First Line Management of Classical Hodgkin Lymphoma

George FollowsCambridge University Hospitals NHS Foundation Trust

georgefollowsaddenbrookesnhsuk

The controversial areas

bull Early stage non-bulky favourable

ndash A move to European classification

ndash RT versus no RT and the role of PET

ndash ABVD cycle number (and Escalated BEACOPP use)

bull Advanced stage

ndash Choice of chemotherapy

ndash Role of RT consolidation

ndash Role of PET

bull Elderly HL

EORTCGHSG

No large mediastinal adenopathy No large mediastinal adenopathy

ESR lt50 without B symptoms ESR lt50 without B symptoms

ESR lt30 with B symptoms ESR lt30 with B symptoms

Age le 50 No E-disease

1-3 lymph node sites involved 1-2 lymph node sites involved

EORTC European Organisation for the Research and Treatment of Cancer GHSG German Hodgkinrsquos Study

Group

Table 1 - Favourable prognosis Stage I-II Hodgkin Lymphoma

EORTC

presence of one or more of the following

GHSG

presence of one or more of the following

Large mediastinal adenopathy Large mediastinal adenopathy

ESR ge 50 without B symptoms ESR ge50 without B symptoms

ESR ge 30 with B symptoms ESR ge30 with B symptoms

Age gt50 E-disease

ge 4 lymph node sites involved ge 3 lymph node sites involved

EORTC European Organisation for the Research and Treatment of Cancer GHSG German Hodgkinrsquos Study

Group

Table 2 - Unfavourable prognosis Stage I-II Hodgkin Lymphoma

(analysis of HD10 and HD11 patients with EORTC and NCIC prognostic tool identified very similar splits in PFS and OS Klimm et al Ann Oncol 2013 Oct 22 [Epub ahead of print])

EORTCGHSG

No large mediastinal adenopathy No large mediastinal adenopathy

ESR lt50 without B symptoms ESR lt50 without B symptoms

ESR lt30 with B symptoms ESR lt30 with B symptoms

Age le 50 No E-disease

1-3 lymph node sites involved 1-2 lymph node sites involved

EORTC European Organisation for the Research and Treatment of Cancer GHSG German Hodgkinrsquos Study

Group

Table 1 - Favourable prognosis Stage I-II Hodgkin Lymphoma

EORTC

presence of one or more of the following

GHSG

presence of one or more of the following

Large mediastinal adenopathy Large mediastinal adenopathy

ESR ge 50 without B symptoms ESR ge50 without B symptoms

ESR ge 30 with B symptoms ESR ge30 with B symptoms

Age gt50 E-disease

ge 4 lymph node sites involved ge 3 lymph node sites involved

EORTC European Organisation for the Research and Treatment of Cancer GHSG German Hodgkinrsquos Study

Group

Table 2 - Unfavourable prognosis Stage I-II Hodgkin Lymphoma

(analysis of HD10 and HD11 patients with EORTC and NCIC prognostic tool identified very similar splits in PFS and OS Klimm et al Ann Oncol 2013 Oct 22 [Epub ahead of print])

EORTC

presence of one or more of the following

GHSG

presence of one or more of the following

Large mediastinal adenopathy Large mediastinal adenopathy

ESR ge 50 without B symptoms ESR ge50 without B symptoms

ESR ge 30 with B symptoms ESR ge30 with B symptoms

Age gt50 E-disease

ge 4 lymph node sites involved ge 3 lymph node sites involved

EORTC European Organisation for the Research and Treatment of Cancer GHSG German Hodgkinrsquos Study

Group

Table 2 - Unfavourable prognosis Stage I-II Hodgkin Lymphoma

(analysis of HD10 and HD11 patients with EORTC and NCIC prognostic tool identified very similar splits in PFS and OS Klimm et al Ann Oncol 2013 Oct 22 [Epub ahead of print])

bull Note the UK has historically tended to treat early stage patients with bulk disease or B symptoms with advanced stage protocols and have not separated favourable and unfavourable early stage HL

bull In contrast there are large trials with high quality data and generally excellent outcomes supporting the favourable unfavourable split

