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Andrew M. Evens, DO, MSc
October 20th, 2018
Professor of Medicine, Rutgers RWJ Medical School Associate Director (Clinical Services), Rutgers CINJ
Director, Lymphoma Program Medical Director, Oncology Service Line, RWJBH
New Brunswick, New Jersey
What is the best upfront approach for the treatment of advanced stage
Hodgkin lymphoma?
Disclosures
• Research advisory boards (w/ honorarium): Jannsen, Seattle Genetics, Pharmacyclics, Affimed, Bayer, Abbie, and Acerta
• Research support: Tesaro, Takeda, Celgene, NIH and NCI
Colleague/Friend: Dr. Nancy Bartlett
• Assigned the PRO position
HodgkinLymphoma:OverarchingGoals
Efficacy
ToxicityCure(OS),Lessprogressionor
relapse(PFS,EFS),lesstreatment Acuteandlate
(morbid&mortal);QOL;financial
Context: prior and contemporaneous studies
• Prior studies with PFS benefit in advanced stage HL using BEACOPP-based therapy o Not widely adopted (primarily d/t toxicity- severe cytopenias,
infection, avascular necrosis, acute leukemia, etc)
• Current status/option: RATHL based approach o Deletion of bleomycin in ~80% pts after 2 cycles of ABVD
(ie, PET-2 negative) o ~20% with + PET-2: escalated BEACOPP-based Rx (not
randomized data to support this) o Only pts ages <60 years CardePetal.JClinOncol2016
MerliFetal.JClinOncol2016MounierNetal.AnnOncol2014Vivianietal.NEnglJMed2011FedericoMetal.JClinOncol2009
JohnsonPetal.NEnglJMed2016
ECHELON-1:A+AVDversusABVDinadvancedcHL
• Inclusioncriteria– cHLstage IIIorIV– ECOGPS 0,1or2– Age ≥18years– Measurabledisease– Adequateliverandrenalfunction
218studysitesin21countriesworldwide
Screen
ing
CT/PE
Tscan
1:1rand
omization
(N=1334) ABVDx6cycles(n=670)
A+AVDx6cycles(n=664)Brentuximabvedotin:1.2mg/kgIVinfusion
Days1&15
EOT
CT/PETscan
Follow-up
Every3monthsfor36months,thenevery
6monthsuntilstudyclosure
End-of-Cycle-2PETscan• Deauville5;couldreceivealternatetherapyper
physician’schoice(notamodifiedPFSevent)
Connorsetal.NEJM2018
Echelon-1: A+AVD
• PROS o First FDA approval of
targeted therapeutic in untreated cHL
o Improved mPFS and PFS (all patients)
o Even greater PFS benefit pts treated in N.America (and other populations)
o All ages o Significantly less
bleomycin lung toxicity
• CONS o Question of modified
PFS (mPFS) endpoint o Lack of OS benefit o More febrile
neutropenia and neuropathy (former less in N.America)
o Cost
ECHELON-1:A+AVDversusABVDinadvancedcHL
• Primaryendpoint:modifiedPFSperIRF– AmodifiedPFSeventwasdefinedasthefirstof:• Progression• Deathfromanycause
Dx Tx Follow-upPET6=D1,2
Dx Tx Follow-upPET6=D3,4,5
Dx Tx Follow-upPET6=D3,4,5
NomodifiedPFSevent
NomodifiedPFSeventDx Tx Follow-upPET6=D1,2 Tx
NomodifiedPFSevent
ModifiedPFSevent
Txw/o“Cheson”progression
• PET6=D3,4,5aftercompletionoffrontlinetherapyfollowedbysubsequentanticancertherapy
PerIRF
ModifiedPFSeventDx Tx Follow-up
PD/deathatanytime
PET6=D1–5
