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Tislelizumab Plus Chemotherapy As First-Line Treatment for Advanced Esophageal Squamous

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Tislelizumab Plus Chemotherapy As First-Line Treatment for Advanced Esophageal Squamous Author Manuscript Published OnlineFirst on June 19, 2020; DOI: 10.1158/1078-0432.CCR-19-3561 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Tislelizumab Plus Chemotherapy as First-line Treatment for Advanced Esophageal Squamous 2 Cell Carcinoma and Gastric/Gastroesophageal Junction Adenocarcinoma 3 4 Jianming Xu1, Yuxian Bai2, Nong Xu3, Enxiao Li4, Buhai Wang5, Jin Wang6, Xiang Li6, Xin Wang6, Xianglin 5 Yuan7 6 7 1Department of Gastrointestinal Oncology, The Fifth Medical Center, Chinese PLA General Hospital, 8 Beijing, China; 2Harbin Medical University Cancer Hospital, Harbin, China; 3The First Affiliated Hospital of 9 Zhejiang University, Hangzhou, China; 4First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, China; 10 5Northern Jiangsu People’s Hospital, Yangzhou, China; 6BeiGene(Beijing) Co., Ltd., Beijing, China; 11 7Tongji Hospital, Wuhan, China 12 13 Corresponding author: 14 Name: Jianming Xu 15 Address: The Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100071 China 16 Email: [email protected] 17 Phone: +86-10-51128358 18 Fax: +86-10-51128358 19 20 Target journal: Clinical Cancer Research 21 Abstract: 250 words (limit: 250 words) 22 Main Text: 3,431 words (limit: 5,000 words) 23 Tables/Figures: 6 tables and figures (limit: 6 tables and/or figures) 24 References: 37 references (limit: 50 references) 25 Statement of translational relevance: 134 words (limit: 120-150 words) 26 27 Keywords (3-5 words): Tislelizumab; programmed cell death-1 (PD-1); immunotherapy; phase 2 clinical 28 trial; Chinese patients 29 Authors’ Disclosures: JW, XL, and XW are employees of BeiGene. JX, YB, NX, EL, BW, and XY 30 declare no conflicts of interest. 31 Running title (60 characters including spaces): Tislelizumab for the treatment of ESCC and G/GEJ 1 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 19, 2020; DOI: 10.1158/1078-0432.CCR-19-3561 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 32 Translational Relevance 33 Advanced stages of esophageal and gastric cancer are associated with 5-year survival rates of ≤10%. 34 Historically, first-line treatment consists of doublet chemotherapy, but novel immuno-oncology therapies 35 are being developed. Immune checkpoint proteins programmed cell death-1 (PD-1) and its ligand, 36 programmed death ligand-1 (PD-L1), play a central role in suppressing antitumor immunity, and 37 dysregulation of the PD-1/PD-L1 axis may be used by cancer cells for immune evasion. PD-1 is an 38 inhibitory receptor involved in negative regulation of T-cell activation that is mainly expressed on activated 39 T cells and is found to be upregulated in tumor-infiltrating lymphocytes. Here we demonstrate that 40 tislelizumab, a monoclonal antibody against PD-1, plus standard-of-care platinum-doublet chemotherapy 41 as first-line treatment, was generally well tolerated and demonstrated durable antitumor activity in 42 Chinese patients with advanced esophageal squamous cell carcinoma or gastric/gastroesophageal 43 junction adenocarcinoma. 44 45 46 47 48 49 50 51 52 2 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 19, 2020; DOI: 10.1158/1078-0432.CCR-19-3561 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 53 Abstract 54 Purpose: This phase 2 study (NCT03469557) assessed safety/tolerability and antitumor activity of 55 first-line tislelizumab, a monoclonal antibody against PD-1, plus chemotherapy in patients with locally 56 advanced/metastatic esophageal squamous cell carcinoma (ESCC) or gastric cancer/gastroesophageal 57 junction (G/GEJ) adenocarcinoma. 58 59 Experimental Design: Patients with ESCC received tislelizumab (200 mg IV every 3 weeks [Q3W]) plus 60 cisplatin (80 mg/m² IV Q3W for ≤6 cycles) and fluorouracil (800 mg/m²/d, Days 1–5 IV Q3W for ≤6 61 cycles); patients with G/GEJ adenocarcinoma received tislelizumab (200 mg IV Q3W) plus oxaliplatin 62 (130 mg/m² IV Q3W for up to six cycles) and oral capecitabine (1000 mg/m² twice daily, Days 1–14 63 Q3W). The safety/tolerability profile of combination therapy was the primary endpoint; secondary 64 endpoints included objective response rate (ORR), duration of response (DoR), disease control rate 65 (DCR), and progression-free survival per RECIST v1.1. Exploratory endpoints included overall survival 66 and potential predictive biomarkers. 67 68 Results: As of March 31, 2019, 30 patients (n=15 per cohort) were enrolled. Most common adverse 69 events considered related to tislelizumab and/or chemotherapy were anemia (n=18), decreased appetite 70 (n=17), nausea (n=16), and asthenia (n=15). One patient experienced fatal hepatic dysfunction, 71 confounded by progressive disease and underlying hepatitis, attributed to treatment by the investigator. 