1、JOURNAL OFCLINICALONCOLOGYO N C O L O G YG R A N DR O U N D SBlocking the Cycle:Cyclin-Dependent Kinase 4/6Inhibitors in Metastatic,Hormone ReceptorPositiveBreast CancerSeth A.Wander,Erica L.Mayer,and Harold J.Burstein,Dana-Farber Cancer Institute;Brigham&Womens Hospital;HarvardMedical School,Boston
2、,MASee accompanying article on page 2875The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context.Acasepresentationisfollowedbyadescriptionofdiagnosticandmanagementchallenges,areviewoftherelevantliterature,andasummaryoftheauthorssuggestedma
3、nagementapproaches.Thegoalofthisseriesistohelpreadersbetterunderstandhowtoapplytheresultsofkeystudies,including those published in Journal of Clinical Oncology,to patients seen in their own clinical practice.A 68-year-old postmenopausal woman was diagnosed with breast cancer 6 years ago when she pre
4、sentedwith a stage II(T2N1),right-sided,invasive ductal carcinoma considered grade 2 of 3 on core biopsy,with a positive fine-needle aspiration of a palpable,ipsilateral axillary lymph node.Immunohisto-chemical analysis was positive for estrogen and progesterone receptor expression and negative forh
5、uman epidermal growth factor receptor 2(HER2)overexpression.She received neoadjuvant dose-dense doxorubicin,cyclophosphamide,and paclitaxel chemotherapy,followed by breast-conservingsurgery and axillary lymph node dissection,which revealed residual disease in three of 11 nodes.Shereceived adjuvant r
6、adiation therapy and initiated letrozole,with excellent compliance during the in-terval 6-year period.While receiving adjuvant letrozole therapy,she reported 3 months of worseningback pain.Skeletal scintigraphy and cross-sectional imaging confirmed widespread osseous metastaticdisease and right supr
7、aclavicular lymph node enlargement(Fig 1).Core biopsy of the involved lymphnode confirmed estrogen receptor(ER)positive(90%),progesterone receptornegative,HER2-negative recurrent metastatic breast cancer.The patient reported mild pain that was adequately con-trolled with over-the-counter anti-inflam
8、matory medications.She has remained active with an excellentperformance status.CHALLENGES IN DIAGNOSIS AND MANAGEMENTThe selective ER degrader(SERD),fulvestrant,which wasUS Food and Drug Administration(FDA)approved fortreatment of advanced breast cancer in 2002,has been thestandard of care for postm
9、enopausal women with hormonereceptor(HR)positive,HER2-negative metastatic breastcancer that developed while receiving adjuvant aromataseinhibitor(AI)therapy or after first-line endocrine therapywith an AI.Recently,a trio of new kinase inhibitors that targetcyclin-dependent kinases 4 and 6(CDK4/6)hav
10、e ushered ina new class of drugs for oncology and new treatment para-digmsinHR-positive,HER2-negativemetastaticbreastcancer.The recent emergence of the CDK4/6 inhibitor class oftherapy has prompted important questions about how best to addthese agents to standard endocrine therapies,how to manage th
11、especific adverse effects of CDK4/6 inhibitors,whether thereare specific biomarkers that could inform patient selection fortreatment,and whether these agents provide important value incancer care.SUMMARY OF THE RELEVANT LITERATUREIn ER-positive breast cancer,estrogen drives production of cyclin D1,w
12、hich binds to and activates CDK4/6.1These active cyclinCDKcomplexes phosphorylate the retinoblastoma(Rb)tumor suppressor,thereby releasing the critical eukaryotic transcriptional activator,E2 factor.2E2 factor is responsible for driving the transcription ofmultiplegenesthatareinvolvedintheG1-Scell-c
13、ycletransitionpoint,a key checkpoint in promoting cellular proliferation.Preclinical workin both cell lines and xenograft models of ER-positive breastcancer revealed potential synergy when CDK4/6 inhibitorswere combined with antiestrogen therapy.3,4CDK4/6 inhibitorsalso seem to have preferential act
