Neranib plus capecitabine versus lapanib plus capecitabine in … › docs › June 4 2019 ASCO 2019...
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Nera%nib plus capecitabine versus lapa%nib plus capecitabine in pa%ents with HER2-posi%ve metasta%c breast cancer previously treated with ≥2 HER2-directed regimens: Findings from the mul%na%onal, randomized, phase 3 NALA trial Cris%na Saura, Mafalda Oliveira, Yin-Hsun Feng, Ming-Shen Dai, Sara A Hurvitz, Sung-Bae Kim, Beverly Moy, SuzeBe Delaloge, William Gradishar, Norikazu Masuda, Marketa Palacova, Maureen E Trudeau, Johanna MaBson, Yoon Sim Yap, Richard Bryce, Bin Yao, Judith Bebchuk, Kiana Keyvanjah, Adam Brufsky, NALA Inves%gators Vall d’Hebron University Hospital, Vall d’Hebron Ins6tute of Oncology (VHIO), Barcelona, Spain; Chi Mei Medical Centre, Tainan, Taiwan; Tri-Service General Hospital, Taipei, Taiwan; UCLA Hematology/Oncology Clinical Research Unit, Santa Monica, CA; University of Ulsan College of Medicine, Seoul, Republic of Korea; MassachuseNs General Hospital Cancer Center, Boston, MA; Ins6tut Gustave Roussy, Villejuif, France; Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; NHO Osaka Na6onal Hospital, Osaka, Japan; Masaryk Memorial Cancer Ins6tute, Brno, Czech Republic; Sunnybrook Health Sciences Centre, Toronto, ON; Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland; Na6onal Cancer Centre Singapore, Singapore, Singapore; Puma Biotechnology Inc, Los Angeles, CA; Magee-Womens Hospital of UPMC, PiNsburgh, PA 1 Adam Brufsky
Transcript of Neranib plus capecitabine versus lapanib plus capecitabine in … › docs › June 4 2019 ASCO 2019...
Nera%nibpluscapecitabineversuslapa%nibpluscapecitabineinpa%entswithHER2-posi%vemetasta%cbreastcancerpreviouslytreatedwith≥2HER2-directedregimens:Findingsfromthemul%na%onal,randomized,phase3NALAtrialCris%naSaura,MafaldaOliveira,Yin-HsunFeng,Ming-ShenDai,SaraAHurvitz,Sung-BaeKim,BeverlyMoy,SuzeBeDelaloge,WilliamGradishar,NorikazuMasuda,MarketaPalacova,MaureenETrudeau,JohannaMaBson,YoonSimYap,RichardBryce,BinYao,JudithBebchuk,KianaKeyvanjah,AdamBrufsky,NALAInves%gatorsValld’HebronUniversityHospital,Valld’HebronIns6tuteofOncology(VHIO),Barcelona,Spain;ChiMeiMedicalCentre,Tainan,Taiwan;Tri-ServiceGeneralHospital,Taipei,Taiwan;UCLAHematology/OncologyClinicalResearchUnit,SantaMonica,CA;UniversityofUlsanCollegeofMedicine,Seoul,RepublicofKorea;MassachuseNsGeneralHospitalCancerCenter,Boston,MA;Ins6tutGustaveRoussy,Villejuif,France;RobertHLurieComprehensiveCancerCenterofNorthwesternUniversity,Chicago,IL;NHOOsakaNa6onalHospital,Osaka,Japan;MasarykMemorialCancerIns6tute,Brno,CzechRepublic;SunnybrookHealthSciencesCentre,Toronto,ON;HelsinkiUniversityHospitalComprehensiveCancerCenter,Helsinki,Finland;Na6onalCancerCentreSingapore,Singapore,Singapore;PumaBiotechnologyInc,LosAngeles,CA;Magee-WomensHospitalofUPMC,PiNsburgh,PA
