(2.6)--Napoli-1研究亚洲人群消化系统肿瘤.pdf
Cancer Science.2020;111:513527.| Received:2 August 2019|Revised:11 November 2019|Accepted:19 November 2019DOI:10.1111/cas.14264 O R I G I N A L A R T I C L ELiposomal irinotecan in metastatic pancreatic adenocarcinoma in Asian patients:Subgroup analysis of the NAPOLI-1 studyYung-Jue Bang1|Chung-Pin Li2,3|Kyung-Hun Lee4|Chang-Fang Chiu5|Joon Oh Park6|Yan-Shen Shan7|Jun Suk Kim8|Jen-Shi Chen9|Hyun-Jeong Shim10|Kun-Ming Rau11|Hye Jin Choi12|Do-Youn Oh4|Bruce Belanger13|Li-Tzong Chen14,15,161Seoul National University College of Medicine,Seoul,Korea2Division of Gastroenterology and Hepatology,Department of Medicine,Taipei Veterans General Hospital,Taipei,Taiwan3National Yang-Ming University School of Medicine,Taipei,Taiwan4Seoul National University Hospital,Cancer Research Institute,Seoul National University College of Medicine,Seoul,Korea5China Medical University Hospital,Taichung,Taiwan6Samsung Medical Center,Sungkyunkwan University School of Medicine,Seoul,Korea7Department of Surgery,National Cheng Kung University Hospital,Tainan,Taiwan8Korea University Guro Hospital,Seoul,Korea9Department of Hematology-Oncology,Linkou Chang Gung Memorial Hospital and Chang Gung University,Tao-Yuan,Taiwan10Chonnam National University Hwasun Hospital,Gwangju,Korea11Kaohsiung Chang Gung Memorial Hospital,Kaohsiung,Taiwan12Severance Hospital,Yonsei University,Seoul,Korea13Ipsen Bioscience,Inc,Cambridge,Massachusetts,USA14National Institute of Cancer Research,National Health Research Institutes(NHRI),Tainan,Taiwan15Department of Internal Medicine,National Cheng Kung University Hospital,National Cheng Kung University,Tainan,Taiwan16Department of Internal Medicine,Kaohsiung Medical University Hospital,Kaohsiung Medical University,Kaohsiung,TaiwanThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License,which permits use,distribution and reproduction in any medium,provided the original work is properly cited and is not used for commercial purposes.2019 The Authors.Cancer Science published by John Wiley&Sons Australia,Ltd on behalf of Japanese Cancer Association.CorrespondenceLi-Tzong Chen,National Institute of Cancer Research,National Health Research Institutes(NHRI),Tainan,Taiwan.Email:leochennhri.edu.twFunding informationThe NAPOLI-1 study(ClinicalTrials.gov identifier:NCT01494506)was sponsored by Merrimack Pharmaceuticals,Inc.,Cambridge,MA,USA.This post-hoc analysis was sponsored by Shire.Although employees of the sponsor were involved in the design,collection,analysis,interpretation,fact-checking of information,and coordination and collation of comments,the content of this manuscript,the interpretation of the data,and the decision to submit the manuscript for publication in Cancer Science was made by the authors independently.AbstractThe global,randomized NAPOLI-1 phase 3 trial reported a survival benefit with li-posomal irinotecan(nal-IRI)plus 5-fluorouracil/leucovorin(nal-IRI+5-FU/LV)in pa-tients with metastatic pancreatic ductal adenocarcinoma(mPDAC)after previous gemcitabine-based therapy.Median overall survival(OS)with nal-IRI+5-FU/LV was 6.1 vs 4.2 months with 5-FU/LV alone(unstratified hazard ratio HR=0.67,P=.012).Herein,we report efficacy and safety results from a post-hoc subgroup analysis of Asian patients treated at Asian centers.Primary study endpoint was OS;secondary endpoints included progression-free survival(PFS),objective response rate(ORR),and safety.Patients receiving nal-IRI+5-FU/LV(n=34)had significantly longer me-dian OS versus 5-FU/LV(n=35)(8.9 vs 3.7 months;unstratified HR=0.51,P=.025).Patients had significantly increased median PFS with nal-IRI+5-FU/LV versus 5-FU/LV (4.0 vs 1.4;unstratified HR=0.48,P=.011),and increased ORR(8.8%vs 