Early stage non-bulky favourable HLGerman HD10

GHLSG HD10

Engert A et al N Engl J Med 2010363640-652

ABVD x 2 + 20 Gy IFRT became the international standard of care

NCIC HD6 Meyer RM et al N Engl J Med 2012366399-408

Early stage non-bulky favourable HLCanadian HD6 trial

From 2005 JCO analysis of the same trial

We evaluated 399 patients Median follow-up is 42 years In comparison with ABVD alone 5-year freedom

from disease progression is superior in patients allocated to radiation therapy (P = 006 93 v 87)

Early stage non-bulky favourable HL

Children and adolescent data - multinational trial GPOH-HD95

JCO 2013 Doumlrffel W et al

bull Large multinational European trial with 1000+ patients 10 year f-up

bullTG1 TG2 TG3

Early stage non-bulky favourable HLGerman HD10

GHLSG HD10

Engert A et al N Engl J Med 2010363640-652

ABVD x 2 + 20 Gy IFRT became the international standard of care

NCIC HD6 Meyer RM et al N Engl J Med 2012366399-408

Early stage non-bulky favourable HLCanadian HD6 trial

From 2005 JCO analysis of the same trial

We evaluated 399 patients Median follow-up is 42 years In comparison with ABVD alone 5-year freedom

from disease progression is superior in patients allocated to radiation therapy (P = 006 93 v 87)

Early stage non-bulky favourable HL

Children and adolescent data - multinational trial GPOH-HD95

JCO 2013 Doumlrffel W et al

bull Large multinational European trial with 1000+ patients 10 year f-up

bullTG1 TG2 TG3

NCIC HD6 Meyer RM et al N Engl J Med 2012366399-408

Early stage non-bulky favourable HLCanadian HD6 trial

From 2005 JCO analysis of the same trial

We evaluated 399 patients Median follow-up is 42 years In comparison with ABVD alone 5-year freedom

from disease progression is superior in patients allocated to radiation therapy (P = 006 93 v 87)

Early stage non-bulky favourable HL

Children and adolescent data - multinational trial GPOH-HD95

JCO 2013 Doumlrffel W et al

bull Large multinational European trial with 1000+ patients 10 year f-up

bullTG1 TG2 TG3

Early stage non-bulky favourable HL

Children and adolescent data - multinational trial GPOH-HD95

JCO 2013 Doumlrffel W et al

bull Large multinational European trial with 1000+ patients 10 year f-up

bullTG1 TG2 TG3

Early stage - Role of PET

UK RAPID trial

3 x ABVD PET

N= 602 patients

94 centres UK

Median age 34 years

(16 to 75)

Median f-up 60 months

RT vs No RT

ABVDx1 + RT

Early stage - Role of PET

bull ITT on 420 PET negative patients

ndash no statistical benefit from RT

bull Per protocol on 392 patients

ndash PFS 971 (RT) vs 908 (no RT) p=002

bull OS no difference between arms

bull 12420 deaths in PET negative group

bull 8145 deaths in PET positive group

bull Median follow-up 5 years only

ndash 5 deaths from HL

ndash 2 301 deaths in lt median age group

ndash 18 301 deaths in gt median age group

(2 young deaths 1x DLBL 1 x RT-related)

