Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in phase Ib/II clinical trial NCT02915432

被引：386

作者：

Wang, F. ^{[1
]}

Wei, X. L. ^{[1
]}

Wang, F. H. ^{[1
]}

Xu, N. ^{[2
]}

Shen, L. ^{[3
]}

Dai, G. H. ^{[4
,5
]}

Yuan, X. L. ^{[6
]}

Chen, Y. ^{[7
]}

Yang, S. J. ^{[8
]}

Shi, J. H. ^{[9
]}

Hu, X. C. ^{[10
,11
]}

Lin, X. Y. ^{[12
]}

Zhang, Q. Y. ^{[13
]}

Feng, J. F. ^{[14
]}

Ba, Y. ^{[15
]}

Liu, Y. P. ^{[16
]}

Li, W. ^{[17
]}

Shu, Y. Q. ^{[18
]}

Jiang, Y. ^{[19
]}

Li, Q. ^{[20
]}

Wang, J. W. ^{[21
]}

Wu, H. ^{[22
]}

Feng, H. ^{[22
]}

Yao, S. ^{[22
]}

Xu, R. H. ^{[1
]}

机构：

[1] Sun Yat Sen Univ, Ctr Canc, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China,Dept Med Oncol, 651 Dong Feng Rd East, Guangzhou 510060, Guangdong, Peoples R China

[2] Zhejiang Univ, Sch Med, Affiliated Hosp 1, Dept Med Oncol, Hangzhou, Zhejiang, Peoples R China

[3] Peking Univ, Lab Carcinogenesis & Translat Res, Minist Natl Educ, Sch Oncol,Beijing Canc Hosp & Inst,Dept GI Oncol, Beijing, Peoples R China

[4] Chinese Peoples Liberat Army Gen Hosp, Dept Med Oncol, Beijing, Peoples R China

[5] Chinese PLA Med Acad, Beijing, Peoples R China

[6] Huazhong Univ Sci & Technol, Tongji Hosp, Dept Oncol, Wuhan, Hubei, Peoples R China

[7] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Dept Abdominal Canc,West China Med Sch,Canc Ctr, Chengdu, Sichuan, Peoples R China

[8] Zhengzhou Univ, Henan Canc Hosp, Dept Internal Med, Affiliated Canc Hosp, Zhengzhou, Henan, Peoples R China

[9] Linyi Canc Hosp, Dept Med Oncol, Linyi, Shandong, Peoples R China

[10] Fudan Univ, Dept Med Oncol, Shanghai Canc Ctr, Shanghai, Peoples R China

[11] Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai, Peoples R China

[12] Fujian Med Univ, Dept Med Oncol, Union Hosp, Fuzhou, Fujian, Peoples R China

[13] Harbin Med Univ, Dept Med Oncol, Canc Hosp, Harbin, Heilongjiang, Peoples R China

[14] Nanjing Med Univ, Affiliated Canc Hosp, Jiangsu Canc Hosp, Dept Oncol,Jiangsu Inst Canc Res, Nanjing, Jiangsu, Peoples R China

[15] Tianjin Canc Hosp, Dept Gastrointestinal Oncol, Tianjin, Peoples R China

[16] China Med Univ, Hosp 1, Dept Med Oncol, Shenyang, Liaoning, Peoples R China

[17] Jilin Univ, Hosp 1, Dept Med Oncol, Changchun, Jilin, Peoples R China

[18] Jiangsu Prov Hosp, Dept Oncol, Nanjing, Jiangsu, Peoples R China

[19] Shantou Univ, Coll Med, Canc Hosp, Digest Med Oncol, Shantou, Peoples R China

[20] Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Dept Med Oncol, Shanghai, Peoples R China

[21] Sun Yat Sen Univ, State Key Lab Oncol South China, Dept Ultrasonog, Canc Ctr,Collaborat Innovat Ctr Canc Med, Guangzhou, Guangdong, Peoples R China

[22] Shanghai Junshi Biosci Co Ltd, Shanghai, Peoples R China

来源：

ANNALS OF ONCOLOGY | 2019年 / 30卷 / 09期

基金：

国家重点研发计划; 中国国家自然科学基金;

关键词：

gastric cancer; immunotherapy; programmed death ligand-1; tumor mutational burden; BLOCKADE; NIVOLUMAB;

D O I：

10.1093/annonc/mdz197

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: High tumor mutational burden (TMB-H) is correlated with enhanced objective response rate (ORR) and progression-free survival (PFS) for certain cancers receiving immunotherapy. This study aimed to investigate the safety and efficacy of toripalimab, a humanized programmed death-1 (PD-1) antibody, in advanced gastric cancer (AGC), and the predictive survival benefit of TMB and PD-L1. Patients and methods: We reported on the AGC cohort of phase Ib/II trial evaluating the safety and activity of toripalimab in patients with AGC, oesophageal squamous cell carcinoma, nasopharyngeal carcinoma and head and neck squamous cell carcinoma. In cohort 1, 58 chemo-refractory AGC patients received toripalimab (3 mg/kg d1, Q2W) as a monotherapy. In cohort 2, 18 chemotherapy-naive AGC patients received toripalimab (360mg d1, Q3W) with oxaliplatin 130 mg/m(2) qd, d1, capecitabine 1000 mg/m(2) b.i.d., d1-d14, Q3W as first-line treatment. Primary end point was ORR. Biomarkers such as PD-L1 and TMB were evaluated for correlation with clinical efficacy. Results: In cohort 1, the ORR was 12.1% and the disease control rate (DCR) was 39.7%. Median PFS was 1.9 months and median OS was 4.8 months. The TMB-H group showed significant superior OS than the TMB-L group [14.6 versus 4.0 months, HR = 0.48 (96% CI 0.24-0.96), P = 0.038], while PD-L1 overexpression did not correlate with significant survival benefit. A 77.6% of patients experienced at least one treatment-related adverse event (TRAE), and 22.4% of patients experienced a grade 3 or higher TRAE. In cohort 2, the ORR was 66.7% and the DCR was 88.9%. A 94.4% of patients experienced at least one TRAE and 38.9% of patients experienced grade 3 or higher TRAEs. Conclusions: Toripalimab has demonstrated a manageable safety profile and promising antitumor activity in AGC patients, especially in combination with XELOX. High TMB may be a predictive marker for OS of AGC patients receiving toripalimab as a single agent.

引用

页码：1479 / 1486

页数：8

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