72 Confirmed ORRs and DCRs were 46.7% and 80%, respectively, for both ESCC and G/GEJ 73 adenocarcinoma. In ESCC, median DoR was 12.8 months (95% CI: 3.5, 12.8); DoR was not yet mature 74 for the G/GEJ cohort. 75 76 Conclusions: Tislelizumab plus chemotherapy demonstrated durable responses with manageable 77 tolerability in patients with advanced ESCC or G/GEJ adenocarcinoma. 78 3 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 19, 2020; DOI: 10.1158/1078-0432.CCR-19-3561 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 79 Introduction 80 Globally, esophageal cancer (EC) and gastric cancer (GC) rank in the top seven most common 81 cancers and in the top six in terms of mortality (1). Incidence rates for both cancer types are significantly 82 higher in East Asia (1). Esophageal cancers are histologically classified as squamous cell carcinoma 83 (ESCC) or adenocarcinoma, and ESCC accounts for 87% of all cases of EC (2). Combination 84 chemotherapy is the recommended first-line treatment for advanced stage ESCC and GC. The 85 combination of cisplatin plus paclitaxel or 5-fluorouracil (5-FU) is the standard first-line regimen for 86 patients with distant metastatic or recurrent ESCC (3); patients with diagnosed inoperable, locally 87 advanced, or metastatic GC generally receive chemotherapy regimens containing a platinum and a 88 fluoropyrimidine, with or without an additional chemotherapy agent (eg, taxanes) (4, 5). However, the 89 prognosis for patients treated with standard-of-care treatment for either advanced stage ESCC or GC 90 remains poor (6, 7). 91 The interplay between immune checkpoint pathway proteins, programmed cell death-1 (PD-1) 92 and programmed cell death-1 ligand (PD-L1), plays a significant role in antitumor immunity. Dysregulation 93 of the PD-1/PD-L1 axis in tumor cells results in evasion of immune surveillance, detection, and 94 destruction (8-12). Moreover, increasing evidence suggests that the antitumor activity of chemotherapy is 95 mediated not only through cytotoxic effects, but also through immunological effects, including reducing 96 T-regulatory cell activity and enhancing cross-presentation of tumor antigens (13-15). As such, combining 97 immune checkpoint inhibitors with chemotherapy may synergistically improve antitumor activity (13-15). 98 Ongoing trials are currently investigating anti-PD-1 antibodies in combination with chemotherapy as 99 first-line treatment of advanced ESCC (16) and advanced G/GEJ adenocarcinoma (17, 18). In the first- 100 line setting, pembrolizumab monotherapy was noninferior to chemotherapy for OS in patients with 101 combined positive score (CPS) ≥1 and had clinically meaningful improvement for OS in CPS ≥10; 102 pembrolizumab in combination with standard chemotherapy did not show superior OS in patients with 103 CPS ≥1 or CPS ≥10 (18). There is currently no efficacy data reported for first-line treatment with anti-PD- 104 L1 antibodies plus chemotherapy in patients with advanced ESCC. 105 Tislelizumab is a humanized monoclonal antibody (mAb) with high affinity and specificity for PD-1 106 that was engineered to minimize binding to FcɣR on macrophages in order to greatly reduce antibody- 4 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 19, 2020; DOI: 10.1158/1078-0432.CCR-19-3561 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 107 dependent phagocytosis, a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy 108 (19). Using structure-guided mutagenesis and Biacore studies, tislelizumab has been found to be 109 structurally differentiated from both pembrolizumab and nivolumab by its unique binding epitopes and 110 binding kinetics (20). In two early phase studies (NCT02407990, CTR20160872), tislelizumab (200 mg) 111 administered intravenously (IV) every 3 weeks (Q3W) was generally well tolerated and demonstrated 112 promising antitumor activity in both Asian and non-Asian patients with advanced solid tumors, including 113 EC and GC (21, 22). The primary objective of this study was to investigate the safety of tislelizumab in 114 combination with 5-FU plus cisplatin in patients with advanced ESCC, or with oxaliplatin plus capecitabine 115 in patients with advanced G/GEJ adenocarcinoma. A secondary objective was to assess the preliminary 116 antitumor activity of tislelizumab in combination with chemotherapy as first-line treatment for advanced 117 ESCC and G/GEJ adenocarcinoma. 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 5 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 19, 2020; DOI: 10.1158/1078-0432.CCR-19-3561 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
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