Connorsetal.NEJM2018
Primary endpoint: modified progression-free survival (mPFS)
• mPFS provided assessment of treatment effectiveness in 1st line HL compared to PFS by scoring additional chemotherapy or radiation due to lack of CR as an event
• As a PET-negative CR (cure) is the expected therapeutic outcome in 1st line HL, mPFS reflects the curative intent of 1st line therapy
• ECHELON-1 study was conducted under a SPA with the FDA
• Could have used different name/synonym (much less debate and consternation): EFS or FFTF, etc
ConnorsJetal.NEJM2018
Echelon-1:ModifiedPFSperindependentreview
TimeA+AVD(95%CI)
ABVD(95%CI)
2-year 82.1(78.7–85.0)
77.2(73.7–80.4)
Medianfollow-up(range):24.9months(0.0–49.3)
Category
A+AVDN=117
ABVDN=146
Progression 90 102
Death 18 22
ModifiedprogressionChemotherapyRadiotherapy
972
22157
1.0
0.8
0.6
0.4
0.2
0.00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
664670
640644
623626
606613
544522
530496
516476
496459
474439
447415
350328
334308
311294
200179
187168
174153
9978
8568
7762
2716
2413
2112
61
41
41
00
00
Timefromrandomizacon(months)
Prob
abilityofm
odified
PFS
No.ofpacentsatrisk:A+AVDABVD
HR0.77(95%CI:0.60–0.98)Log-ranktestp-value:0.035
A+AVDABVD
CensoredCensored
0.9
0.7
0.5
0.3
0.1
ModifiedPFSescmates
Numberofevents
ConnorsJetal.NEJM2018
Delta=5%
Echelon-1:ModifiedPFSperinvescgator
1.0
0.8
0.6
0.4
0.2
0.00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
Prob
abilityofm
odified
PFS
664670
643643
626628
613611
540514
524492
516476
497463
479448
456426
361343
347319
325299
206186
192171
180157
10282
8771
7963
2816
2413
2112
52
32
32
00
00
No.ofpacentsatrisk:A+AVDABVD
0.1
0.3
0.5
0.7
0.9
Timefromrandomizacon(months)
HR0.73(95%CI:0.57‒0.92)Log-ranktestp-value:0.007
ModifiedPFSescmates
Numberofevents
Medianfollow-up(range):25.0months(0.0–49.3)
TimeA+AVD(95%CI)
ABVD(95%CI)
2-year 81.0(77.6–83.9)
74.4(70.7–77.7)
Category
A+AVDN=123
ABVDN=164
Progression 73 103
Death 15 22
Modifiedprogression 35 39A+AVDABVD
CensoredCensored
Delta=6.6%
ConnorsJetal.NEJM2018
PFSperINV
• HR=0.70,p=0.006• 2yeareventrates:
84.2%vs78.0%;delta=6.2%
• NOTE:subsequenttherapywasnotconsideredaneventnorcensoredinthisanalysis
NumberofP atients -at-R is k0 0664 643 626 613 567 548 537 514 494 470 373 357 334 212 197 185 105 90 81 28 24 21 5 3 30 0670 643 628 615 545 519 499 481 465 442 354 330 309 192 177 163 85 73 65 16 13 12 2 2 2ABVD
A+AVD
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
T ime(Months)fromRandomiz a tion
0.0
0.2
0.4
0.6
0.8
1.0
Pro
gre
ssion-Fre
eSurvival
Pro
bab
ilityof
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
T ime(Months)fromRandomiz a tion
0.0
0.2
0.4
0.6
0.8
1.0
Pro
gre
ssion-Fre
eSurvival
Pro
bab
ilityof
Cens oredABVDCens oredA+AVD
Numofevents A +AVD:101A BVD:140Haz ardratio(95% CI):0.700(0.542,0.904)Log-ranktes tp-value:0.006
Kaplan-MeierEscmates
A+AVD(95%CI)[atrisk]
ABVD(95%CI)[atrisk]
