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      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

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          Key Points

          Question

          What is the performance of toripalimab, a programmed cell death 1 (PD-1) antibody, and JS311, a novel PD ligand 1 (PD-L1) immunohistochemistry assay, among patients with non–small cell lung cancer?

          Findings

          In this phase 1 trial that enrolled 41 patients with advanced non–small cell lung cancer, toripalimab exhibited encouraging antitumor activity and manageable safety, with median progression-free survival of 11.2, 2.3, and 2.8 months, stratified by PD-L1 tumor proportion scores of at least 50%, 1% to 49%, and less than 1%, respectively. In a cohort of 280 specimens from patients with non–small cell lung cancer, JS311 was highly consistent with previously verified PD-L1 assays.

          Meaning

          In this study, toripalimab and JS311 exhibited potential utility in future clinical practice for patients with non–small cell lung cancer.

          Abstract

          This phase 1 trial assesses the safety, antitumor activity, and pharmacokinetics of toripalimab in patients with advanced non–small cell lung cancer (NSCLC) and evaluates the utility of JS311, a novel programmed death cell ligand 1 immunohistochemistry assay.

          Abstract

          Importance

          Programmed cell death 1 (PD-1) antibodies have shown substantial survival benefit in patients with advanced non–small cell lung cancer (NSCLC). Toripalimab is a promising and practicable PD-1 antibody; however, its performance in NSCLC has not been established.

          Objectives

          To assess the safety, antitumor activity, and pharmacokinetics of toripalimab in patients with advanced NSCLC and to evaluate the utility of JS311, a novel PD ligand 1 (PD-L1) immunohistochemistry (IHC) assay.

          Design, Setting, and Participants

          This single-arm open-label phase 1 trial enrolled 41 patients with advanced NSCLC that had progressed after at least 3 lines of therapy between September 21, 2017, and June 5, 2018, with a median (interquartile range) follow-up of 14.9 (3.2-22.5) months and included a cohort study comparing JS311 with other PD-L1 IHC assays that included 280 NSCLC specimens collected from January 1, 2016, to May 21, 2018. Data collection was conducted from September 21, 2017, to September 27, 2019, and analysis was conducted from September 27, 2019, to December 30, 2019.

          Exposure

          Enrolled patients were administered a single dose of toripalimab, under 2 manufacturing processes and scales (200 L and 500 L), for safety and pharmacokinetic analysis within 28 days, followed by subsequent multidose infusions every 2 weeks. PD-L1 expression was determined by IHC with JS311, comparing its results with results from 22C3, 28-8, and SP263 simultaneously.

          Main Outcomes and Measures

          Progression-free survival (PFS) and overall survival (OS), estimated by Kaplan-Meier curves, and continuous variables compared by t test or Mann-Whitney test. Correlations between PD-L1 IHC antibodies were evaluated by Spearman correlation test.

          Results

          A total of 41 patients (29 [70.7%] men) with a median (interquartile range) age of 59 (53 to 63) years who experienced disease progression following chemotherapy were included. The most common treatment-related adverse events were rash (6 [14.6%]), increased amylase level (5 [12.2%]), and increased aspartate aminotransferase level (5 [12.2%]). In 35 patients included in the pharmacokinetic analysis, drug exposure and area under curve after 1 dose was similar under both manufacturing processes and scales (mean [SD] for 200-L group: 12 465.28 [4128.17] hour × μg/mL; for 500-L group: 12 331.42 [2472.58] hour × μg/ml). In 28 patients included in the response and survival analysis, the median PFS and OS were 2.8 (95% CI, 2.7 to 4.6) months and 13.8 months (95% CI, 10.0 months to not reached), respectively. Stratified by PD-L1 tumor proportion score of at least 50%, 1% to 49%, and less 1%, median PFS rates were 11.2 months (95% CI, 2.3 months to not evaluable), 2.3 (95% CI, 1.7 to 2.7) months, and 2.8 (95% CI, 2.7 to 4.6) months, respectively. A total of 4 anti–PD-L1 IHC antibodies were compared during PD-L1 staining, using 280 NSCLC specimens. The consistency rates between the 4 antibodies were 80.8% to 89.5% (ρ, 0.619 to 0.790) and 93.3% to 95.5% (ρ, 0.691 to 0.773), with PD-L1 tumor proportion scores of 1% and 50% as cut points, respectively.

