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1、 Vol 4 August 2019 611ArticlesNivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer:a non-randomised,multicentre,open-label,phase 1 studyMakoto Ueno,Masafumi Ikeda,Chigusa Morizane,Satoshi Kobayashi,Izumi Ohno,Shuns

2、uke Kondo,Naohiro Okano,Keisuke Kimura,Suguru Asada,Yoshinobu Namba,Takuji Okusaka,Junji FuruseSummaryBackground This study aimed to assess the safety and tolerability of the immune checkpoint inhibitor nivolumab,as monotherapy or combined with chemotherapy,in Japanese patients with biliary tract ca

3、ncer.Methods This multicentre,open-label,phase 1 trial was done at four cancer centres in Japan.Eligible patients were aged 2079 years,had biliary tract adenocarcinoma(intrahepatic bile duct cancer,extrahepatic bile duct cancer,gallbladder cancer,or ampullary cancer),Eastern Cooperative Oncology Gro

4、up performance status 0 or 1,adequate hepatic,renal,and haematological function,and tumour tissue samples for PD-L1 expression analysis.Patients with unresectable or recurrent biliary tract cancer that was refractory or intolerant to gemcitabine-based treatment regimens received nivolumab monotherap

5、y(240 mg every 2 weeks monotherapy cohort).Chemotherapy-naive patients with unresectable or recurrent biliary tract cancer received nivolumab(240 mg every 2 weeks)and cisplatin(25 mg/m)plus gemcitabine(1000 mg/m)chemotherapy(combined therapy cohort).The primary objective was to assess tolerability a

6、nd safety.The primary objective was assessed in the safety population of all patients who had received at least one dose of nivolumab.This study is registered with www.clinicaltrials.jp,number JapicCTI-153098,and follow-up is ongoing.Findings 30 patients were enrolled into each cohort between Jan 13

7、,2016,and April 19,2017.Data cutoff was Aug 31,2017.In the monotherapy cohort,the most frequently reported treatment-related adverse events were decreased appetite(five 17%),malaise(four 13%),and pruritus(four 13%).Grade 34 treatment-related adverse events were reported by three(10%)patients(rash,ma

8、culopapular rash,and amylase increase)and treatment-related serious adverse events were reported by one(3%)patient(pleurisy).In the combined therapy cohort,the most frequently reported treatment-related adverse events were neutrophil count decrease(any grade 25 83%;grade 34 in 23 77%patients)and pla

9、telet count decrease(any grade 25 83%of 30;grade 34 in 15 50%patients).Six(20%)patients reported 11 treatment-related serious adverse events(platelet count decrease three patients,febrile neutropenia two patients,neutrophil count decrease,anaemia,anaphylactic reaction,decreased appetite,pyrexia,and

10、myocarditis one patient each).In the monotherapy cohort,median overall survival was 52 months(90%CI 4587),median progression-free survival was 14 months(90%CI 1414),and one of 30 patients had an objective response.In the combined therapy cohort,median overall survival was 154 months(90%CI 118not est

11、imable),median progression-free survival was 42 months(90%CI 2856),and 11 of 30 patients had an objective response.Interpretation Nivolumab had a manageable safety profile and signs of clinical activity in patients with unresectable or recurrent biliary tract cancer.This initial assessment of nivolu

12、mab for the treatment of advanced biliary tract cancer provides supportive evidence for future larger randomised studies of nivolumab in this difficult to treat cancer.Funding Ono Pharmaceutical Co Ltd and Bristol-Myers Squibb Inc.Copyright 2019 Elsevier Ltd.All rights reserved.Lancet Gastroenterol

13、Hepatol 2019;4:61121Published Online May 17,2019 http:/dx.doi.org/10.1016/S2468-1253(19)30086-XSee Comment page 575Department of Gastroenterology,Hepatobiliary and Pancreatic Medical Oncology Division,Kanagawa Cancer Center,Yokohama,Kanagawa,Japan(M Ueno MD,S Kobayashi MD);Department of Hepatobiliar

14、y and Pancreatic Oncology,National Cancer Center Hospital East,Kashiwa,Chiba,Japan(M Ikeda MD,I Ohno MD);Hepatobiliary and Pancreatic Oncology Division,National Cancer Center Hospital,Chuo-ku,Tokyo,Japan(C Morizane MD,S Kondo MD,T Okusaka MD);Department of Medical Oncology,Kyorin University Faculty

15、of Medicine,Mitaka,Tokyo,Japan(N Okano MD,Prof J Furuse MD);and Ono Pharmaceutical Co,Ltd,Chuo-ku,Osaka,Japan(K Kimura MSc,S Asada MHSc,Y Namba MD)Correspondence to:Dr Makoto Ueno,Department of Gastroenterology,Hepatobiliary and Pancreatic Medical Oncology Division,Kanagawa Cancer Center,Yokohama,Ka

