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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 Zhan, 2023. "Neoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35431-x
    DOI: 10.1038/s41467-022-35431-x
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    1. Mikhail Shugay & Dmitriy V Bagaev & Maria A Turchaninova & Dmitriy A Bolotin & Olga V Britanova & Ekaterina V Putintseva & Mikhail V Pogorelyy & Vadim I Nazarov & Ivan V Zvyagin & Vitalina I Kirgizova, 2015. "VDJtools: Unifying Post-analysis of T Cell Receptor Repertoires," PLOS Computational Biology, Public Library of Science, vol. 11(11), pages 1-16, November.
    2. Mel Greaves & Carlo C. Maley, 2012. "Clonal evolution in cancer," Nature, Nature, vol. 481(7381), pages 306-313, January.
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    1. Jian-Xian Lin & Yi-Hui Tang & Hua-Long Zheng & Kai Ye & Jian-Chun Cai & Li-Sheng Cai & Wei Lin & Jian-Wei Xie & Jia-Bin Wang & Jun Lu & Qi-Yue Chen & Long-Long Cao & Chao-Hui Zheng & Ping Li & Chang-M, 2024. "Neoadjuvant camrelizumab and apatinib combined with chemotherapy versus chemotherapy alone for locally advanced gastric cancer: a multicenter randomized phase 2 trial," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Jia Wei & Xiaofeng Lu & Qin Liu & Yao Fu & Song Liu & Yang Zhao & Jiawei Zhou & Hui Chen & Meng Wang & Lin Li & Ju Yang & Fangcen Liu & Liming Zheng & Haitao Yin & Yang Yang & Chong Zhou & Ping Zeng &, 2023. "Neoadjuvant sintilimab in combination with concurrent chemoradiotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: a single-arm phase 2 trial," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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