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1、 Published online March 20,2020 https:/doi.org/10.1016/S1470-2045(20)30109-1 1ArticlesPemigatinib for previously treated,locally advanced or metastatic cholangiocarcinoma:a multicentre,open-label,phase 2 studyGhassan K Abou-Alfa,Vaibhav Sahai,Antoine Hollebecque,Gina Vaccaro,Davide Melisi,Raed Al-Ra

2、jabi,Andrew S Paulson,Mitesh J Borad,David Gallinson,Adrian G Murphy,Do-Youn Oh,Efrat Dotan,Daniel V Catenacci,Eric Van Cutsem,Tao Ji,Christine F Lihou,Huiling Zhen,Luis Fliz,Arndt VogelSummaryBackground Fibroblast growth factor receptor(FGFR)2 gene alterations are involved in the pathogenesis of ch

3、olangiocarcinoma.Pemigatinib is a selective,potent,oral inhibitor of FGFR1,2,and 3.This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated,locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements.Methods In

4、this multicentre,open-label,single-arm,multicohort,phase 2 study(FIGHT-202),patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group(ECOG)performance status of 02 recruited from 146 academic or community-based sites

5、in the USA,Europe,the Middle East,and Asia were assigned to one of three cohorts:patients with FGFR2 fusions or rearrangements,patients with other FGF/FGFR alterations,or patients with no FGF/FGFR alterations.All enrolled patients received a starting dose of 135 mg oral pemigatinib once daily(21-day

6、 cycle;2 weeks on,1 week off)until disease progression,unacceptable toxicity,withdrawal of consent,or physician decision.The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements,assessed centrally in all patients who rece

7、ived at least one dose of pemigatinib.This study is registered with ClinicalTrials.gov,NCT02924376,and enrolment is completed.Findings Between Jan 17,2017,and March 22,2019,146 patients were enrolled:107 with FGFR2 fusions or rearrangements,20 with other FGF/FGFR alterations,18 with no FGF/FGFR alte

8、rations,and one with an undetermined FGF/FGFR alteration.The median follow-up was 178 months(IQR 116213).38(355%95%CI 265454)patients with FGFR2 fusions or rearrangements achieved an objective response(three complete responses and 35 partial responses).Overall,hyperphosphataemia was the most common

9、all-grade adverse event irrespective of cause(88 60%of 146 patients).93(64%)patients had a grade 3 or worse adverse event(irrespective of cause);the most frequent were hypophosphataemia(18 12%),arthralgia(nine 6%),stomatitis(eight 5%),hyponatraemia(eight 5%),abdominal pain(seven 5%),and fatigue(seve

10、n 5%).65(45%)patients had serious adverse events;the most frequent were abdominal pain(seven 5%),pyrexia(seven 5%),cholangitis(five 3%),and pleural effusion(five 3%).Overall,71(49%)patients died during the study,most frequently because of disease progression(61 42%);no deaths were deemed to be treat

11、ment related.Interpretation These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements.Funding Incyte Corporation.Copyright 2020 Elsevier Ltd.All rights reserved.IntroductionCholangiocarcinomas are a gro

12、up of heterogeneous tumours classified as intrahepatic or extrahepatic(perihilar and distal)based on the tumour location in the biliary tract.1 Comprehensive genomic profiling has identified several potentially actionable oncogenic alterations in patients with cholangiocarcinoma,2 including in genes

13、 encoding fibroblast growth factor receptor(FGFR).Somatic alterations in FGFR can lead to aberrant FGFR signalling,which can drive tumor igenesis by enhancing cellular proliferation,migration,survival,and invasion,as well as angiogenesis.3 FGFR2 fusions and rearrangements are found almost exclusivel

14、y in intrahepatic cholangio carcinoma,occurring in 1016%of patients.46 Consequently,in addition to other targeted agents,FGFR inhibitors are garnering interest as potential therapeutics for cholangiocarcinoma.7Surgery is currently the only curative treatment for cholangiocarcinoma;however,surgery is

15、 an option for only around 35%of patients8 and,of those who undergo potentially curative resection,approximately 35%subsequently relapse within 2 years.9 The standardofcare Lancet Oncol 2020Published Online March 20,2020 https:/doi.org/10.1016/S1470-2045(20)30109-1See Online/Comment https:/doi.org/1

16、0.1016/S1470-2045(20)30152-2Department of Medicine,Memorial Sloan Kettering Cancer Center,New York,NY,USA(Prof G K Abou-Alfa MD);Weill Medical College,Cornell University,New York,NY,USA(Prof G K Abou-Alfa);Rogel Cancer Center,University of Michigan,Ann Arbor,MI,USA(V Sahai MBBS);Gustave Roussy,Ville

17、juif,France(A Hollebecque MD);Providence Cancer Center Oncology and Hematology Care Clinic,Portland,OR,USA(G Vaccaro MD);Digestive Molecular Clinical Oncology Unit,University of Verona,Verona,Italy(D Melisi MD);University of Kansas Cancer Center,Kansas City,KS,USA(R Al-Rajabi,MD);Baylor Charles A Sa