          Conclusions and Relevance

          In this study, toripalimab exhibited encouraging antitumor activity and manageable safety profiles among patients with heavily treated NSCLC. The novel PD-L1 IHC antibody JS311 was highly consistent with previously verified PD-L1 IHC assays.

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          Most cited references29

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          Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer

          Nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, disrupts PD-1-mediated signaling and may restore antitumor immunity.
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            Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial

            First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater.
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              Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC

              The cancer-cell-killing property of atezolizumab may be enhanced by the blockade of vascular endothelial growth factor-mediated immunosuppression with bevacizumab. This open-label, phase 3 study evaluated atezolizumab plus bevacizumab plus chemotherapy in patients with metastatic nonsquamous non-small-cell lung cancer (NSCLC) who had not previously received chemotherapy.
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                Author and article information

                Journal
                JAMA Netw Open
                JAMA Netw Open
                JAMA Netw Open
                JAMA Network Open
                American Medical Association
                2574-3805
                5 October 2020
                October 2020
                5 October 2020
                : 3
                : 10
                : e2013770
                Affiliations
                [1 ]Department of Medical Oncology, State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
                [2 ]Department of Pathology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
                [3 ]Department of Thoracic Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
                [4 ]Department of Medical Oncology, Affiliated Hospital of Qinghai University, Qinghai, China
                Author notes
                Article Information
                Accepted for Publication: May 18, 2020.
                Published: October 5, 2020. doi:10.1001/jamanetworkopen.2020.13770
                Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Wang Z et al. JAMA Network Open.
                Corresponding Authors: Jie Wang, MD, PhD, State Key Laboratory of Molecular Oncology, Department of Medical Oncology ( zlhuxi@ 123456163.com ), and Ning Lv, MD, PhD, Department of Pathology ( nlu03@ 123456126.com ), National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuannanli, Chaoyang District, Beijing 100021, PR China.
                Author Contributions: Drs Lv and J. Wang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Z. Wang, Ying, Xu, and Yuan contributed equally to this work and served as co–first authors.
                Concept and design: Z. Wang, Ying, Xu, Z. Zhao, Lv, J. Wang.
                Acquisition, analysis, or interpretation of data: Z. Wang, Ying, Xu, Yuan, Duan, Bai, Guo, Li, Yang, Wan, Fei, Z. Zhao, Du, J. Zhao, J. Wang.
                Drafting of the manuscript: Z. Wang, Ying, Xu, Yuan, Duan, Yang, Wan, Z. Zhao, Du, J. Zhao, J. Wang.
                Critical revision of the manuscript for important intellectual content: Z. Wang, Bai, Guo, Li, Fei, Lv, J. Wang.
                Statistical analysis: Z. Wang, Xu, Yuan, Guo, Li, Yang, Z. Zhao, Du, j. Wang.
                Obtained funding: Bai, J. Wang.
                Administrative, technical, or material support: Z. Wang, Duan, Guo, Wan, J. Zhao, J. Wang.
                Supervision: Z. Wang, Fei, Lv, J. Wang.
                Conflict of Interest Disclosures: None reported.
                Funding/Support: This work was supported by development project 2019YFC1315700 of the National Key Research and Development Project to Dr J. Wang; grant 81630071 from the National Natural Sciences Foundation Key Program to Dr J. Wang; grants CIFMS 2016-I2M-3-008 to Dr J. Wang and 2017-I2M-1-005 to Dr Z. Wang from the CAMS Innovation Fund for Medical Sciences; grant KY201701 from the Aiyou Foundation to Dr J. Wang; Ministry of Education Innovation Team development project IRT-17R10 to Dr J. Wang; grant 2018PT31035 from CAMS Key Lab of Translational Research on Lung Cancer to Dr J. Wang; grant 81871889 from the National Natural Sciences Foundation to Dr Z. Wang; and grant 2018RC320009 from the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences to Dr Z. Wang.
                Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
                Article
                zoi200519
                10.1001/jamanetworkopen.2020.13770
                7536589
                33017026
                a7a82331-6f5e-4ccf-9d7c-ab43b2afd2d4
                Copyright 2020 Wang Z et al. JAMA Network Open.

                This is an open access article distributed under the terms of the CC-BY License.

                History
                : 16 February 2020
                : 18 May 2020
                Categories
                Research
                Original Investigation
                Online Only
                Oncology

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