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Disclosureinforma%on–AdamBrufsky
AdamBrufsky
Consul%ngorAdvisoryRole
Eisai,MyriadPharmaceu%cals,Merck,BioarrayTherapeu%cs,PumaBiotechnology,GenomicHealth,NanoStringTechnologies,BioTheranos%cs,Lilly,Bayer,Novar%s,Celgene,Agendia,Genentech/Roche,Pfizer
• Nera%nib:pan-HER(HER1,2,and4)TKI
• Breadthoftargetsfornera%nibinHERfamilyofreceptors(HER1,2,and4fornera%nib;HER1and2forlapa%nib)
• Nera%nibbindsirreversiblytoHER1,2,and4;lapa%nibbindsreversibly
3Rabindranetal.CancerRes2004
Nera%nibUSPI2018
Aberrant HER activation by: • Gene amplification • Receptor overexpression • Somatic mutations
HER2:EGFR HER2:HER3 HER2:HER2 HER2:HER4 EGFR:EGFR
MAPK pathway PI3K pathway
HER receptor dimerization
Kinase activation
Downstream signal transduction
Tumor growth, survival, and spread
Neratinib
RAS
RAF
MEK
ERK
PI3K
AKT
mTOR
• Cell cycle control and proliferation • Cell survival and decreased apoptosis • Cellular migration and metastasis • Angiogenesis
Nucleus
AdamBrufsky
Nera%nib:Anirreversiblepan-HERTKI
TKI,tyrosinekinaseinhibitor
• Extendedadjuvant:ApprovedbyFDAandEMAbasedonreducedriskofrecurrenceofiDFSeventwithnera%nibvsplaceboinExteNET1
• Neoadjuvant:HigherpCRrateswithchemotherapy+nera%nibvschemotherapy+trastuzumabinpa%entswithHER2+breastcancerinI-SPY22
• Metasta%cHER2+disease:
– Study2206:Promisingefficacywithnera%nib+capecitabineintrastuzumab-pretreatedpa%ents(recommendeddoses:nera%nib240mg/d+capecitabine1500mg/m2)3
– NSABPFB-10:Evidenceofefficacywithnera%nib+T-DM1inpa%entspreviouslytreatedwithtrastuzumab+pertuzumab4
– NEfERT-T:DelayedCNSprogressionwithnera%nib+paclitaxelinpa%entswithHER2+brainmetastases5
– TBCRC022:Nera%nib+capecitabineac%veagainstrefractorybrainmetastasesinpa%entswithHER2+brainmetastases6
4AdamBrufsky1.Mar%netal.LancetOncol2017;2.Parketal.NEnglJMed2016;3.Sauraetal.JClinOncol2014
4.Abrahametal.JClinOncol2018;5.Awadaetal.JAMAOncol2016;6.Freedmanetal.JClinOncol2019
Clinicalexperiencewithnera%nib
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Stra%fica%onvariables• NumberofpriorHER2therapiesforMBC• Diseaseloca%on• HRstatus• Geographicloca%on
Inclusioncriteria• Metasta%cbreastcancer(MBC)• CentrallyconfirmedHER2+disease• ≥2linesofHER2-directedtherapyforMBC• Asymptoma%candstablebrain
metastasespermiBed
Nera%nib240mg/d+Capecitabine1500mg/m214/21d
Loperamide(cycle1)a
Lapa%nib1250mg/d+Capecitabine2000mg/m214/21d
R(1:1)
Follow-up(survival)
PD
PD
Endpoints• Co-primary:PFS(centrallyconfirmed)andOS• Secondary:PFS(local),ORR,DoR,CBR,interven%onfor
CNSmetastases,safety,healthoutcomes
Noendocrinetherapypermi\ed
Loperamide4mgwithfirstdoseofnera%nib,followedby2mgevery4hforfirst3d,thenloperamide2mgevery6–8hun%lendofCycle1.Therea`erasneeded