18、mmons Cancer Center,Baylor University Medical Center,Dallas,TX,USA(A S Paulson MD);Mayo Clinic Cancer Center,Phoenix,AZ,USA(M J Borad MD);Morristown Memorial Hospital,Carol Cancer Center,Morristown,NJ,USA(D Gallinson DO);Sidney Kimmel Comprehensive Cancer Center,Johns Hopkins University School of Me

19、dicine,Baltimore,MD,USA(A G Murphy,MD);Cancer Research Institute,Seoul National University College of Medicine,Seoul National University Hospital,Seoul,South Korea(Prof D-Y Oh MD);Fox Chase Cancer Center,Philadelphia,PA,USA(E Dotan MD);University of Chicago Medicine,Chicago,IL,USA(D V Catenacci MD);

20、University HospitalsArticles2 Published online March 20,2020 https:/doi.org/10.1016/S1470-2045(20)30109-1Gasthuisberg,Leuven,Belgium(Prof E Van Cutsem MD);Clinical Digestive Oncology,KU Leuven,Leuven,Belgium(Prof E Van Cutsem);Incyte Corporation,Wilmington,DE,USA(T Ji PhD,C F Lihou BS,H Zhen PhD,L F

21、liz MD);and Hannover Medical School,Hannover,Germany(Prof A Vogel MD)Correspondence to:Prof Ghassan K Abou-Alfa,Department of Medicine,Memorial Sloan Kettering Cancer Center,New York,NY 10065,USA abou-algmskcc.orgfirstline treatment for locally advanced or metastatic cholangiocarcinoma is gemcitabin

22、e plus cisplatin.10 There is no established standardofcare after failure of firstline chemotherapy,and the efficacy of secondline chemo therapy regimens for advanced biliary cancer remains low.1113Pemigatinib is a selective,potent,oral competitive inhibitor of FGFR1,FGFR2,and FGFR3.14 We report the

23、final results from the multicentre,openlabel phase 2 FIbroblast Growth factor receptor inhibitor in oncology and Hematology Trial(FIGHT202),evaluating the safety and antitumour activity of pemigatinib in previously treated patients with locally advanced or metastatic cholangio carcinoma,with or with

24、out FGF/FGFR alterations.MethodsStudy design and participantsThis openlabel,singlearm phase 2 trial was done at 146 academic or communitybased sites in the USA,Europe,the Middle East,and Asia(appendix pp 24).Patients were identified during routine clinical practice.Eligible patients were aged 18 yea

25、rs or older,had a histological or cytological diagnosis of locally advanced or metastatic cholangiocarcinoma with documented disease progression following at least one previous systemic cancer therapy(previous treatment with selective FGFR inhibitors was not permitted),radiologically measurable dise

26、ase according to Response Evaluation Criteria in Solid Tumors version 1.1(RECIST 1.1),Eastern Cooperative Oncology Group(ECOG)performance status of 2 or less,life expectancy of at least 12 weeks,and previously treated and clinically stable brain or CNS metastases without corticosteroids for at least

27、 4 weeks(corticosteroids were otherwise allowed without restriction).Patients were also required to have adequate hepatic and renal function(total bilirubin 30 mL/min calculated with the CockcroftGault formula),serum phosphate less than or equal to the Research in contextEvidence before this studyTh

28、e incidence of intrahepatic cholangiocarcinoma has steadily increased worldwide over the past several decades,as have annual age-adjusted mortality rates.The standard-of-care first-line treatment for locally advanced or metastatic cholangiocarcinoma is gemcitabine plus cisplatin.However,treatment op

29、tions are limited in the second-line setting.Several potentially actionable oncogenic alterations have been identified in patients with cholangiocarcinoma,including alterations in the fibroblast growth factor receptor(FGFR)gene.We searched PubMed and the American Society of Clinical Oncology and Eur

30、opean Society for Medical Oncology abstract databases for manuscripts and abstracts published from database inception to Nov 14,2019,without language restrictions.The search terms used were(“cholangiocarcinoma”OR“biliary tract cancer”)AND(“fibroblast growth factor receptor”OR“FGFR”).We identified 67

31、 publications supporting a role for FGFR inhibitors in the treatment of intrahepatic cholangiocarcinoma,and for clinical trials in molecularly selected patient populations.Preclinical studies show that pemigatinib is a selective,potent,oral competitive inhibitor of FGFR1,FGFR2,and FGFR3.There are cu

32、rrently no published clinical studies of pemigatinib in this patient population.Added value of this studyThe FIbroblast Growth factor receptor inhibitor in oncology and Hematology Trial(FIGHT-202)is an international,open-label phase 2 trial evaluating the safety and antitumour activity of pemigatini