14、ivity in ER-positive luminal breastcancercell lines and in a subset of HER2-positive cell lines,but hadlimited efficacy in triple-negative,nonluminal cells.32866 2017 by American Society of Clinical OncologyJournal of Clinical Oncology,Vol 35,No 25(September 1),2017:pp 2866-2870VOLUME35NUMBER25SEPTE
15、MBER1,2017Downloaded from ascopubs.org by 180.175.88.35 on December 18,2018 from 180.175.088.035Copyright 2018 American Society of Clinical Oncology.All rights reserved.First-Line Metastatic SettingThese preclinical observations set the stage for the rationaldevelopment of CDK4/6 inhibitors as thera
16、pies for ER-positivemetastatic breast cancer.Three CDK4/6 inhibitorspalbociclib(Ibrance;Pfizer,New York,New York),ribociclib(Kisqali;Novartis,Basel,Switzerland),and abemaciclib(Lilly,Indianapolis,Indiana)have undergone extensive clinical exploration along nearly identicaldevelopment pathways.Each ha
17、s been evaluated in randomizedclinicaltrialsaseitherfirst-orsecond-linetreatmentsincombinationwith standard endocrine therapy for postmenopausal women withER-positive,HER2-negative metastatic breast cancer,with a primaryend point of progression-free survival(PFS;Table 1).Palbociclib wasinitially exp
18、lored in a randomized,phase II,open-label study,PALOMA-1,5in which 165 patients were randomly assigned to re-ceive letrozole alone or in combination with palbociclib as first-linetherapy.Patients could have received prior adjuvant AI;however,discontinuation must have occurred at least 1 year before
19、enroll-ment.The PALOMA-1 study demonstrated a significant im-provement in PFS favoring combination therapy(20.2 months v10.2 months;hazard ratio,0.488).On the basis of these results,the US FDAgrantedpalbociclibaccelerated approvalinearly2015as initial therapy for postmenopausal women with HR-positiv
20、e,HER2-negative advanced breast cancer in combination withletrozole.Results from PALOMA-1 were subsequently validated inthe larger,randomized,placebo-controlled,phase III PALOMA-2study.6InPALOMA-2,666postmenopausalpatientswithtreatment-na ve metastatic HR-positive,HER2-negative breast cancer wereran
21、domly assigned to receive letrozole and placebo or letrozoleand palbociclib.Palbociclib was associated with significant im-provement in PFS among patients who received combinationtherapy(24.8 months v 14.5 months;hazard ratio,0.58).Nearly identical results have recently been reported for thecombinat
22、ion of ribociclib and letrozole as first-line therapy.In thephase III,placebo-controlled MONALEESA-2 study,668 patientswere randomly assigned to receive ribociclib and letrozole ver-sus letrozole and placebo.7Again,patients were allowed to havereceived prior AI therapy if the treatment interval exce
23、eded12 months.Median PFS for the ribociclib-based arm exceeded24 months,whereas letrozole alone yielded a median PFS of 14.7(hazard ratio,0.56).On the basis of these results,ribociclib wasrecently granted US FDA approval in combination with an AI asinitial therapy for postmenopausal women with HR-po
24、sitive,HER2-negative metastatic breast cancer.Abemaciclib has also been evaluated as a first-line treatment incombinationwithanonsteroidalAIaspartoftherandomized,double-blind,placebo-controlled phase III MONARCH-3 trial that accrued493 women(NCT02246621).A press release from Lilly on April 24,2017,s
25、tatedthatMONARCH-3alsodemonstratedanimprovementinPFS with the addition of CDK4/6 inhibitor to AI therapy.8Second-Line and Refractory Metastatic SettingAll three CDK4/6 inhibitors have also been assessed in ran-domized trials with the shared study design of fulvestrant with orwithout CKD4/6 inhibitor