n=621
NALAstudydesign
Co-primaryendpointsofPFSandOS
• ConductedunderanFDASpecialProtocolAssessment
• Studyposi%veifeitherco-primaryendpointmet:– p<0.01forPFS(419targeteventsrequiredfor85%power)– p<0.04forOS(378targeteventsrequiredfor85%power)
Plannedanalyses
• Stra%fiedlog-ranktest;Kaplan–MeiercurvesforPFSandOS
• Stra%fiedCoxpropor%onalhazardsmodelforhazardra%os– Prespecifiedrestrictedmeansanalysis,ifpropor%onalhazardsassump%ondidnothold1
• Gray’stestofcumula%veincidenceforCNSendpoints
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NALA
Sta%s%calmethods
1.Unoetal.JClinOncol2014
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Nera%nib+Capecitabine(n=307)
Lapa%nib+Capecitabine(n=314)
Age<65years,n(%) 244(79) 248(79)Geographicregion,n(%)Europe 121(39) 123(39)NorthAmerica 59(19) 65(21)Restofworld 127(41) 126(40)
HR+(ER+and/orPR+),n(%) 181(59) 186(59)Diseaseloca%onatenrollment,n(%)Non-visceralonly 60(20) 61(19)Visceral 247(80) 253(81)
Denovometasta%cdisease,n(%) 139(45) 136(43)No.ofpriorHER2targetedtherapiesforMBC,n(%)2 215(70) 215(68)≥3 92(30) 99(32)
PriorHER2therapiesforMBC,n(%)Trastuzumabonly 124(40) 113(36)Trastuzumab+pertuzumab 24(8) 23(7)Trastuzumab+T-DM1 58(19) 64(20)Trastuzumab+pertuzumab+T-DM1 101(33) 114(36)
NALA
Baselinecharacteris%cs
307 183 113 69 54 35 20 13 9 7 3 2 2314 183 82 39 24 9 8 3 2 2 2 2 1
N+CL+C
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1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 3 6 9 12 15 18 21 24 27 30 33 36
Timesincerandomiza%on(months)
PFSprob
ability
No.atrisk:
Nera%nib+Capecitabine
Lapa%nib+Capecitabine
8
15%
29%38%
47%
7%
16%
Hazardra%o(95%CI) Log-rankp-value
0.76(0.63–0.93) 0.0059
NALA
CentrallyconfirmedPFS(co-primaryendpoint)
307 183 113 69 54 35 20 13 9 7 3 2 2314 183 82 39 24 9 8 3 2 2 2 2 1
N+CL+C
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1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 3 6 9 12 15 18 21 24 27 30 33 36
No.atrisk:
Nera%nib+Capecitabine
Lapa%nib+Capecitabine
9
2.2months
MeanPFS(months) p-value
8.80.0003
6.6
Restric%on:24months
NALA
Prespecifiedrestrictedmeansanalysis–PFS
Timesincerandomiza%on(months)
PFSprob
ability
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SubgroupOverallAgegroup<65years≥65yearsRaceWhiteAsian,black,orotherGeographicregionNorthAmericaEuropeRestofworldDiseaseloca%onVisceralNon-visceralonlyHRstatusHR–HR+No.ofpriorHER2regimens2≥3
N
621
492129
355266
124244253
500121
254367
430191
210vs223
169vs18141vs42
125vs11785vs106
41vs4683vs7886vs99
181vs18529vs38
82vs108128vs115
148vs15162vs72
Hazardra%o(95%CI)
0.76(0.63–0.93)
0.74(0.60–0.91)0.83(0.53–1.28)
0.86(0.67–1.11)0.63(0.47–0.85)
0.81(0.53–1.25)0.99(0.72–1.35)0.55(0.41–0.75)
0.85(0.69–1.04)0.44(0.26–0.73)
0.42(0.31–0.57)1.08(0.84–1.40)
0.76(0.60–0.96)0.71(0.50–1.00)
