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)