Difference
1year 88.4(85.6,90.7)[n=537]
82.2(78.9,84.9)[n=499]
6.2
2year 84.2(81.1,86.9)[n=334]
78.0(74.4,81.1)[n=309]
6.2
Mostclinicallyimportanttreatment-emergentadiverseeventsIncidence(anygrade)≥20%+febrileneutropenia
Commonadverseevents,%*A+AVD(N=662) ABVD(N=659)
Anygrade Grade≥3 Anygrade Grade≥3Neutropenia 58 54 45 39Constipation 42 2 37 <1Vomiting 33 3 28 1Fatigue 32 3 32 1Peripheralsensoryneuropathy 29 5 17 <1Diarrhea 27 3 18 <1Pyrexia 27 3 22 2Neuropathyperipheral 26 4 13 <1Abdominalpain 21 3 10 <1Stomatitis 21 2 16 <1Febrileneutropenia 19 19 8 8
ConnorsJetal.NEJM2018
Summaryoftreatment-emergentfebrileneutropeniaandadverseeventsbyprimaryprophylaxiswithG-CSF
• G-CSFprimaryprophylaxisforA+AVDresultedinanoverallsafetyprofilecomparabletoABVD• G-CSFprimaryprophylaxiswasrecommendedforallA+AVDpatientsaftertheinterimsafety
analysis• G-CSFprimaryprophylaxisisrecommendedforallA+AVDpatients
0% 10% 20% 30% 40% 50% 60% 70% 80% 90%
100% Neutropenia*
73%
35%
A+AVD ABVD
No(n=579)
Yes(n=83)
No(n=616)
Yes(n=43)
≥Grade3 Grade1–2100908070
50403020
0
6057%
21%
G-CSFprimaryprophylaxis†
Patien
ts(%
)
0%
10%
20%
30%
40%
50% Febrile neutropenia
A+AVD ABVD
No(n=579)
Yes(n=83)
No(n=616)
Yes(n=43)
21%
11%8% 7%
50
40
30
20
10
0
Patien
ts(%
)
0% 10% 20% 30% 40% 50% 60% 70% 80% 90%
100% All grade ≥3 TEAEs
87%
57%67%
47%
A+AVD ABVD
Yes(n=83)
No(n=616)
Yes(n=43)
No(n=579)
100908070
50403020
0
60
Patien
ts(%
)
1010
Peripheral neuropathy and pulmonary events
Summary of on-study and follow-up deaths
6of7w/oprimaryGCSFprophylaxis
Summaryofsubsequenttherapy
• 33%fewerA+AVDpatientsreceivedsubsequentchemotherapy• 33%fewerA+AVDpatientsreceivedsubsequenthigh-dosechemotherapy+transplant
Typeofsubsequenttherapy,n(%)A+AVDN=662
ABVDN=659
Patientswith≥1subsequentanticancertherapy 121(18) 144(22)
Subsequenttreatment–totalPatientsreceivingsystemictherapyandradiation
SystemicTotal*RadiationTotal*
Typesofsystemictreatment(+/-radiation)*
ChemotherapyHigh-dosechemotherapy+transplantImmunotherapy
Radiationonly*
121(100)
80(66)52(43)
66(55)36(30)10(8)
41(34)
144(100)
111(77)52(36)
99(69)54(38)16(11)
33(23)
*SumsofsubsetsexceedtotalsbecausesomepaEentsreceivedmorethanonesystemictreatmentorsystemic+radiaEontreatment
Echelon-1ForestplotofmodifiedPFSperIRF
ConnorsJetal.NEJM2018
0.1 0.5 1
FavorsABVD
Hazardratio
FavorsA+AVD
Overall 117/664(17.6) 146/670(21.8) 0.770(0.603–0.982)Age<60years 93/580(16.0) 117/568(20.6) 0.733(0.558–0.963)Age≥60years 24/84(28.6) 29/102(28.4) 1.005(0.585–1.727)
Age<45years 70/451(15.5) 83/423(19.6) 0.733(0.533–1.009)Age≥45years 47/213(22.1) 63/247(25.5) 0.862(0.590–1.257)
Region:Americas 41/261(15.7) 58/262(22.1) 0.651(0.437–0.972)Region:NorthAmerica 38/250(15.2) 57/247(23.1) 0.595(0.394–0.897)Region:Europe 62/333(18.6) 74/336(22.0) 0.833(0.594–1.167)Region:Asia 14/70(20.0) 14/72(19.4) 0.908(0.427–1.933)