Hazardra%o(95%CI)
Nera%nib+CapecitabinebeBer Lapa%nib+CapecitabinebeBer
0.2514
Interac%ontestp-value
0.463
0.166
0.051
0.007
<0.001
0.614
EventsN+CvsL+C
NALA
PFS:Forestplot
11
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57
Timesincerandomiza%on(months)
OSprob
ability
307 294 275 244 220 182 142 112 82 13 6 2 1314 303 273 240 208 170 132 107 84 12 8 3 1
N+CL+C
No.atrisk:6467
4747
1822
1517
44
3436
2827
MeanOS(months)
Hazardra%o(95%CI) Log-rankp-value
24.00.88(0.72–1.07) 0.2086
22.2
Restric%on:48months
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NALA
OS(co-primaryendpoint)
1.7months
Nera%nib+Capecitabine
Lapa%nib+Capecitabine
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N
621
492129
355266
124244253
500121
254367
430191
192vs218
149vs17143vs47
113vs12279vs96
46vs5170vs8576vs82
165vs18027vs38
87vs101105vs117
139vs14953vs69
Hazardra%o(95%CI)
0.88(0.72–1.07)
0.86(0.69–1.08)0.86(0.57–1.30)
0.88(0.68–1.13)0.85(0.63–1.14)
1.06(0.71–1.58)0.82(0.60–1.13)0.83(0.60–1.13)
0.94(0.76–1.16)0.60(0.36–0.98)
0.76(0.57–1.01)0.94(0.72–1.22)
0.95(0.75–1.19)0.71(0.50–1.02)
Hazardra%o(95%CI)
Interac%ontestp-value
0.941
0.939
0.313
0.067
0.252
0.146
EventsN+CvsL+C
Nera%nib+CapecitabinebeBer Lapa%nib+CapecitabinebeBer
0.313.5
SubgroupOverallAgegroup<65years≥65yearsRaceWhiteAsian,black,orotherGeographicregionNorthAmericaEuropeRestofworldDiseaseloca%onVisceralNon-visceralonlyHRstatusHR–HR+No.ofpriorHER2regimens2≥3
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NALA
OS:Forestplot
Timetointerven%onforCNSmetastases
13
100
90
80
70
60
50
40
30
20
10
00 6 12 18 24 30 36 42 48 54 60
Cumula%
veincide
nce(%
)
Timesincerandomiza%on(months)
Nera%nib+CapecitabineLapa%nib+CapecitabineOverallcumula%veincidence(Gray’stest):22.8%vs29.2%;p=0.043
Interven%on
Nera%nib+Capecitabine(n=55/307)
Lapa%nib+Capecitabine(n=75/314)
Radia%ontherapy 11% 15%
Surgery/procedure 2% 3%
An%cancermedica%on 1% 1%
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NALA
Responserateanddura%onofresponse
14
84 64 39 29 22 15 11 8 3 3 2 272 54 24 12 8 3 1 0
Timesincerandomiza%on(months)
Prob
abilityofcon
%nuingre
spon
se
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 3 6 9 12 15 18 21 24 27 30 33
Nera%nib+CapecitabineLapa%nib+Capecitabine
N+CL+C
No.atrisk:
Nera%nib+Capecitabine
(n=256)Lapa%nib+Capecitabine
(n=270) p-valueObjec%veresponserate 33% 27% 0.1201
Clinicalbenefitrate 45% 36% 0.0328
Mediandura%onofresponse 8.5months 5.6months
Hazardra%o(95%CI) 0.50(0.33–0.74) 0.0004
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NALA
Nera%nib+Capecitabine(n=303)
Lapa%nib+Capecitabine(n=311)
Lapa%nib/Nera%nib
Mediandura%onoftreatment,months 5.7 4.4
Dosereduc%on,n(%) 73(24) 61(20)
Dosehold,n(%) 145(48) 134(43)
Capecitabine
Mediandura%onoftreatment,months 5.5 4.8
Dosereduc%on,n(%) 117(39) 152(49)
