Toripalimab Plus Chemotherapy for Patients With Treatment-Naive Advanced Non-Small-Cell Lung Cancer: A Multicenter Randomized Phase III Trial (CHOICE-01)
Zhijie Wang, Lin Wu, Baolan Li, Ying Cheng, Xiaoling Li, Xicheng Wang, Liang Han, Xiaohong Wu, Yun Fan, Yan Yu, Dongqing Lv, Jianhua Shi, Jianjin Huang, Shaozhang Zhou, Baohui Han, Guogui Sun, Qisen Guo, Youxin Ji, Xiaoli Zhu, Sheng Hu, Wei Zhang, Qiming Wang, Yuming Jia, Ziping Wang, Yong Song, Jingxun Wu, Meiqi Shi, Xingya Li, Zhigang Han, Yunpeng Liu, Zhuang Yu, An-Wen Liu, Xiuwen Wang, Caicun Zhou, Diansheng Zhong, Liyun Miao, Zhihong Zhang, Hui Zhao, Jun Yang, Dong Wang, Yingyi Wang, Qiang Li, Xiaodong Zhang, Mei Ji, Zhenzhou Yang, Jiuwei Cui, Beili Gao, Buhai Wang, Hu Liu, Lei Nie, Mei He, Shi Jin, Wei Gu, Yongqian Shu, Tong Zhou, Jian Feng, Xinmei Yang, Cheng Huang, Bo Zhu, Yu Yao, Xiongwen Tang, Jianjun Yu, Ellen Maher, Hui Feng, Sheng Yao, Patricia Keegan, Jie Wang, Zhijie Wang, Lin Wu, Baolan Li, Ying Cheng, Xiaoling Li, Xicheng Wang, Liang Han, Xiaohong Wu, Yun Fan, Yan Yu, Dongqing Lv, Jianhua Shi, Jianjin Huang, Shaozhang Zhou, Baohui Han, Guogui Sun, Qisen Guo, Youxin Ji, Xiaoli Zhu, Sheng Hu, Wei Zhang, Qiming Wang, Yuming Jia, Ziping Wang, Yong Song, Jingxun Wu, Meiqi Shi, Xingya Li, Zhigang Han, Yunpeng Liu, Zhuang Yu, An-Wen Liu, Xiuwen Wang, Caicun Zhou, Diansheng Zhong, Liyun Miao, Zhihong Zhang, Hui Zhao, Jun Yang, Dong Wang, Yingyi Wang, Qiang Li, Xiaodong Zhang, Mei Ji, Zhenzhou Yang, Jiuwei Cui, Beili Gao, Buhai Wang, Hu Liu, Lei Nie, Mei He, Shi Jin, Wei Gu, Yongqian Shu, Tong Zhou, Jian Feng, Xinmei Yang, Cheng Huang, Bo Zhu, Yu Yao, Xiongwen Tang, Jianjun Yu, Ellen Maher, Hui Feng, Sheng Yao, Patricia Keegan, Jie Wang
Abstract
Purpose: The CHOICE-01 study investigated the efficacy and safety of toripalimab in combination with chemotherapy as a first-line treatment for advanced non-small-cell lung cancer (NSCLC).
Patients and methods: Patients (N = 465) with treatment-naive, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) once every 3 weeks in combination with chemotherapy for 4-6 cycles, followed by the maintenance of toripalimab or placebo once every 3 weeks plus standard care. Stratification factors included programmed death ligand-1 expression status, histology, and smoking status. The primary end point was progression-free survival (PFS) by investigator per RECIST v1.1. Secondary end points included overall survival and safety.