33、b in 146 previously treated patients with locally advanced or metastatic cholangiocarcinoma.Among 107 patients with FGFR2 fusions or rearrangements,38(36%)achieved an objective response.This encouraging antitumour activity was observed across demographic and disease subgroups,including in heavily pr

34、etreated patients.The most common all-cause adverse event was hyperphosphataemia.Notable aspects of this study include incorporation of FGFR2 fusion partner-agnostic next-generation sequencing(ability to detect both known and novel FGFR2 fusions),and an independent central review of clinical respons

35、es.Moreover,the international design facilitated the enrolment of a large number of patients with cholangiocarcinoma with FGF/FGFR alterations(mostly FGFR2 rearrangements),despite this being a relatively rare cancer and a rare genomic alteration.This achievement provides impetus for future clinical

36、trials in cholangiocarcinoma and in other rare cancers,for which achieving sufficient patient enrolment numbers can be challenging.Taken together,the data from this study add to a growing body of evidence supporting a role for FGFR inhibitors and other targeted agents for the treatment of cholangioc

37、arcinoma by demonstrating that pemigatinib possesses antitumour activity and is associated with a manageable safety profile in patients with FGFR2 fusions or rearrangements.Implications of all the available evidenceBased on the encouraging findings from this study,an international,phase 3,randomised

38、,active-controlled trial is currently recruiting patients to compare pemigatinib with gemcitabine plus cisplatin chemotherapy as first-line therapy for unresectable or metastatic cholangiocarcinoma with FGFR2 rearrangements(FIGHT-302;ClinicalTrials.gov,NCT03656536).Pemigatinib could add to the range

39、 of treatments available to patients with cholangiocarcinoma and FGFR2 fusions or rearrangements,for whom current systemic therapies are not sufficiently effective.See Online for appendixA Published online March 20,2020 https:/doi.org/10.1016/S1470-2045(20)30109-1 3institutional ULN,and serum calciu

40、m within the institutional normal range.Eligible patients had no history of HIV infection,did not have active hepatitis B or C virus infection,did not have an abnormal echocardiogram or uncontrolled cardiac disease,had no history or current evidence of ectopic mineralisation or calcification,and had

41、 no clinically significant corneal or retinal disorders confirmed by ophthalmological examination.The protocol(appendix p 26)was approved by each institutional review board or independent ethics committee;the trial was performed in accordance with the Declaration of Helsinki.Patients gave written,in

42、formed consent for inclusion in the study.ProceduresBefore assessment for eligibility,patients were pre screened centrally for FGF/FGFR status using massively parallel DNA sequencing(FoundationOne,Foundation Medicine,Cambridge,MA,USA;appendix p 4).15 Patients who already had an FGF/FGFR status repor

43、t based on local assessment(Clinical Laboratory Improvement Amendments CLIAcertified)or an existing FoundationOne report were also included.Retrospective central confirmation of locally documented FGF/FGFR status with FoundationOne was required for cohort assignment.Based on the centrally confirmed

44、results,patients were assigned to one of three cohorts:patients with FGFR2 fusions or rearrangements,patients with other FGF/FGFR alterations,or patients with no FGF/FGFR alterations.All patients selfadministered oral pemigatinib at a starting dose of 135 mg once daily(21day cycle;2 weeks on,1 week

45、off),irrespective of cohort assignment,until radiological disease progression,unacceptable toxicity,withdrawal of consent,or physician choice.This dose regimen was supported by pharmacokinetic and pharmacodynamic results from a phase 1/2 study of pemigatinib for advanced malignancies.16 Pemigatinib

46、dosing could be interrupted for up to 14 days to allow for resolution of toxicities(appendix p 7).Hyper phosphataemia,an expected ontarget pharmacological effect of FGFR inhibition,was managed using dietary modifications,phosphatelowering therapy,or dose modifications(appendix p 4).Tumour response w

47、as assessed by independent review according to RECIST 1.1.Disease was assessed by CT(or MRI,according to the investigators discretion)every 6 weeks for the first 12 weeks,and every 9 weeks thereafter,until disease progression or discontinuation for any reason other than disease progression.Safety wa

48、s assessed based on National Cancer Institute Common Terminology Criteria for Adverse Events(CTCAE)version 4.03,17 vital signs,12lead electrocardiograms,and clinical laboratory tests including mean serum phosphate levels.Mean 1,25dihydroxyvitamin D3(1,25OH2D3)and parathyroid hormone levels were also

49、 determined as they are central in phosphate homoeostasis.18 Safety was assessed at screening,during treatment(day 1,8,and 15 of cycle 1,and day 1 of subsequent cycles),at the end of treatment,and during followup(30 days after discontinuation of treatment).OutcomesThe primary endpoint was the propor

50、tion of patients with FGFR2 fusions or rearrangements who achieved an objective response(best overall response of confirmed complete response or confirmed partial response),assessed by independent central review.Secondary endpoints were the proportion of patients with an objective response in patien