Dosehold,n(%) 178(59) 184(59)
Treatmentexposure
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NALA
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Nera%nib+Capecitabine(n=303) Lapa%nib+Capecitabine(n=311)
Allgrade Grade3/4 Allgrade Grade3/4Treatment-emergentAE,% 100 61 99 60Diarrhea 83 24* 66 13*Hand-footsyndrome 46 10 56 11Hypokalemia 12 5 14 6Nausea 53 4 42 3Vomi%ng 46 4 31 2Fa%gue 34 3 31 3Neutropenia 7 3 5 2Asthenia 12 3 12 2Decreasedappe%te 35 3 22 2Dehydra%on 6 2 6 2
Treatmentdiscon%nua%onduetotreatment-emergentAEs:N+C:10.9%;L+C:14.5%
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NALA
Mostfrequentgrade3/4adverseevents
*NoGrade4diarrhea
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Nera%nib+Capecitabine(n=303)
Lapa%nib+Capecitabine(n=311)
Maximumtoxicity,n(%)
Grade1 91(30) 111(36)
Grade2 87(29) 56(18)
Grade3 74(24) 39(13)
Timetofirstonsetofdiarrhea,days
Grade2or3 9 18
Grade3 11 38
Mediancumula%vedura%onperpa%ent,days
Grade2or3 7 9
Grade3 4 4
Treatmentdiscon%nua%onduetodiarrhea:N+C:2.6%L+C:2.3%
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NALA
Incidenceanddura%onofdiarrhea
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EORTCQLQ-C30summaryscoreMeanscoreover%me
EORTCQLQ-C30GlobalhealthstatusMeanscoreover%me
100
90
80
70
60
50
40
30
20
10
0Baseline C3D1 C5D1 C7D1 C9D1 C11D1
275 265 210 181 147 70281 270 215 178 132 32
Studycycle
Meanscore±SE
C13D1 C15D1 C17D1 C19D1
11290
9964
8044
5527
100
90
80
70
60
50
40
30
20
10
0Baseline C3D1 C5D1 C7D1 C9D1 C11D1
277 267 212 182 150 71283 273 219 179 133 32
N+CL+C
No.ofpa%ents:
Studycycle
Meanscore±SE
C13D1 C15D1 C17D1 C19D1
11593
9964
8144
5527
Nera%nib+Capecitabine
Lapa%nib+Capecitabine
Nera%nib+Capecitabine
Lapa%nib+Capecitabine
N+CL+C
No.ofpa%ents:
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NALA
Pa%entreportedoutcomes
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• NALAmetitsprimaryobjec%ve:N+CsuperiortoL+Cin≥3LHER2+MBC– SignificantPFSbenefitfavoringN+C:HR=0.76;p=0.0059– NumericalimprovementinOSfavoringN+C:HR=0.88;p=0.2086
• Fewerpa%entsrequiredinterven%onforsymptoma%cCNSmetastaseswithN+C(p=0.043),sugges%veofadelayinCNSprogression– Consistentwithresultsfrompreviousnera%nibstudies1,2
• Dura%onofresponsesignificantlyimprovedwithN+C:HR=0.50;p=0.0004
• Nonewsafetysignalsseen.Discon%nua%onsduetodiarrhea2.3%withN+Candamediancumula%vedura%onofgrade3diarrheaof4days
• TrialresultssuggestN+Cisaneffec%veop%onfortrea%ngprogressiveHER2+MBC
1.Awadaetal.JAMAOncol2016;2.Mar%netal.LancetOncol2017
NALA
Conclusions
Theauthorswouldliketothankpa%entsandtheirfamilies,andtheinves%gatorsandsitestaffforpar%cipa%nginthistrial
WealsothanktheIndependentDataMonitoringCommiBeeandtheSteeringCommiBee
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Thankyou
