianjin Key Laboratory of Digestive Cancer
Jihui Hao: Tianjin Key Laboratory of Digestive Cancer

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Immune checkpoint inhibitors (ICIs) have limited efficacy in microsatellite stable (MSS) metastatic colorectal cancer (mCRC), and combination therapy needs to be further explored. In this single-arm, open-label, phase II trial (NCT04745130), we evaluate the efficacy and safety of the combination therapy of antiangiogenesis (regorafenib) and ICI (sintilimab) in patients with MSS mCRC. The primary endpoint is overall survival (OS). Secondary endpoints include progression free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. The median OS and PFS are 14.1 months (95% CI: 10.5–17.7) and 4.1 months (95% CI: 3.4–4.8), respectively. The ORR is 21.4%, DCR is 63.1%, and DoR is 13.0 months (95% CI: 2.5–23.5). Patients with RAS/RAF wild-type exhibit significantly longer median OS (23.3 months, 95% CI: 10.0–36.6) compared to those with mutations (12.1 months, 95% CI: 8.4–15.8). The combination therapy is well tolerated and has limited toxicity. Biomarker analysis, including transcriptome sequencing and multiplex immunohistochemistry staining are performed. The efficacy of this combination treatment is tied to specific gene expressions governing tumor metabolism. Moreover, the effectiveness of immunotherapy depends on the abundance of immune cells, as well as the distance between immune cells and tumor cells.

Date: 2025
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DOI: 10.1038/s41467-025-56748-3

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