0;P=.114).514|BANG et Al.1|INTRODUCTIONPancreatic cancer continues to have a bleak prognosis,1 with an es-timated 4.6-months median overall survival(OS;all stages from di-agnosis2)and only limited improvement in 5-year and 1-year survival rates.The incidence of pancreatic cancer is projected to rise over the next 10-15 years,and it is predicted to become the second leading cause of cancer-related death in the USA by 2030.3 According to 2018 GLOBOCAN estimates,the age-standardized incidence rate(ASR)for pancreatic cancer in Asia is 3.9/100 000 persons and that of death is 3.6,compared with 7.7 and 7.0 for the USA and Europe combined.4 A recent study including 40 European countries reported estimated ASR of 11.5/100 000 for incidence and 10.9 for death.5Chemotherapy for metastatic pancreatic cancer is guided by pa-tient performance status(PS).Accordingly,in patients with good PS,first-line chemotherapy of metastatic pancreatic adenocarcinoma(mPAC)usually comprises FOLFIRINOX(5-fluorouracil and leucov-orin 5-FU/LV+irinotecan+oxaliplatin)or gemcitabine in combi-nation with nab-paclitaxel.2,6-9 In those with worse PS,treatment may be limited to gemcitabine monotherapy,oral 5-FU agents such as S-1,infusional 5-FU or best supportive care.2,7,8,10 For patients with mPAC that progressed following gemcitabine-based therapy,combination treatment with liposomal irinotecan(nal-IRI)and 5-FU/LV has recently been approved by regulatory agencies in numerous countries.These approvals followed positive results from the global phase 3 NAPOLI-1 trial(NCT01494506).11 In the intention-to-treat(ITT)population,nal-IRI+5-FU/LV combination significantly in-creased median OS versus 5-FU/LV alone(6.1 vs 4.2 months;un-stratified hazard ratio HR=0.67,P=.012).The new formulation of the topoisomerase I inhibitor nal-IRI com-prises irinotecan sucrosofate salt encapsulated in pegylated liposomes.The formulation protects the drug from premature conversion and activation in the liver.As a consequence,circulation in the plasma in patients is extended.12-14 The higher vascular permeability of tumor tissues may promote diffusion of nal-IRI from the circulation,with sub-sequent tumor-associated macrophage uptake and activation of the drug leading to an increase in local SN-38 concentrations.13,15-17 Time over the exposure threshold of the tumors to the active irinotecan me-tabolite,SN-38,has also been shown to increase in preclinical tumor models,and in plasma compared with tumor tissue,thereby increasing preclinical activity at lower levels.12-14In NAPOLI-1,ethnic origin was included as one of the stratifi-cation criteria(Caucasian vs East Asian vs all others).11 Asian pa-tients furthermore represent a large and diverse population with possible differences in pancreatic cancer incidence,mortality,and treatment options among Asian countries as compared with data available for Western populations.1,4,5,18-21 Regional differences in treatment outcomes have been observed in pancreatic cancer,and other diseases(eg,advanced gastric cancer).22-24 Previous work has also indicated differences in drug metabolism affecting the plasma concentration of SN-38 and irinotecan after nal-IRI treatment be-tween patients of East Asian ethnicity and Caucasian ethnicity.14,25 It was reported that Asian patients had a significantly higher mean maximum plasma concentration(Cmax)of unencapsulated SN-38 and a lower Cmax of total irinotecan after dosing with nal-IRI compared with Caucasian patients,which was associated with increased grade 3 or 4 neutropenia and decreased grade 3 or 4 diarrhea in Asian versus Caucasian patients.25 Therefore,we carried out a post-hoc subgroup analysis of the NAPOLI-1 study assessing the efficacy and safety of nal-IRI+5-FU/LV