Tislelizumab plus cetuximab and irinotecan in refractory microsatellite stable and RAS wild-type metastatic colorectal cancer: a single-arm phase 2 study

Xiaojing Xu, Luoyan Ai, Keshu Hu, Li Liang, Minzhi Lv, Yan Wang, Yuehong Cui, Wei Li, Qian Li, Shan Yu, Yi Feng, Qing Liu, Ying Yang, Jiao Zhang, Fei Xu, Yiyi Yu () and Tianshu Liu ()
Additional contact information
Xiaojing Xu: Fudan University
Luoyan Ai: Fudan University
Keshu Hu: Fudan University
Li Liang: Fudan University
Minzhi Lv: Fudan University
Yan Wang: Fudan University
Yuehong Cui: Fudan University
Wei Li: Fudan University
Qian Li: Fudan University
Shan Yu: Fudan University
Yi Feng: Fudan University
Qing Liu: Fudan University
Ying Yang: Ltd
Jiao Zhang: Ltd
Fei Xu: Ltd
Yiyi Yu: Fudan University
Tianshu Liu: Fudan University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Immunotherapy confers little to no benefit in the treatment of microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Mechanistic insights suggested that epidermal growth factor receptor (EGFR) antibody plus irinotecan might augment the tumor immune response in mCRC. Therefore, we conducted a proof-of-concept, single-arm, phase 2 study (ChiCTR identifier: ChiCTR2000035642) of a combination treatment regimen including tislelizumab (anti-PD-1), cetuximab (anti-EGFR) and irinotecan in 33 patients with MSS and RAS wild-type (WT) mCRC who were previously treated with ≥2 lines of therapy. The primary endpoint was met, with a confirmed objective response rate of 33%. As secondary endpoints, the disease control rate was 79%, and the median progression-free survival and overall survival were 7.3 and 17.4 months respectively. Among the 33 patients, 32 (97.0%) had treatment-related adverse events (AEs). Three (9.1%) reported grade ≥ 3 AEs, including rash (n = 1), neutropenia (n = 2). The post-hoc evaluation of dynamic circulating tumor DNA using next generation sequencing and the analysis of peripheral immune proteomics landscape using Olink revealed that lower variant allele frequency (VAF) at baseline, greater reduction in VAF on treatment, and a hot peripheral macroenvironment were associated with the treatment response independently. Our study showed the antitumor activity of tislelizumab, cetuximab, and irinotecan combination with a tolerable safety profile in previously treated MSS and RAS WT mCRC.

Date: 2024
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DOI: 10.1038/s41467-024-51536-x

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