IPS:0–1 22/141(15.6) 25/141(17.7) 0.832(0.469–1.476)IPS:2–3 57/354(16.1) 68/351(19.4) 0.791(0.555–1.126)IPS:4–7 38/169(22.5) 53/178(29.8) 0.703(0.463–1.066)
StageIII 40/237(16.9) 43/246(17.5) 0.923(0.600–1.420)StageIV 77/425(18.1) 102/421(24.2) 0.712(0.530–0.957)
Bsymptoms:Present 77/399(19.3) 94/381(24.7) 0.744(0.550–1.007)Bsymptoms:Absent 40/265(15.1) 52/289(18.0) 0.792(0.524–1.196)
Extranodalsites:0 40/217(18.4) 39/228(17.1) 1.043(0.671–1.621)Extranodalsites:1 36/217(16.6) 45/223(20.2) 0.748(0.481–1.164)Extranodalsites:>1 39/194(20.1) 57/193(29.5) 0.666(0.443–1.001)
Gender:Male 64/378(16.9) 90/398(22.6) 0.705(0.511–0.973)Gender:Female 53/286(18.5) 56/272(20.6) 0.862(0.592–1.255)
Subgroup A+AVD ABVDEvent/N(%)
Hazardratio(95%CI)
OldercHLptstreatedwithsequenKalA-AVD
EvensAetal.JClinOncol2018(online)
PET1 and CT1 (Staging)
BV x 2 cycles (1.8 mg/kg q 3 wks)
AVD x 6 cycles
BV consolidation (1.8 mg/kg q 3 wks x4)
PET2 (first 22pts)
CT + PET (all pts)
• Phase II investigator-initiated study
• Untreated advanced-stage elderly HD (=/> 60 yo)
• Simon 2-stage with plan of 48 total pts
• Primary endpoint: complete remission (CR) rate after AVD
• CGA (CIRS-G) and HRQL assessments
• Study of “early” FDG-PET • Lugano criteria utilizing
FDG-PET/CT (Deauville)
OldercHLptsSequencalA-AVD:Efficacy
EvensAetal.JClinOncol2018(online)
BV x 2 AVD x 3 AVD x 3 BV x 4
ORR 87% CR 30%
(PET)
ORR 98% CR 76%
ORR 95% CR 90%
ORR 95% CR 93%
(N=48) (N=41)
ITT (n=48) after 6 AVD: ORR 88% and CR 81%
OldercHLptsSequencalA-AVD:Safety
EvensAetal.JClinOncol2018(online)
• SAE seen in 42% of pts
• Grade 2 PN in 33% pts (27% sensory) • Majority reversible
Grade 3/4 SAE Percent Infection 15% Febrile Neutropenia 6% Elevated transaminases 6% Renal insufficiency 6% UTI 6% Pneumonia 6% Hyponatremia 6% Fatigue 6% Diarrhea 4% Pancreatitis 4% Peripheral neuropathy 4% Pruritis 2%
OldercHLptsSequencalA-AVD:Survival
2-year EFS 80% 2-Year PFS 84% 2-year OS 93%
EvensAetal.JClinOncol2018(online)
Delta=10.6%
RamchandrenRetal.ASCO2018
Delta=12.8%
RamchandrenRetal.ASCO2018
Delta=11.7%RamchandrenRetal.ASCO2018
Echelon-1: Summary of Action on Drug by Region
• Dose delays higher in Europe than in North America o ~55% vs 35% in A+AVD o Applies to all drugs, difference most noticeable in A+AVD
• Dose reductions and holds higher in North America than Europe o Primarily applies to BV o Less impact on rest of regimen
• Similar rate of BV discontinuation • Bleomycin discontinued at higher rate in North America
A+AVD(N=662) ABVD(N=659)
America(N=260)
Europe(N=332)
Asia(N=70)
America(N=255)
Europe(N=333)
Asia(N=71)
PaPentswithNeutropenia
164(63%)
238(72%)
53(76%)
143(56%)
172(52%)
46(65%)
Percentofneutropeniasleadingtodosedelays
37/164(23%)
102/238(43%)
20/53(38%)
39/143(27%)
64/172(37%)
14/46(30%)
Overallsurvival?
• MulPtudeofeffecPvesalvagetherapies,namelyautologousstemcelltransplantandcheckpointinhibitors(others)
• PFSimportant(towhatdegreeandtradeoffs)!