Early stage - Role of PET

EORTCLYSA H10

bull Early stage favourable an unfavourable trial

bull All patients 2 x ABVD then PET

bull Complex sub-dividing thereafter

EORTCLYSA H10

N = 1950

EORTCLYSA H10

UnfavourableFavourable

4 x ABVD + ISRT

6 x ABVD

3 x ABVD + ISRT

4 x ABVD

1059 iPET2 negative patients

EORTCLYSA H10

UnfavourableFavourable

4 x ABVD + ISRT

6 x ABVD

3 x ABVD + ISRT

4 x ABVD

1059 iPET2 negative patients

EORTCLYSA H10

2 x ABVD + 2 x escB + INRT

3 - 4 x ABVD + INRT

361 iPET2 positive patients ndash median 45 years f-up

Early Stage Unfavourable ndash HD14

German trial

bull gt1500 patients

ABVD x 4 + 30Gy IFRT

vs

escalated BEACOPP x 2 + ABVD x 2 + 30Gy IFRT

Early Stage Unfavourable ndash HD14

escB x 2 + ABVD x 2 + IFRT30Gy

ABVD x 4 + IFRT30Gy

N = 1528

bull HD10 ndash 75 years f-upbull 1190 patients 46 second cancers at 75 years median f-up

bull NCIC HD6 ndash 12 years f-up

ndash ABVD only ndash1196 (05) second cancer at 12 years f-up (seems very low)

bull GPOH-HD95 (paediatric trial)ndash No RT - 1165 = second cancer

ndash RT - 20 746 = second cancer (27) 14 of 17 solid cancers in RT field

bull EORTCLYSA H10 ndash 5 years f-upndash No RT ndash 16540 = 30 second cancer

ndash RT ndash 261385 = 19 second cancer

Early stage Second cancers

Early stage HL

bull The facts

ndash Whole cohort survival very good

ndash Young patients death rate very low indeed

ndash Think about ABVD cycle number

ndash Think very carefully about each case where RT is withheld ( Role for including other risk assessments such as TMTV ndash not discussed)

Advanced Stage Hodgkin Lymphoma

bull Choice of chemotherapy

ndash ABVD vs escalated BEACOPP vs others

bull Who should get radiotherapy consolidation

bull Can we use PET to guide decision making for points 1 and 2

The ABVD ndash escBEACOPP consensus

bull ABVD and escalated BEACOPP will both cure the majority of advanced stage HL patients

bull The majority of advanced stage HL patients do not need radiotherapy consolidation

bull Escalated BEACOPP is a more lsquoeffectiversquo HL therapy

bull Escalated BEACOPP is a more lsquotoxicrsquo HL therapy

bull The lsquorelative gainrsquo for escBEACOPP is more for higher risk patients

The ABVD ndash escBEACOPP controversies

bull Should escBEACOPP be reserved for poorer risk patients

bull How should we optimally escalate de-escalate between the two

bull Will the addition of BV to either regimen have a role to play in the UK

Advanced Stage Hodgkin Lymphoma

bull The German escalated BEACOPP journey

HD9

(8 x escB)

10 year f-up 2009

HD15

(6 x escB)

HD18

(4 x escB)

5 year f-up 2017

HD18

bull All patients started with 2 x escalated BEACOPP

bull iPET2 randomised (D12 = negative = 50)ndash PET + variations with rituximab (made no difference)

ndash PET - total 4 cycles vs 6 or 8 cycles

HD18 ndash iPET did not affect outcome

Borchman et al (2017) Lancet

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

Early stage - Role of PET

bull ITT on 420 PET negative patients

ndash no statistical benefit from RT

bull Per protocol on 392 patients

ndash PFS 971 (RT) vs 908 (no RT) p=002

bull OS no difference between arms

bull 12420 deaths in PET negative group

bull 8145 deaths in PET positive group

bull Median follow-up 5 years only

ndash 5 deaths from HL

ndash 2 301 deaths in lt median age group

ndash 18 301 deaths in gt median age group

(2 young deaths 1x DLBL 1 x RT-related)