Results: At the final PFS analysis, PFS was significantly longer in the toripalimab arm than in the placebo arm (median PFS, 8.4 v 5.6 months, hazard ratio = 0.49; 95% CI, 0.39 to 0.61; two-sided P < .0001). At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm (median OS not reached v 17.1 months, hazard ratio = 0.69; 95% CI, 0.53 to 0.92; two-sided P = .0099). The incidence of grade ≥ 3 adverse events was similar between the two arms. Treatment effects were similar regardless of programmed death ligand-1 status. Genomic analysis using whole-exome sequencing from 394 available tumor samples revealed that patients with high tumor mutational burden were associated with significantly better PFS in the toripalimab arm (median PFS 13.1 v 5.5 months, interaction P = .026). Notably, patients with mutations in the focal adhesion-PI3K-Akt signaling pathway achieved significantly better PFS and OS in the toripalimab arm (interaction P values ≤ .001).
Conclusion: Toripalimab plus chemotherapy significantly improves PFS and OS in patients with treatment-naive advanced NSCLC while having a manageable safety profile. Subgroup analysis showed the OS benefit was mainly driven by the nonsquamous subpopulation.
Trial registration: ClinicalTrials.gov NCT03856411.
Conflict of interest statement
Zhijie Wang
Speakers' Bureau: Roche China, MSD
Lin Wu
Employment: AstraZeneca, Roche, Bristol Myers Squibb, MSD, Pfizer, Lilly, Boehringer Ingelheim, Merck, Innovent Biologics, Hengrui Pharmaceutical
Qiming Wang
Consulting or Advisory Role: Hansoh Pharma
Research Funding: Hansoh Pharma (Inst)
Tong Zhou
Speakers' Bureau: AstraZeneca, Roche China, Novartis
Xiongwen Tang
Employment: TopAlliance BioSciences Inc
Stock and Other Ownership Interests: TopAlliance BioSciences Inc
Jianjun Yu
Employment: TopAlliance BioSciences Inc, Predicine
Stock and Other Ownership Interests: TopAlliance BioSciences Inc, Predicine
Ellen Maher
Employment: TopAlliance BioSciences Inc
Travel, Accommodations, Expenses: TopAlliance BioSciences Inc
Hui Feng
Employment: Shanghai Junshi BioSciences, TopAlliance BioSciences Inc
Leadership: Shanghai Junshi BioSciences, TopAlliance BioSciences Inc
Stock and Other Ownership Interests: Shanghai Junshi BioSciences
Patents, Royalties, Other Intellectual Property: Shanghai Junshi BioSciences Inc patent
Travel, Accommodations, Expenses: 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 as employee of TopAlliance Biosciences Inc
Patricia Keegan
Employment: TopAlliance Biosciences
No other potential conflicts of interest were reported.
Figures
References
- Molina JR, Yang P, Cassivi SD, et al. : Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 83:584-594, 2008
- Sung H, Ferlay J, Siegel RL, et al. : Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209-249, 2021
- Qiu H, Cao S, Xu R: Cancer incidence, mortality, and burden in China: A time-trend analysis and comparison with the United States and United Kingdom based on the global epidemiological data released in 2020. Cancer Commun (Lond) 41:1037-1048, 2021
- West H, McCleod M, Hussein M, et al. : Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 20:924-937, 2019
- Paz-Ares L, Luft A, Vicente D, et al. : Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 379:2040-2051, 2018
- Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. : Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378:2078-2092, 2018
- Wei XL, Ren C, Wang FH, et al. : A phase I study of toripalimab, an anti-PD-1 antibody, in patients with refractory malignant solid tumors. Cancer Commun (Lond) 40:345-354, 2020
- Tang B, Chi Z, Chen Y, et al. : Safety, efficacy, and biomarker analysis of toripalimab in previously treated advanced melanoma: Results of the POLARIS-01 multicenter phase II trial. Clin Cancer Res 26:4250-4259, 2020
- Wang FH, Wei XL, Feng J, et al. : Efficacy, safety, and correlative biomarkers of toripalimab in previously treated recurrent or metastatic nasopharyngeal carcinoma: A phase II clinical trial (POLARIS-02). J Clin Oncol 39:704-712, 2021
