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

• Published in: Nature communications Vol. 14; no. 1; pp. 8 - 16
• Main Authors: Li, Song, Yu, Wenbin, Xie, Fei, Luo, Haitao, Liu, Zhimin, Lv, Weiwei, Shi, Duanbo, Yu, Dexin, Gao, Peng, Chen, Cheng, Wei, Meng, Zhou, Wenhao, Wang, Jiaqian, Zhao, Zhikun, Dai, Xin, Xu, Qian, Zhang, Xue, Huang, Miao, Huang, Kai, Wang, Jian, Li, Jisheng, Sheng, Lei, Liu, Lian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.01.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 49/23; 49/39; 631/67/1504/1829; 692/4028/67/1059/2325; 692/4028/67/1504/1829; 82/51; Antiangiogenic agents; Antiangiogenics; Biomarkers; Cancer; Cancer therapies; Chemotherapy; Clinical trials; Conversion; Effectiveness; Gastric cancer; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - therapeutic use; Immunotherapy; Inhibitors; Lymphocytes; Lymphocytes T; Medical prognosis; Microenvironments; Microsatellite instability; multidisciplinary; Mutation; Neoadjuvant Therapy; Oxaliplatin; Patients; PD-1 protein; PD-L1 protein; Progression-Free Survival; Science; Science (multidisciplinary); Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Survival; T cell receptors; Toxicity; Tumor Microenvironment; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35431-x

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. Immune checkpoint inhibitors and antiangiogenic agents have shown some activity in patients with late-stage gastric cancer. Here the authors report the results of a phase II trial of neoadjuvant anti-PD1 (camrelizumab), antiangiogenic agent (apatinib), and chemotherapy (S-1 ± Oxaliplatin) in stage T4a/bN + M0 gastric cancer patients.