• Index/realpaEent:31yofemale(working/singlemotherwith2children)withstageIVBcHL(anemia,lymphopenic,leukocytosisandboneinvolvement)– PaPentpreference(acuteandlong-termconsequences)
Studysummaryandconclusions• ECHELON-1results
– AmongbestoutcomesreportedtodateforuntreatedadvancedstageHL– SignificantlysuperiormPFSandPFSwithbrentuximabvedocnin
combinaconwithAVDvsABVD– Independentreview:23%reducconinriskofprogression,deathorneed
foraddiconalanccancertherapy(absolute5%)– Invescgatorreview:28%reducconinriskofprogression,deathorneedfor
addiconalanccancertherapy(absolute7%)– BenefitmoreprominentinN.America:absolute11-13%;RRreduccon50%– Manageable/differenttoxicityprofile
• Bleomycincompletelyomined• G-CSFprimaryprophylaxisrecommendedforallpts• 67%ofptswithPNintheA+AVDarmhadresoluconorimprovement
• Otherconsideracons– Longertermfollow-up(efficacyandtoxicity);QOLanalyses;addiconal/
confirmingdata(communityoncology);cost(includedownstreamRx)
• Primary endpoint: PFS • Secondary endpoints: EFS, OS, CR
470 pts
Newly diagnosed Stage III-IV
Hodgkin lymphoma (ages >11)
R A N D O M I Z E
Nivolumab + AVD 6 cycles
Nivolumab 240mg days 1,15 Doxorubicin 25mg/m2 days 1,15 Vinblastine 6mg/m2 days 1,15
Dacarbazine 375mg/m2 days 1,15
Brentuximab vedotin + AVD
6 cycles BV 1.2mg/kg days 1,15
Doxorubicin 25mg/m2 days 1,15 Vinblastine 6mg/m2 days 1,15
Dacarbazine 375mg/m2 days 1,15
470 pts
1:1
Stratification: • Age • IPS
• ISRT eligible
NewNorthAmericanCooperacveGroupStudyforAdvancedStageHodgkinLymphoma:S1826
Thankyou…………
Acknowledgements
• Clinical mentors: L.Gordon, V.Diehl, S.Horning, many others
• Colleagues, collaborators, and
patients
AddiconalEchelon-1data
• A+AVDconsistentlydemonstratedimprovedefficacyacrosstradiPonaldefiniPonsofPFS,EFS,DFS,andall13sensiPvityanalysesofmPFS– PFSwhereeventsincludeddeath,PD,receiptofsalvagechemoforresidualdisease
(RATHLdefiniEonofPFS)• HR=0.687• 2yeareventrates:84%vs77.3%;delta=6.7%
– PFSwhereeventsincludedeathandPDonly• HR=0.70,p=0.006• 2yeareventrates:84.2%vs78.0%;delta=6.2%
• RadiaPonrarelyusedinNorthAmericaandequalacrossbotharms(3%ofpts)– RadiaPonA+AVDvsABVD:8ptsvs6pts– RadiaPonresultedinthesamenumberofmPFSeventineacharm,A+AVDvs
ABVD:1ptvs1pt• FerPlityissimilarwithA+AVDandABVD
– PregnanciesinpaPentsandpartnersA+AVDvsABVD:42vs36• Abilitytobesalvagedwithhighdosechemotherapyappearssimilarwith
A+AVDandABVD– SimilarproporPonrelapsingptsproceededtoSCTagersalvagechemo:54%vs54%
Echelon-1ForestplotofmodifiedPFSperIRF
RadiaconUseinNorthAmerica:Echelon-1study
SummaryofRadiaconandmPFSIRFModifiedEvents–NorthAmericanPacents
A+AVD ABVD Total
NumberofPaPents
250 247 497
RadiaPonasfirstsubsequentanPcancertherapyn(%)
8(3) 6(2) 14(3)
mPFSIRFmodifiedeventduetoradiaPonn(%)
1(0.4) 1(0.4) 2(0.4)
SummaryofsecondaryefficacyendpointsOS,CR,ORR,andPETnegativitybyIRF
• Keysecondaryendpoint-InterimOS:HR0.721(95%CI:0.443–1.173;p=0.186)infavorofA+AVDversusABVD
– InterimOSanalysisbasedon67deaths
– FinalOSanalysisplannedafter112deaths
• AllsecondaryefficacyendpointstrendedinfavorofA+AVD
*PerCheson2007;†Cochran-Mantel-Haenszel,chi-squaretest;ORR,overallresponserate
Patientswithevent,n(%)
A+AVDN=664
ABVDN=670
p-value†
CRrate*atendofrandomizedregimen 488(73) 472(70) 0.224
ORR*atendofrandomizedregimen 569(86) 553(83) 0.116
PETDeauvillescore1or2aftercompletionoffrontlinetherapy 563(85) 537(80) 0.025
PETDeauvillescore1,2,or3aftercycle2 588(89) 577(86) 0.181
PETDeauvillescore4,or5aftercycle24
5Unavailable
26(4)
21(3)29(4)
28(4)
30(4)35(5)