26、 as second-line therapy for metastaticcancer after AI treatment in postmenopausal women(Table 1).The randomized,placebo-controlled PALOMA-3 study ex-plored the utility of palbociclib with fulvestrant in HR-positive,Fig 1.Representative imaging.Nuclear medicine bone scan and computedtomography cross-
27、sectional imaging study revealing widespread osseous meta-static disease in this patient with recurrent estrogen receptorpositive,humanepidermal growth factor receptor 2negative breast cancer.Arrows indicate areasof osseous metastatic disease.Table 1.Select Randomized Clinical Studies of Endocrine T
28、herapy Plus CDK4/6-Directed Therapy in Estrogen ReceptorPositive Metastatic Breast CancerStudyRegimenPhaseNo.PFS,EndocrineAlone(months)PFS,1 CDK 4/6Inhibitor(months)Hazard Ratio(95%CI)First linePALOMA-1Letrozole with or without palbociclibII16510.220.20.488(0.319 to 0.748)PALOMA-2Letrozole with or w
29、ithout palbociclibIII66614.524.80.58(0.46 to 0.72)MONALEESA-2Letrozole with or without ribociclibIII66814.7NR0.56(0.43 to 0.72)MONARCH-3NSAI with or without abemaciclibIII493NCT02246621*Second linePALOMA-3Fulvestrant with or without palbociclibIII5214.69.50.46(0.36 to 0.59)MONARCH-2Fulvestrant with
30、or without abemaciclibIII6699.316.40.553(0.449 to 0.681)MONALEESA-3Fulvestrant with or without ribociclibIII725NCT02422615Abbreviations:CDK4/6,cyclin-dependent kinase 4/6;PFS,progression-free survival;NSAI,nonsteroidal aromatase inhibitor.*Interim analysis reportedly met primary end point of improve
31、d PFS in the combination arm.8jco.org 2017 by American Society of Clinical Oncology2867Metastatic,Hormone ReceptorPositive Breast CancerDownloaded from ascopubs.org by 180.175.88.35 on December 18,2018 from 180.175.088.035Copyright 2018 American Society of Clinical Oncology.All rights reserved.HER2-
32、negative metastatic breast cancer.9,10In this trial,patientswere required to have experienced progression with prior endocrinetherapy for advanced breast cancer or developed recurrence within12 months of adjuvant endocrine therapy,and 521 patients wererandomly assigned to receive palbociclib with fu
33、lvestrant versusfulvestrant and placebo.Palbociclib-based therapy improved PFScompared with fulvestrant alone(9.5 months v 4.6 months)witha hazard ratio of 0.46(95%CI,0.36 to 0.59).Neither the degree ofprior endocrine sensitivity,nor a patients menopausal statuspremenopausal women could initiate con
34、current ovariansuppressionseemed to impact the response to combinationtherapy.On the basis of these results,in early 2016,palbociclib wasgranted approval by the US FDA in combination with fulvestrantfor women with HR-positive,HER2-negative metastatic breastcancer with disease progression after endoc
35、rine therapy.The study by Sledge et al,11which accompanies this article,provides data from the MONARCH-2 trial,which explored the ef-ficacy of abemaciclib with fulvestrant in HR-positive,HER2-negativeadvanced breast cancer.This double-blind,placebo-controlled,phaseIII study included postmenopausal w
36、omen who had experiencedprogression either on first-line endocrine therapy for metastaticdisease,on neoadjuvant or adjuvant endocrine therapy,or within12 months of the end of adjuvant endocrine therapy.A total of 669patients were randomly assigned to receive abemaciclib and fulves-trant or fulvestra
37、nt and placebo.Combination therapy significantlyimproved PFS compared with fulvestrant alone(16.4 months v9.3 months),with a hazard ratio of 0.553(95%CI,0.449 to 0.681).Different durations of PFS for the fulvestrant control arm inPALOMA-3andMONARCH-2maysuggestunderlyingdifferencesinthe patient popul
38、ation and the sensitivity of tumors to fulvestranttherapy;the hazard ratio for relative benefit from the CDK4/6 in-hibitors is essentially the same between the two trials.Ofnote,despitethesignificantimprovementsobservedinPFSinboth the first-line and second-line metastatic setting,mature overallsurvi
