5、消化系统肿瘤消化系统肿瘤 (10).pdf
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1、1ChenX,etal.J Immunother Cancer 2020;8:e001240.doi:10.1136/jitc-2020-001240Open access Camrelizumab plus gemcitabine and oxaliplatin(GEMOX)in patients with advanced biliary tract cancer:a single-arm,open-label,phase II trialXiaofeng Chen,1,2,3 Xiaofeng Wu,4 Hao Wu,1 Yanhong Gu,1 Yang Shao,5 Qianwen
2、Shao,1 Feipeng Zhu,6 Xiao Li,7 Xiaofeng Qian,4 Jun Hu,8 Fengjiao Zhao,1 Weidong Mao,9 Jing Sun,1 Jian Wang,1 Gaohua Han,10 Changxian Li,4 Yongxiang Xia,4 Poshita Kumari Seesaha,1 Dongqin Zhu,5 Huajun Li,11 Junling Zhang,12 Guoqiang Wang,13 Xuehao Wang,4 Xiangcheng Li,4 Yongqian Shu 1,3To cite:ChenX,
3、WuX,WuH,etal.Camrelizumab plus gemcitabine and oxaliplatin(GEMOX)in patients with advanced biliary tract cancer:a single-arm,open-label,phase II trial.Journal for ImmunoTherapy of Cancer 2020;8:e001240.doi:10.1136/jitc-2020-001240 Additional material is published online only.To view,please visit the
4、 journal online(http:/dx.doi.org/10.1136/jitc-2020-001240).XC and XW are joint first authors.Accepted 29 September 2020For numbered affiliations see end of article.Correspondence toDr Yongqian Shu;shuyongqian Dr Xiangcheng Li;drlixc Original research Author(s)(or their employer(s)2020.Re-use permitt
5、ed under CC BY.Published by BMJ.ABSTRACTBackground Immune checkpoint inhibitors monotherapy has been studied in patients with advanced biliary tract cancer(BTC).The aim of this study was to assess the efficacy and safety of camrelizumab,plus gemcitabine and oxaliplatin(GEMOX)as first-line treatment
6、in advanced BTC and explored the potential biomarkers associated with response.Methods In this single-arm,open-label,phase II study,we enrolled stage IV BTC patients.Participants received camrelizumab(3 mg/kg)plus gemcitabine(800 mg/m2)and oxaliplatin(85 mg/m2).Primary endpoints were 6-month progres
7、sion-free survival(PFS)rate and safety.Secondary endpoints were objective response rate(ORR),PFS and overall survival(OS).Exploratory endpoints included association between response and tumor mutational burden(TMB),blood TMB,dynamic change of ctDNA and immune microenvironment.Results 54 patients wit
8、h advanced BTC were screened,of whom 38 eligible patients were enrolled.One patient withdrew informed consent before first dose treatment.Median follow-up was 11.8 months.The 6-month PFS rate was 50%(95%CI 33 to 65).Twenty(54%)out of 37 patients had an objective response.The median PFS was 6.1 month
9、s and median OS was 11.8 months.The most common treatment-related adverse events(TRAEs)were fatigue(27(73%)and fever(27(73%).The most frequent grade 3 or worse TRAEs were hypokalemia(7(19%)and fatigue(6(16%).The ORR was 80%in patients with programmed cell death ligand-1(PD-L1)tumor proportion score(
10、TPS)1%versus 53.8%in PD-L1 TPS 0.05),except that PFS was associated with blood TMB.Patients with positive post-treatment ctDNA had shorter PFS(p=0.007;HR,2.83;95%CI 1.27 to 6.28).Conclusion Camrelizumab plus GEMOX showed a promising antitumor activity and acceptable safety profile as first-line trea
11、tment in advanced BTC patients.Potential biomarkers are needed to identify patients who might respond to camrelizumab plus GEMOX.Trial registration number NCT03486678.INTRODUCTIONBiliary tract cancer(BTC)is a rare type of malignant tumor accounting for about 3%of all gastrointestinal malignancies.1
12、The global incidence rate was 21.1%and the mortality rate was 17.4%in 2017.2 Due to the aggressive nature of BTC,most patients present with an advanced BTC and cannot be surgically resected when diagnosed.3 For these patients,gemcitabine plus cisplatin or gemcitabine plus oxaliplatin(GEMOX)have show