Early stage - Role of PET

EORTCLYSA H10

bull Early stage favourable an unfavourable trial

bull All patients 2 x ABVD then PET

bull Complex sub-dividing thereafter

EORTCLYSA H10

N = 1950

EORTCLYSA H10

UnfavourableFavourable

4 x ABVD + ISRT

6 x ABVD

3 x ABVD + ISRT

4 x ABVD

1059 iPET2 negative patients

EORTCLYSA H10

UnfavourableFavourable

4 x ABVD + ISRT

6 x ABVD

3 x ABVD + ISRT

4 x ABVD

1059 iPET2 negative patients

EORTCLYSA H10

2 x ABVD + 2 x escB + INRT

3 - 4 x ABVD + INRT

361 iPET2 positive patients ndash median 45 years f-up

Early Stage Unfavourable ndash HD14

German trial

bull gt1500 patients

ABVD x 4 + 30Gy IFRT

vs

escalated BEACOPP x 2 + ABVD x 2 + 30Gy IFRT

Early Stage Unfavourable ndash HD14

escB x 2 + ABVD x 2 + IFRT30Gy

ABVD x 4 + IFRT30Gy

N = 1528

bull HD10 ndash 75 years f-upbull 1190 patients 46 second cancers at 75 years median f-up

bull NCIC HD6 ndash 12 years f-up

ndash ABVD only ndash1196 (05) second cancer at 12 years f-up (seems very low)

bull GPOH-HD95 (paediatric trial)ndash No RT - 1165 = second cancer

ndash RT - 20 746 = second cancer (27) 14 of 17 solid cancers in RT field

bull EORTCLYSA H10 ndash 5 years f-upndash No RT ndash 16540 = 30 second cancer

ndash RT ndash 261385 = 19 second cancer

Early stage Second cancers

Early stage HL

bull The facts

ndash Whole cohort survival very good

ndash Young patients death rate very low indeed

ndash Think about ABVD cycle number

ndash Think very carefully about each case where RT is withheld ( Role for including other risk assessments such as TMTV ndash not discussed)

Advanced Stage Hodgkin Lymphoma

bull Choice of chemotherapy

ndash ABVD vs escalated BEACOPP vs others

bull Who should get radiotherapy consolidation

bull Can we use PET to guide decision making for points 1 and 2

The ABVD ndash escBEACOPP consensus

bull ABVD and escalated BEACOPP will both cure the majority of advanced stage HL patients

bull The majority of advanced stage HL patients do not need radiotherapy consolidation

bull Escalated BEACOPP is a more lsquoeffectiversquo HL therapy

bull Escalated BEACOPP is a more lsquotoxicrsquo HL therapy

bull The lsquorelative gainrsquo for escBEACOPP is more for higher risk patients

The ABVD ndash escBEACOPP controversies

bull Should escBEACOPP be reserved for poorer risk patients

bull How should we optimally escalate de-escalate between the two

bull Will the addition of BV to either regimen have a role to play in the UK

Advanced Stage Hodgkin Lymphoma

bull The German escalated BEACOPP journey

HD9

(8 x escB)

10 year f-up 2009

HD15

(6 x escB)

HD18

(4 x escB)

5 year f-up 2017

HD18

bull All patients started with 2 x escalated BEACOPP

bull iPET2 randomised (D12 = negative = 50)ndash PET + variations with rituximab (made no difference)

ndash PET - total 4 cycles vs 6 or 8 cycles

HD18 ndash iPET did not affect outcome

Borchman et al (2017) Lancet

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

bull 12420 deaths in PET negative group

bull 8145 deaths in PET positive group

bull Median follow-up 5 years only

ndash 5 deaths from HL

ndash 2 301 deaths in lt median age group

ndash 18 301 deaths in gt median age group

(2 young deaths 1x DLBL 1 x RT-related)

Early stage - Role of PET

EORTCLYSA H10

bull Early stage favourable an unfavourable trial

bull All patients 2 x ABVD then PET

bull Complex sub-dividing thereafter

EORTCLYSA H10

N = 1950

EORTCLYSA H10

UnfavourableFavourable

4 x ABVD + ISRT

6 x ABVD

3 x ABVD + ISRT

4 x ABVD

1059 iPET2 negative patients

EORTCLYSA H10

UnfavourableFavourable

4 x ABVD + ISRT

6 x ABVD

3 x ABVD + ISRT

4 x ABVD

1059 iPET2 negative patients

EORTCLYSA H10

2 x ABVD + 2 x escB + INRT

3 - 4 x ABVD + INRT

361 iPET2 positive patients ndash median 45 years f-up

Early Stage Unfavourable ndash HD14

German trial

bull gt1500 patients

ABVD x 4 + 30Gy IFRT

vs

escalated BEACOPP x 2 + ABVD x 2 + 30Gy IFRT

Early Stage Unfavourable ndash HD14

escB x 2 + ABVD x 2 + IFRT30Gy

ABVD x 4 + IFRT30Gy

N = 1528

bull HD10 ndash 75 years f-upbull 1190 patients 46 second cancers at 75 years median f-up

