Neoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer

Song Li, Wenbin Yu, Fei Xie, Haitao Luo, Zhimin Liu, Weiwei Lv, Duanbo Shi, Dexin Yu, Peng Gao, Cheng Chen, Meng Wei, Wenhao Zhou, Jiaqian Wang, Zhikun Zhao, Xin Dai, Qian Xu, Xue Zhang, Miao Huang, Kai Huang, Jian Wang, Jisheng Li, Lei Sheng and Lian Liu ()
Additional contact information
Song Li: Cheeloo College of Medicine, Shandong University
Wenbin Yu: Cheeloo College of Medicine, Shandong University
Fei Xie: Cheeloo College of Medicine, Shandong University
Haitao Luo: Shenzhen Yucebio Technology Co., Ltd., Shenzhen
Zhimin Liu: Zibo Municipal Central Hospital, Binzhou Medical College
Weiwei Lv: Cheeloo College of Medicine, Shandong University
Duanbo Shi: Cheeloo College of Medicine, Shandong University
Dexin Yu: Cheeloo College of Medicine, Shandong University
Peng Gao: Cheeloo College of Medicine, Shandong University
Cheng Chen: Cheeloo College of Medicine, Shandong University
Meng Wei: Cheeloo College of Medicine, Shandong University
Wenhao Zhou: Shenzhen Yucebio Technology Co., Ltd., Shenzhen
Jiaqian Wang: Shenzhen Yucebio Technology Co., Ltd., Shenzhen
Zhikun Zhao: Shenzhen Yucebio Technology Co., Ltd., Shenzhen
Xin Dai: Shandong Provincial Hospital of Traditional Chinese Medicine
Qian Xu: Cheeloo College of Medicine, Shandong University
Xue Zhang: Cheeloo College of Medicine, Shandong University
Miao Huang: Cheeloo College of Medicine, Shandong University
Kai Huang: Cheeloo College of Medicine, Shandong University
Jian Wang: Cheeloo College of Medicine, Shandong University
Jisheng Li: Cheeloo College of Medicine, Shandong University
Lei Sheng: Cheeloo College of Medicine, Shandong University
Lian Liu: Cheeloo College of Medicine, Shandong University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Despite neoadjuvant/conversion chemotherapy, the prognosis of cT4a/bN+ gastric cancer is poor. Immune checkpoint inhibitors (ICIs) and antiangiogenic agents have shown activity in late-stage gastric cancer, but their efficacy in the neoadjuvant/conversion setting is unclear. In this single-armed, phase II, exploratory trial (NCT03878472), we evaluate the efficacy of a combination of ICI (camrelizumab), antiangiogenesis (apatinib), and chemotherapy (S-1 ± oxaliplatin) for neoadjuvant/conversion treatment of cT4a/bN+ gastric cancer. The primary endpoints are pathological responses and their potential biomarkers. Secondary endpoints include safety, objective response, progression-free survival, and overall survival. Complete and major pathological response rates are 15.8% and 26.3%. Pathological responses correlate significantly with microsatellite instability status, PD-L1 expression, and tumor mutational burden. In addition, multi-omics examination reveals several putative biomarkers for pathological responses, including RREB1 and SSPO mutation, immune-related signatures, and a peripheral T cell expansion score. Multi-omics also demonstrates dynamic changes in dominant tumor subclones, immune microenvironments, and T cell receptor repertoires during neoadjuvant immunotherapy. The toxicity and post-surgery complications are limited. These data support further validation of ICI- and antiangiogenesis-based neoadjuvant/conversion therapy in large randomized trials and provide candidate biomarkers.

Date: 2023
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DOI: 10.1038/s41467-022-35431-x

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