in Asian patients treated at Asian centers,the results of which are presented here.2|METHODS2.1|Study overviewMethodology and design of the NAPOLI-1 study have been described in detail and published elsewhere.11 In summary,NAPOLI-1 was a nal-IRI monotherapy(n=50)numerically improved efficacy endpoints versus 5-FU/LV(n=48):median OS was 5.8 versus 4.3 months(HR=0.83,P=.423)and me-dian PFS was 2.8 versus 1.4 months(HR=0.69,P=.155).Grade 3 neutropenia was reported more frequently with nal-IRI+5-FU/LV versus 5-FU/LV(54.5%vs 3.4%),and incidence of grade 3 diarrhea was comparable between the two arms(3.0%vs 6.9%).This subgroup analysis confirms nal-IRI+5-FU/LV as an efficacious treatment option that improves survival in Asian patients with mPDAC that progressed after gemcitabine-based therapy,with a safety profile agreeing with previous findings.The nal-IRI+5-FU/LV regimen should represent a new standard of care for these patients in Asia.(Clinicaltrials.gov:NCT01494506)K E Y W O R D SAsian subgroup,clinical trial,phase 3,liposomal irinotecan,metastatic pancreatic cancer,NAPOLI-1|515BANG et Al.global,randomized phase 3 trial evaluating the safety and efficacy of nal-IRI+5-FU/LV(80 mg/m2 irinotecan hydrochloride trihydrate salt equivalent to 70 mg/m2 irinotecan free base,followed by 400 mg/m2 LV prior to 2400 mg/m2 5-FU,every 2 weeks)in adult patients with mPAC that had progressed after gemcitabine-based therapy com-pared with 5-FU/LV alone(200 mg/m2 LV before 2000 mg/m2 5-FU weekly for the first 4 weeks of each 6-week chemotherapy cycle).A third arm comprised nal-IRI monotherapy(120 mg/m2 irinotecan hy-drochloride trihydrate salt,equivalent to 100 mg/m2 irinotecan free base every 3 weeks).Although initially designed to compare nal-IRI monotherapy with 5-FU/LV alone,the NAPOLI-1 trial was amended to add the nal-IRI+5-FU/LV arm when safety data on the combination be-came available.26 Patients were randomized 1:1:1.All patients received best supportive care according to local institutional standards as part of their participation in the study.Prophylactic use of granulocyte-colony stimulating factor(G-CSF)was permitted only in patients who experienced 1 episode of grade 3/4 neutropenia or neutropenic fever while on study treatment,or with documented grade 3/4 neutropenia or neutropenic fever while receiving prior antineoplastic therapy.Prior to randomization,patients were stratified by ethnic-ity(Caucasian vs East Asian vs all others),baseline albumin levels(40 g/L vs 1.5 109 cells/L.Patients with active central nervous sys-tem metastasis,clinically significant gastrointestinal disorders and severe arterial thromboembolic events 6 months before enrolment were excluded.2.3|OutcomesPrimary efficacy endpoint of NAPOLI-1 was OS,with secondary end-points including progression-free survival(PFS),time to treatment failure(TTF),and overall response rate(ORR).Safety and tolerability of study regimens were also evaluated.2.4|Statistical analysesData described in this subgroup analysis are based on the NAPOLI-1 trial primary analysis data cut-off date of February 14,2014.Median OS,OS rate at 12 months,and PFS were all estimated using the Kaplan-Meier method.Treatment group comparisons were done for patients receiving the nal-IRI+5-FU/LV combination compared with those receiving 5-FU/LV combination control who were in-cluded after the protocol amendment.Hazard ratios(HR)were de-rived using the Cox proportional hazards model,with treatment as the independent variable.Overall survival comparisons were done using unstratified log-rank tests;PFS and TTF were analyzed using the log-rank method;ORR using Fishers exact test.P-values are de-scriptive and significance is defined at P .05.ORR was defined