bull NCIC HD6 ndash 12 years f-up

ndash ABVD only ndash1196 (05) second cancer at 12 years f-up (seems very low)

bull GPOH-HD95 (paediatric trial)ndash No RT - 1165 = second cancer

ndash RT - 20 746 = second cancer (27) 14 of 17 solid cancers in RT field

bull EORTCLYSA H10 ndash 5 years f-upndash No RT ndash 16540 = 30 second cancer

ndash RT ndash 261385 = 19 second cancer

Early stage Second cancers

Early stage HL

bull The facts

ndash Whole cohort survival very good

ndash Young patients death rate very low indeed

ndash Think about ABVD cycle number

ndash Think very carefully about each case where RT is withheld ( Role for including other risk assessments such as TMTV ndash not discussed)

Advanced Stage Hodgkin Lymphoma

bull Choice of chemotherapy

ndash ABVD vs escalated BEACOPP vs others

bull Who should get radiotherapy consolidation

bull Can we use PET to guide decision making for points 1 and 2

The ABVD ndash escBEACOPP consensus

bull ABVD and escalated BEACOPP will both cure the majority of advanced stage HL patients

bull The majority of advanced stage HL patients do not need radiotherapy consolidation

bull Escalated BEACOPP is a more lsquoeffectiversquo HL therapy

bull Escalated BEACOPP is a more lsquotoxicrsquo HL therapy

bull The lsquorelative gainrsquo for escBEACOPP is more for higher risk patients

The ABVD ndash escBEACOPP controversies

bull Should escBEACOPP be reserved for poorer risk patients

bull How should we optimally escalate de-escalate between the two

bull Will the addition of BV to either regimen have a role to play in the UK

Advanced Stage Hodgkin Lymphoma

bull The German escalated BEACOPP journey

HD9

(8 x escB)

10 year f-up 2009

HD15

(6 x escB)

HD18

(4 x escB)

5 year f-up 2017

HD18

bull All patients started with 2 x escalated BEACOPP

bull iPET2 randomised (D12 = negative = 50)ndash PET + variations with rituximab (made no difference)

ndash PET - total 4 cycles vs 6 or 8 cycles

HD18 ndash iPET did not affect outcome

Borchman et al (2017) Lancet

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

EORTCLYSA H10

bull Early stage favourable an unfavourable trial

bull All patients 2 x ABVD then PET

bull Complex sub-dividing thereafter

EORTCLYSA H10

N = 1950

EORTCLYSA H10

UnfavourableFavourable

4 x ABVD + ISRT

6 x ABVD

3 x ABVD + ISRT

4 x ABVD

1059 iPET2 negative patients

EORTCLYSA H10

UnfavourableFavourable

4 x ABVD + ISRT

6 x ABVD

3 x ABVD + ISRT

4 x ABVD

1059 iPET2 negative patients

EORTCLYSA H10

2 x ABVD + 2 x escB + INRT

3 - 4 x ABVD + INRT

361 iPET2 positive patients ndash median 45 years f-up

Early Stage Unfavourable ndash HD14

German trial

bull gt1500 patients

ABVD x 4 + 30Gy IFRT

vs

escalated BEACOPP x 2 + ABVD x 2 + 30Gy IFRT

Early Stage Unfavourable ndash HD14

escB x 2 + ABVD x 2 + IFRT30Gy

ABVD x 4 + IFRT30Gy

N = 1528

bull HD10 ndash 75 years f-upbull 1190 patients 46 second cancers at 75 years median f-up