16、nagawa 2418515,Japan uenomkcch.jpIntroductionBiliary tract cancer is a heterogeneous group of cancers including intrahepatic bile duct cancer,extrahepatic bile duct cancer,gallbladder cancer,and ampullary cancer.1 Incidence of biliary tract cancer varies worldwide,with high incidences in east Asia,i

17、ncluding Japan,and Latin America.2 In Japan in 2013,22 102 cases of biliary tract cancer were diagnosed3 and 18 225 deaths were attributed to the disease.4 5-year survival is generally poor.5 Treatment of biliary tract cancer is challenging because complete surgical resection is not feasible in most

18、 patients and recurrence is common.1,6 Furthermore,treatment options for patients with unresectable disease are scarce.1 Combination chemotherapy with cisplatin plus gemcitabine was the first regimen to show a survival benefit in a randomised phase 3 study(ABC-02)7 in Articles612 Vol 4 August 2019pa

19、tients with advanced biliary tract cancer,leading to this regimen becoming a standard of care.8 However,the benefit of traditional chemotherapy seems to have reached a limit and,therefore,new effective treatment options for biliary tract cancer,with different mechanisms of action,are needed.1 Additi

20、onally,no established second-line treatment regimen is available for patients with biliary tract cancer.8,9PD-1 is an immune checkpoint receptor expressed by activated T cells.10 The PD-1 ligands,PD-L1 and PD-L2,are expressed by tumour cells and tumour-infiltrating immune cells.10 Binding of PD-L1 o

21、r PD-L2 to PD-1 inhibits T-cell activation,which promotes immune tolerance,allowing tumour cells to proliferate undetected by immuno surveillance.10 Nivolumab is a human monoclonal antibody against PD-1 that inhibits binding of PD-L1 and PD-L2 to PD-1 and therefore enhances the immune response to tu

22、mours.11 Nivolumab has been shown to have antitumour activity in a wide range of tumours,including metastatic melanoma,squamous non-small-cell lung cancer,and renal cell carcinoma.11 Studies of PD-L1 expression have reported PD-L1 positivity in tumour cells and tumour-infiltrating immune cells in di

23、fferent types of biliary tract cancer,1214 suggesting that biliary tract cancer is potentially responsive to PD-1 or PD-L1 blockade therapy.This phase 1 study provides an initial assessment of nivolumab as first-line treatment(in combination with chemotherapy)or as second-line or later treatment(as

24、monotherapy)in Japanese patients with advanced biliary tract cancer.MethodsStudy designThis was a multicentre,open-label,phase 1 trial done at four cancer centres in Japan.We assessed two cohorts:a nivolumab monotherapy cohort of patients with unresectable or recurrent biliary tract cancer refractor

25、y or intolerant to gemcitabine-based treatment regimens and a nivolumab with cisplatin plus gemcitabine combination therapy cohort of patients with unresectable or recurrent biliary tract cancer who have not previously had chemotherapy.The study protocol was approved by each sites ethics review boar

26、d and the study was done in accordance with the principles of the Declaration of Helsinki,the Guideline for Good Clinical Practice,and applicable local regulations.PatientsPatients with unresectable or recurrent biliary tract cancer that was refractory or intolerant to gemcitabine-based treatment re

27、gimens were eligible for the monotherapy cohort.Patients with unresectable or recurrent biliary tract cancer who had not previously received chemo-therapy were eligible for the combination therapy cohort;previous adjuvant therapy was not permitted.The main inclusion criteria for both cohorts were as

28、 follows:histologically or cytologically confirmed biliary tract Research in contextEvidence before this studyWe searched PubMed and American Society of Clinical Oncology(ASCO)and European Society for Medical Oncology(ESMO)conference abstracts with combinations of the search terms“biliary tract canc

29、er”,“nivolumab”,“pembrolizumab”,and“immunotherapy”,with no publication date or language restrictions.We found few clinical trials of immunotherapy in patients with advanced biliary tract cancer.Nivolumab was reported to be well tolerated with promising efficacy in a phase 2 study of previously treat

30、ed patients with advanced biliary tract cancer.The anti-PD-1 antibody pembrolizumab was also reported to have manageable toxicity,and durable antitumour activity in a subset of patients in the biliary tract cancer cohort of the KEYNOTE-158 and KEYNOTE-028 studies(KEYNOTE-028 was done in patients wit

31、h PD-L1 expression in 1%of tumour cells or tumour-infiltrating lymphocytes).The randomised phase 3 ABC-02 study established combination chemotherapy with cisplatin plus gemcitabine as a standard of care for first-line treatment of unresectable or recurrent biliary tract cancer.However,no established

32、 second-line treatment is available.Added value of this studyIn this study,we assessed the safety and efficacy of nivolumab monotherapy in treated patients and,for the first time to the best of our knowledge,nivolumab in combination with chemotherapy in chemotherapy-naive patients.Nivolumab was well

33、 tolerated and had a manageable safety profile when given as monotherapy in previously treated patients with advanced biliary tract cancer and when combined with cisplatin plus gemcitabine chemotherapy in chemotherapy-naive patients.Implications of all the available evidenceThis initial assessment o