13、n prolonged median overall survival(mOS,11.7 months and 9.5 months,respec-tively)and have become the first-line options for advanced BTC patients.4 5 However,the toxicity of gemcitabine plus cisplatin are higher than GEMOX.6 In practice,68 cycles of GEMOX regimen are more frequently selected in the
14、treatment of patients with BTC with an acceptable safety profile.7 However,the OS is far from satisfactory and the 5-year survival rate is less than 10%.3 Hence,there remains an unmet need to develop more effective treatment options for patients with unresectable BTC.Immune checkpoint inhibitors(ICI
15、s)such as programmed cell death-1(PD-1)and programmed cell death ligand-1(PD-L1)antibodies,have gained great success in various types of cancers.8 In patients with BTC,pembrolizumab has been approved in patients with micro-satellite instability high or deficiency in mismatch repair according to pan-
16、cancer studies.9 Several clinical studies involving ICI as second-line treatment in Protected by copyright.on December 19,2020 at USP-Universidade de Sao Paulo.http:/ Immunother Cancer:first published as 10.1136/jitc-2020-001240 on 10 November 2020.Downloaded from 2ChenX,etal.J Immunother Cancer 202
17、0;8:e001240.doi:10.1136/jitc-2020-001240Open access patients with BTC also show promising results,like for instance the KEYNOTE 028 and KEYNOTE 158 trials with pembrolizumab and a phase II trial with nivolumab.1012 Therefore,the application of ICIs in BTC looks promising.Recently,immunotherapy combi
18、ned with chemo-therapy has been investigated in many types of cancers and has shown promising antitumor efficacy.13 14 For example,in the KEYNOTE0189 study,pembrolizumab combined with pemetrexed plus carboplatin,as first-line therapy,prolonged the OS in non-small cell lung cancer(NSCLC).15 SHR-1210(
19、camrelizumab)combined with gemcitabine plus cisplatin yielded promising safety and efficacy in recurrent or metastatic nasopharyngeal carci-noma.14 However,whether the combination of ICIs with chemotherapy would improve the clinical outcomes in advanced BTC has not yet been explored.Herein we report
20、 the results from a prospective single-arm open label trial assessing the safety and anti-tumor activity of camrelizumab,a fully humanized IgG4-PD-1 monoclonal antibody with high affinity combined with GEMOX regimen in advanced BTC patients.METHODSStudy design and participantsThis study was a single
21、-arm,phase II trial assessing the safety and antitumor activity of camrelizumab plus GEMOX in patients with advanced BTC(online supple-mental file 2).Eligible patients were aged 1875 years with histologically confirmed stage IV advanced BTC including cholangiocarcinoma and gallbladder cancer.Additio
22、nal inclusion criteria included an Eastern Coop-erative Oncology Group performance status of 0 or 1 and presence of at least one measurable lesion assessed using the Response Evaluation Criteria in Solid Tumors version 1.1(RECIST version 1.1).Patients were required to have an estimated life expectan
23、cy of 12 weeks or more and adequate organ function(neutrophil count of 1.5109 cells/L,hemoglobin concentrations of 90 g/L,platelet cell count of 100109 cells/L,bilirubin 1.5ULN,blood glutamate transaminase 60 mL/min(calculated using Cockcroft-Gault formula)and left ventricular ejection fraction 50%)
24、.Patients who received previous treat-ment with drugs specifically targeting T-cell costimula-tion or checkpoint pathways and those with previous or concurrent malignancies(except curatively treated skin basal cell carcinoma or cervical carcinoma in situ)were excluded from the study.ProceduresEnroll
25、ed participants received camrelizumab(3 mg/kg,total dose 200 mg,Intravenous drips(ivd),D1/2W)plus gemcitabine(800 mg/m2,ivd,D1/2W)and oxal-iplatin(85 mg/m2,ivd,D2/2W).Chemotherapy lasted for no more than 12 cycles.Once chemotherapy intol-erance occurred or at end of 12 cycles,patients with objective
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