bull NCIC HD6 ndash 12 years f-up

ndash ABVD only ndash1196 (05) second cancer at 12 years f-up (seems very low)

bull GPOH-HD95 (paediatric trial)ndash No RT - 1165 = second cancer

ndash RT - 20 746 = second cancer (27) 14 of 17 solid cancers in RT field

bull EORTCLYSA H10 ndash 5 years f-upndash No RT ndash 16540 = 30 second cancer

ndash RT ndash 261385 = 19 second cancer

Early stage Second cancers

Early stage HL

bull The facts

ndash Whole cohort survival very good

ndash Young patients death rate very low indeed

ndash Think about ABVD cycle number

ndash Think very carefully about each case where RT is withheld ( Role for including other risk assessments such as TMTV ndash not discussed)

Advanced Stage Hodgkin Lymphoma

bull Choice of chemotherapy

ndash ABVD vs escalated BEACOPP vs others

bull Who should get radiotherapy consolidation

bull Can we use PET to guide decision making for points 1 and 2

The ABVD ndash escBEACOPP consensus

bull ABVD and escalated BEACOPP will both cure the majority of advanced stage HL patients

bull The majority of advanced stage HL patients do not need radiotherapy consolidation

bull Escalated BEACOPP is a more lsquoeffectiversquo HL therapy

bull Escalated BEACOPP is a more lsquotoxicrsquo HL therapy

bull The lsquorelative gainrsquo for escBEACOPP is more for higher risk patients

The ABVD ndash escBEACOPP controversies

bull Should escBEACOPP be reserved for poorer risk patients

bull How should we optimally escalate de-escalate between the two

bull Will the addition of BV to either regimen have a role to play in the UK

Advanced Stage Hodgkin Lymphoma

bull The German escalated BEACOPP journey

HD9

(8 x escB)

10 year f-up 2009

HD15

(6 x escB)

HD18

(4 x escB)

5 year f-up 2017

HD18

bull All patients started with 2 x escalated BEACOPP

bull iPET2 randomised (D12 = negative = 50)ndash PET + variations with rituximab (made no difference)

ndash PET - total 4 cycles vs 6 or 8 cycles

HD18 ndash iPET did not affect outcome

Borchman et al (2017) Lancet

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

EORTCLYSA H10

N = 1950

EORTCLYSA H10

UnfavourableFavourable

4 x ABVD + ISRT

6 x ABVD

3 x ABVD + ISRT

4 x ABVD

1059 iPET2 negative patients

EORTCLYSA H10

UnfavourableFavourable

4 x ABVD + ISRT

6 x ABVD

3 x ABVD + ISRT

4 x ABVD

1059 iPET2 negative patients

EORTCLYSA H10

2 x ABVD + 2 x escB + INRT

3 - 4 x ABVD + INRT

361 iPET2 positive patients ndash median 45 years f-up

Early Stage Unfavourable ndash HD14

German trial

bull gt1500 patients

ABVD x 4 + 30Gy IFRT

vs

escalated BEACOPP x 2 + ABVD x 2 + 30Gy IFRT

Early Stage Unfavourable ndash HD14

escB x 2 + ABVD x 2 + IFRT30Gy

ABVD x 4 + IFRT30Gy

N = 1528

bull HD10 ndash 75 years f-upbull 1190 patients 46 second cancers at 75 years median f-up

bull NCIC HD6 ndash 12 years f-up

ndash ABVD only ndash1196 (05) second cancer at 12 years f-up (seems very low)

bull GPOH-HD95 (paediatric trial)ndash No RT - 1165 = second cancer

ndash RT - 20 746 = second cancer (27) 14 of 17 solid cancers in RT field

bull EORTCLYSA H10 ndash 5 years f-upndash No RT ndash 16540 = 30 second cancer

ndash RT ndash 261385 = 19 second cancer

Early stage Second cancers

Early stage HL

bull The facts

ndash Whole cohort survival very good

ndash Young patients death rate very low indeed

ndash Think about ABVD cycle number

ndash Think very carefully about each case where RT is withheld ( Role for including other risk assessments such as TMTV ndash not discussed)