as the percentage of patients with best overall response(complete re-sponse CR or partial response PR)in the population.Best overall response was graded according to RECIST v1.1 criteria.3|RESULTSOf the 417 patients included in the NAOPLI-1 study,132 patients en-rolled at 13 participating centers in Asia(five in the Republic of Korea and eight in Taiwan)were included in the current post-hoc analysis(Figure 1).These patients were randomly assigned to receive nal-IRI+5-FU/LV(n=34),nal-IRI monotherapy(n=50),or 5-FU/LV(n=48).Of the 48 patients assigned to receive 5-FU/LV,35 enrolled after the pro-tocol amendment adding the nal-IRI+5-FU/LV combination arm,and served as comparator for the combination treatment arm.This analysis focuses on comparison of the nal-IRI+5-FU/LV combination with 5-FU/LV control(enrolled after the proto-col amendment)in patients from the Asia region.In the NAPOLI-1 study,nal-IRI monotherapy showed clinical activity versus 5-FU/LV:ORR was 6.0%versus 0.7%(P=.020),and median PFS was 2.7 versus 1.6 months(HR=0.81,P=.100).Although median OS was 4.9 months with nal-IRI monotherapy versus 4.2 months with 5-FU/LV(HR=0.99;P=.942),this did not reach statistical significance.Therefore,data for nal-IRI monotherapy are included in the present analysis for completeness(Tables 1-5 and Figure 2).3.1|Patient baseline characteristics and demographicsPatient demographics and baseline clinical characteristics were generally balanced across the nal-IRI+5-FU/LV and 5-FU/LV treat-ment arms(Table 1).Some differences between the Asia region compared with the overall ITT population became apparent:all pa-tients treated at Asian centers were of Asian ethnicity compared 516|BANG et Al.with approximately one-third in the overall population.A higher proportion of Asian patients had a baseline KPS of 90-100 versus the overall population for nal-IRI+5-FU/LV and 5-FU/LV,respec-tively,and fewer Asian patients in the nal-IRI+5-FU/LV arm had stage IV disease at initial diagnosis compared to the overall popu-lation(Table 1).In the nal-IRI+5-FU/LV and 5-FU/LV arms,fewer Asian patients had received 2 lines of prior metastatic therapy compared with the overall population.Correspondingly,the pro-portion of patients who received one line of prior metastatic ther-apy was increased among Asian patients(Table 1).Only a single Asian patient in the nal-IRI+5-FU/LV arm was homozygous for the UGT1A1*28 genotype(Table 1).Fewer Asian patients had previ-ously received gemcitabine monotherapy,whereas gemcitabine-containing combinations had been used more frequently compared with the overall population.A minority of Asian patients had pre-viously received treatment containing non-liposomal irinotecan.A greater proportion of patients in the present analysis received post-study anticancer therapy compared with the overall popula-tion,with fluorouracil-containing therapies being the most com-monly used in both populations(Table 1).3.2|Efficacy3.2.1|Overall survivalAsian patients who received nal-IRI+5-FU/LV experienced a longer median OS(8.9 months 95%confidence interval(CI):4.4-10.4)compared with those who received 5-FU/LV(3.7 months 2.7-6.4)(unstratified HR=0.51,P=.025)(Table 2,Figure 2A).Median OS in patients who received nal-IRI monotherapy was 5.8 months(4.8-7.4)versus 4.3 months(3.1-5.7)with 5-FU/LV alone(unstrati-fied HR=0.83,P=.423)(Figure 2B).Six-month OS rate of patients in the nal-IRI+5-FU/LV arm was 62%(95%CI:0.4-0.8)versus 34%FIGURE 1CONSORT diagram explaining the patient population included in this subgroup analysis(ITT population).5-FU,5-fluorouracil;LV,leucovorin(folinic acid);nal-IRI,liposomal irinotecan;ITT,intention-to-treat|517BANG et Al.TABLE 1Baseline demographics and clinical characteristics
