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Toripalimab Plus Chemotherapy for First Line Treatment of Advanced Non-Small Cell Lung Cancer (Choice-01): Final Os and Biomarker Exploration of a Randomized, Double-Blind, Phase 3 Trial
Background: Toripalimab plus chemotherapy significantly improves progression-free survival (PFS) in patients with treatment-naive advanced non-small cell lung cancer (NSCLC). This study presents the final analysis of overall survival (OS) and offers insights of biomarkers utilizing circulating tumor DNA (ctDNA).
Methods: CHOICE-01 is a randomized, double-blind, phase 3 study. 465 patients with treatment-naïve, locally advanced, or metastatic NSCLC were enrolled from 59 centers. Patients were randomized 2:1 to receive toripalimab or placebo combined with chemotherapy. The primary endpoint was PFS. Secondary endpoints included OS and safety. Tumor tissues and blood samples were prospectively collected for exploratory biomarker analysis. This trial is registered with ClinicalTrials.gov, NCT03856411.
Findings: From April 2, 2019, to August 5, 2020, 465 eligible patients were 2:1 randomized to toripalimab group (n=309) or placebo group (n=156). As of the data cutoff date of August 31, 2022, 283 death events triggered the final analysis of OS. We found a significant improvement in OS in the toripalimab group, with a median OS of 23.8 months vs. 17.0 months (HR=0.69, 95%CI: 0.57-0.93, nominal P=0.01). This survival benefit was particularly notable in the non-squamous(non-SCC) subgroup. Genomic sequencing of ctDNA exhibited high concordance with tumor tissue profiling and independently confirmed that patients with high tumor mutational burden, mutations in the FA-PI3K-Akt and IL-7 signaling pathways benefited more from the toripalimab treatment. A reduction in ctDNA on cycle 3 day 1 was further demonstrated to be associated with better clinical outcome for patients treated with the combination therapy.
Interpretation: Toripalimab plus chemotherapy yields significant improvements in OS as a first-line treatment. The study highlights the utility of ctDNA as a surrogate for tumor tissue, providing novel prospects for predicting efficacy of immuno-chemotherapy through continuous ctDNA monitoring.
Trial Registration: This trial is registered with ClinicalTrials.gov, NCT03856411.
Funding: This work was supported by National key R&D program of China
Declaration of Interest: Qiming Wang Consulting or Advisory Role: Hansoh Pharma Research Funding: Hansoh Pharma (Inst) ianjun Yu Employment:TopAlliance BioSciences Inc, Predicine Stock and Other Ownership Interests: TopAlliance BioSciences Inc, Predicine Shang li Cai Employment: Burning Rock Biotech Yiran Cai Employment: Burning Rock Biotech Xianmin Luo Employment: Shanghai Junshi Biosciences Sheng Yao Employment: TopAlliance BioSciences Inc, Shanghai Junshi BioSciences Leadership: Shanghai Junshi BioSciences Stock and Other Ownership Interests: Shanghai Junshi BioSciences Patents, Royalties, Other Intellectual Property: Patent applications asemployee of TopAlliance Biosciences Inc No other potential conflicts of interest were reported.
Ethical Approval: Informed consent was acquired from all participants. Approval for this study was obtained from the institutional review board at each participating site.
Zhong, Jia and Fei, Kailun and Wu, Lin and Li, Baolan and Wang, Zhijie and Cheng, Ying and Li, Xiao-Ling and Wang, Xicheng and Han, Liang and Wu, Xiaohong and Fan, Yun and Yu, Yan and Lv, Dongqing and Shi, Jianhua and Huang, Jianjin and Zhou, Shaozhang and Han, Baohui and Sun, Guogui and Guo, Qisen and Ji, Youxin and Zhu, Xiaoli and Hu, Sheng and Zhang, Wei and Wang, Qiming and Jia, Yuming and Wang, Ziping and Song, Yong and Wu, Jingxun and Shi, Meiqi and Li, Xingya and Han, Zhigang and Liu, Yunpeng and Yu, Zhuang and Liu, Anwen and Wang, Xiuwen and Zhou, Caicun and Zhong, Diansheng and Miao, Liyun and Zhang, Zhihong and Zhao, Hui and Yang, Jun and Wang, Dong and Wang, Yingyi and Li, Qiang and Zhang, Xiaodong and Ji, Mei and Yang, Zhenzhou and Cui, Jiuwei and Gao, Beili and Wang, Buhai and Liu, Hu and Nie, Lei and He, Mei and Jin, Shi and Gu, Wei and Shu, Yongqian and Zhou, Tong and Feng, Jian and Yang, Xinmei and Huang, Cheng and Zhu, Bo and Yao, Yu and Yao, Sheng and Yu, Jiajun and Cai, Shangli and Cai, Yiran and Xu, Jiachen and Luo, Xianming and Duan, Jianchun and Wang, Jie, Toripalimab Plus Chemotherapy for First Line Treatment of Advanced Non-Small Cell Lung Cancer (Choice-01): Final Os and Biomarker Exploration of a Randomized, Double-Blind, Phase 3 Trial. Available at SSRN: https://ssrn.com/abstract=4908793
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