- Sheng X, Chen H, Hu B, et al. : Recombinant humanized anti-PD-1 monoclonal antibody toripalimab in patients with metastatic urothelial carcinoma: Results of an open-label phase II clinical study Polaris-03. J Clin Oncol 38, 2020. (suppl 6; abstr 5040)
- Mai H-Q, Chen Q-Y, Chen D, et al. : Toripalimab or placebo plus chemotherapy as first-line treatment in advanced nasopharyngeal carcinoma: A multicenter randomized phase 3 trial. Nat Med 27:1536-1543, 2021
- Liu H, Guo L, Zhang J, et al. : Glycosylation-independent binding of monoclonal antibody toripalimab to FG loop of PD-1 for tumor immune checkpoint therapy. MAbs 11:681-690, 2019
- Fu J, Wang F, Dong LH, et al. : Preclinical evaluation of the efficacy, pharmacokinetics and immunogenicity of JS-001, a programmed cell death protein-1 (PD-1) monoclonal antibody. Acta Pharmacol Sin 38:710-718, 2017
- Wang Z, Ying J, Xu J, et al. : Safety, antitumor activity, and pharmacokinetics of toripalimab, a programmed cell death 1 inhibitor, in patients with advanced non-small cell lung cancer: A phase 1 trial. JAMA Netw Open 3:e2013770, 2020
- Yang J, Dong L, Yang S, et al. : Safety and clinical efficacy of toripalimab, a PD-1 mAb, in patients with advanced or recurrent malignancies in a phase I study. Eur J Cancer 130:182-192, 2020
- Ramos-Casals M, Brahmer JR, Callahan MK, et al. : Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers 6:38, 2020
- Hellmann MD, Nathanson T, Rizvi H, et al. : Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell 33:843-852 e4, 2018
- Rizvi NA, Hellmann MD, Snyder A, et al. : Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124-128, 2015
- Miao D, Margolis CA, Vokes NI, et al. : Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors. Nat Genet 50:1271-1281, 2018
- Brahmer J, Reckamp KL, Baas P, et al. : Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123-135, 2015
- Rizvi NA, Mazières J, Planchard D, et al. : Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): A phase 2, single-arm trial. Lancet Oncol 16:257-265, 2015
- Wang F, Wei XL, Wang FH, et al. : 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. Ann Oncol 30:1479-1486, 2019
- Wang ZX, Cui C, Yao J, et al. : Toripalimab plus chemotherapy in treatment-naive, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial. Cancer Cell 40:277-288 e3, 2022
- Nishio M, Barlesi F, West H, et al. : Atezolizumab plus chemotherapy for first-line treatment of nonsquamous NSCLC: Results from the randomized phase 3 IMpower132 trial. J Thorac Oncol 16:653-664, 2021
- Gadgeel S, Rodriguez-Abreu D, Speranza G, et al. : Updated analysis from KEYNOTE-189: Pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol 38:1505-1517, 2020
- Paz-Ares L, Vicente D, Tafreshi A, et al. : A randomized, placebo-controlled trial of pembrolizumab plus chemotherapy in patients with metastatic squamous NSCLC: Protocol-specified final analysis of KEYNOTE-407. J Thorac Oncol 15:1657-1669, 2020
- Jiang H, Hegde S, Knolhoff BL, et al. : Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med 22:851-860, 2016
- Jian M, Yunjia Z, Zhiying D, et al. : Interleukin 7 receptor activates PI3K/Akt/mTOR signaling pathway via downregulation of Beclin-1 in lung cancer. Mol Carcinog 58:358-365, 2019
- Miao D, Margolis CA, Gao W, et al. : Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359:801-806, 2018
- Zhou H, Liu J, Zhang Y, et al. : PBRM1 mutation and preliminary response to immune checkpoint blockade treatment in non-small cell lung cancer. NPJ Precis Oncol 4:6, 2020
- Chang E, Gong Y, Vallejo JJ, et al. : FDA analysis of outcomes in Asian patients (pts) with metastatic non-small cell lung cancer (mNSCLC) receiving immune checkpoint inhibitors (ICI). J Clin Oncol 37, 2019. (suppl 15; abstr e20690)
- Gene Set Enrichment Analysis: Molecular signatures database.
Source: PubMed