34、f nivolumab in the treatment of unresectable or recurrent biliary tract cancer,which demonstrated a manageable safety profile and signs of antitumour activity,provides the basis for larger,randomised studies in this difficult-to-treat cancer.The finding that PD-L1 expression status might be associat

35、ed with longer overall survival suggests that it might be possible to identify patients with advanced biliary tract cancer who would benefit from nivolumab treatment.However,further investigation is required,including whether PD-L1 expression is associated with response to nivolumab when it is given

36、 in combination with chemotherapy.Biomarker analyses should be included in future studies to help establish the role of nivolumab in the first-line and second-line settings.A Vol 4 August 2019 613adenocarcinoma(intrahepatic bile duct cancer,extra-hepatic bile duct cancer,gallbladder cancer,and ampul

37、lary cancer);age 2079 years;at least one measurable lesion as defined in the Response Evaluation Criteria in Solid Tumors(RECIST),version 1.1;Eastern Cooperative Oncology Group(ECOG)performance status of 0 or 1;life expectancy of at least 90 days;adequate hepatic(aspartate aminotransferase and alani

38、ne amino-transferase 150 international units(IU)per L for patients who had had biliary drainage or 100 IU/L for those who had not;total bilirubin 30 mg/dL for patients who had had biliary drainage or 20 mg/dL for those who had not),renal(creatinine 15 mg/dL for the monotherapy cohort or 12 mg/dL for

39、 the combination therapy cohort or creatinine clearance measured value or estimated value using the Cockcroft-Gault equation 45 mL/min for the monotherapy cohort or 50 mL/min for the combination therapy cohort),haematological(neutrophils 1500 cells per L,haemoglobin 90 g/dL),and coagulation(platelet

40、s 100 000 per L)function;and tumour tissue samples for analysis of PD-L1 expression and microsatellite instability status.The main exclusion criteria for the two cohorts were as follows:previous receipt of nivolumab or antibodies against PD-1,PD-L1,PD-L2,CD137,or CTLA-4,or any other therapeutic anti

41、bodies or pharmacotherapies for regulation of T cells;receiving systemic corticosteroids or immunosuppressants in the 28 days before enrolment;concurrent autoimmune disease or a history of chronic or recurrent autoimmune disease;pleurodesis or pericardial adhesion in the 28 days before enrolment;pos

42、itive test results for HIV antibody,human T-cell leukaemia virus type 1 antibody,hepatitis C virus antibody,hepatitis B surface protein antigen,hepatitis B surface protein antibody,hepatitis B core protein antibody,or any detectable hepatitis B virus DNA;multiple primary cancers(except completely re

43、sected basal cell carcinoma,stage I squamous cell carcinoma,carcinoma in situ,intramucosal carcinoma,and superficial bladder cancer,and any other cancers that have not recurred for at least 5 years);brain or meningeal metastases(unless asymptomatic and requiring no treatment);and uncontrollable or s

44、ignificant cardio vascular disease(appendix).All patients provided written informed consent before enrolling in the study.ProceduresIn both the monotherapy and combined therapy cohorts,nivolumab 240 mg was administered intravenously over 30 min every 2 weeks,with a minimum interval of 10 days betwee

45、n doses.Treatment continued until complete response or progressive disease,unacceptable toxicity,or investigator decision.Dose reduction of nivolumab was not permitted.Patients in the combination therapy cohort also received cisplatin 25 mg/m administered intravenously over 60 min followed by gemcit

46、abine 1000 mg/m administered intravenously over 30 min.Patients received cisplatin and gemcitabine on day 1 and day 8 of a 3-week cycle(or day 1 of a 2-week cycle if the patient was not able to receive cisplatin plus gemcitabine on day 8 for two consecutive cycles).Cisplatin was given up to 16 times

47、(400 mg/m in total);after the last dose of cisplatin,cisplatin plus gemcitabine therapy was stopped and gemcitabine monotherapy(1000 mg/m)was started.The dose of gemcitabine was reduced from 1000 mg/m to 800 mg/m in patients who had any of the following events,for which a causal relationship to gemc

48、itabine could not be ruled out:grade 4 or worse neutrophil count decrease;grade 4 or worse platelet count decrease or grade 3 requiring blood transfusion;grade 3 or worse febrile neutropenia;grade 3 or worse infection;grade 3 or worse rash;other grade 3 or worse non-haematological toxicity;or if the

49、 dose reduction of gemcitabine was clinically justified in the investigators or subinvestigators opinion.The dose of gemcitabine was reduced from 800 mg/m to 600 mg/m in patients who had a second of these events.An increase in the dose of gemcitabine was not permitted after it had been reduced.Dose

50、reduction of cisplatin was not permitted.During the screening period,tumour tissue samples for analysis of PD-L1 expression and microsatellite instability were collected from patients in whom a biopsy could be safely done;preserved samples were used for patients who were unable to undergo biopsy.Tum