39、val results have not yet been published from any of the largerandomized studies outlined above.Similarly,with proven activity ineither the first or second line of treatment,it is not known whichtimepointwouldyieldtheoptimaluseor valueofaCDK4/6inhibitor.ToxicityAll three CDK4/6 inhibitors are availab
40、le in oral form and arereasonably well tolerated(Table 2).Both palbociclib and ribociclibare daily medications,administered intermittently on a 3-week on/1-week off schedule.Abemaciclib,in contrast,is administeredcontinuously as a twice-per-day medication.Abemaciclib hasdemonstrated appreciable conc
41、entrations in the CSF,which mayprovetobeaclinicaladvantage,thoughtherecurrentlyarenodatatosuggest the value of this pharmacologic property.12The toxicityprofiles of palbociclib and ribociclib are similar.Because of thecytostatic effects of these agents on bone marrow progenitor cells,ribociclib and
42、palbociclib cause frequent neutropenia(Table 2;.74%all-grade toxicity;54%to 67%grade 3 or 4 toxicity);however,despite the frequency of neutropenia,febrile neutropeniaand other serious infections are exceedingly rare with palbocicliband ribociclib as a result of the rapid neutrophil maturation upondr
43、ug withdrawal.13Because of the high rates of neutropenia,a CBCwith differential should be obtained on day 1 of each cycle and onday 14 of cycles 1 and 2.Palbociclib dose reductions to 100 mg or75 mg for persistent neutropenia are common.Reassuringly,a de-tailed safety analysis from the PALOMA-3 tria
44、l demonstrated nodetrimental impact on efficacy from the protocol-specified dosereduction.14Both agents may also cause occasional low-gradefatigue,nausea,and hair thinning.Ribociclib causes occasionallow-grade diarrhea,and patients on ribociclib require laboratoryand ECG monitoring for rare instance
45、s of liver function test el-evations and QT prolongation,respectively.In the MONARCH-2 trial of fulvestrant with or without abe-maciclib,seriousadverse eventsthat were possibly relatedtothestudydrug occurred at a low rate:8.8%of all patients who received abe-maciclib versus 1.3%of patients who recei
46、ved placebo.Comparedwith the other agents,abemaciclib had lower rates of neutropeniabut greater degrees of diarrhea(Table 2;diarrhea,86.4%all grade,13.4%grade 3,and 0%grade 4 toxicity).Diarrhea was effectivelymanaged with antidiarrheal medications,and the majority ofpatients did not require treatmen
47、t modification.Less than 3%ofpatients discontinued the study drug as a result of diarrhea.BiomarkersVariability noted in response to CDK4/6-directed therapyunderscoresthecriticalneedtoestablishtumorattributesthatmightserve as predictive biomarkers of response or resistance.Charac-terization of prima
48、ry breast tumors as part of the effort of TheCancer Genome Atlas revealed high rates of cyclin D1 amplificationin luminal tumors,15which is consistent with older findings on thebasis of immunohistochemical analysis.16Rb loss or mutation,which would,in theory,render CDK4/6 inhibition ineffective asTa
49、ble 2.Dosing and Toxicity for Cyclin-Dependent Kinase 4/6 InhibitorsCommon Adverse Event*Palbociclib(125 mg per day3 weeks on,1 week off)Ribociclib(600 mg per day3 weeks on,1 week off)Abemaciclib(200 mg twice per daycontinuous)All GradesGrade 3 and 4All GradesGrade 3 and 4All GradesGrade 3 and 4Neut
50、ropenia74-8154-6774594627Thrombocytopenia16-222-3NRNR163Fatigue37-402-4372403Diarrhea21-261-43518613Nausea25-350-2522453QTc prolongationNRNR3NRNRNRNOTE.Data are given as percent.Abbreviation:NR,not reported;QTc,corrected QT interval.*Common adverse events in phase III trials in the metastatic settin