Advanced Stage Hodgkin Lymphoma

bull Choice of chemotherapy

ndash ABVD vs escalated BEACOPP vs others

bull Who should get radiotherapy consolidation

bull Can we use PET to guide decision making for points 1 and 2

The ABVD ndash escBEACOPP consensus

bull ABVD and escalated BEACOPP will both cure the majority of advanced stage HL patients

bull The majority of advanced stage HL patients do not need radiotherapy consolidation

bull Escalated BEACOPP is a more lsquoeffectiversquo HL therapy

bull Escalated BEACOPP is a more lsquotoxicrsquo HL therapy

bull The lsquorelative gainrsquo for escBEACOPP is more for higher risk patients

The ABVD ndash escBEACOPP controversies

bull Should escBEACOPP be reserved for poorer risk patients

bull How should we optimally escalate de-escalate between the two

bull Will the addition of BV to either regimen have a role to play in the UK

Advanced Stage Hodgkin Lymphoma

bull The German escalated BEACOPP journey

HD9

(8 x escB)

10 year f-up 2009

HD15

(6 x escB)

HD18

(4 x escB)

5 year f-up 2017

HD18

bull All patients started with 2 x escalated BEACOPP

bull iPET2 randomised (D12 = negative = 50)ndash PET + variations with rituximab (made no difference)

ndash PET - total 4 cycles vs 6 or 8 cycles

HD18 ndash iPET did not affect outcome

Borchman et al (2017) Lancet

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

EORTCLYSA H10

UnfavourableFavourable

4 x ABVD + ISRT

6 x ABVD

3 x ABVD + ISRT

4 x ABVD

1059 iPET2 negative patients

EORTCLYSA H10

UnfavourableFavourable

4 x ABVD + ISRT

6 x ABVD

3 x ABVD + ISRT

4 x ABVD

1059 iPET2 negative patients

EORTCLYSA H10

2 x ABVD + 2 x escB + INRT

3 - 4 x ABVD + INRT

361 iPET2 positive patients ndash median 45 years f-up

Early Stage Unfavourable ndash HD14

German trial

bull gt1500 patients

ABVD x 4 + 30Gy IFRT

vs

escalated BEACOPP x 2 + ABVD x 2 + 30Gy IFRT

Early Stage Unfavourable ndash HD14

escB x 2 + ABVD x 2 + IFRT30Gy

ABVD x 4 + IFRT30Gy

N = 1528

bull HD10 ndash 75 years f-upbull 1190 patients 46 second cancers at 75 years median f-up

bull NCIC HD6 ndash 12 years f-up

ndash ABVD only ndash1196 (05) second cancer at 12 years f-up (seems very low)

bull GPOH-HD95 (paediatric trial)ndash No RT - 1165 = second cancer

ndash RT - 20 746 = second cancer (27) 14 of 17 solid cancers in RT field

bull EORTCLYSA H10 ndash 5 years f-upndash No RT ndash 16540 = 30 second cancer

ndash RT ndash 261385 = 19 second cancer

Early stage Second cancers

Early stage HL

bull The facts

ndash Whole cohort survival very good

ndash Young patients death rate very low indeed

ndash Think about ABVD cycle number

ndash Think very carefully about each case where RT is withheld ( Role for including other risk assessments such as TMTV ndash not discussed)

Advanced Stage Hodgkin Lymphoma

bull Choice of chemotherapy

ndash ABVD vs escalated BEACOPP vs others

bull Who should get radiotherapy consolidation

bull Can we use PET to guide decision making for points 1 and 2

The ABVD ndash escBEACOPP consensus

bull ABVD and escalated BEACOPP will both cure the majority of advanced stage HL patients

bull The majority of advanced stage HL patients do not need radiotherapy consolidation

bull Escalated BEACOPP is a more lsquoeffectiversquo HL therapy

bull Escalated BEACOPP is a more lsquotoxicrsquo HL therapy

bull The lsquorelative gainrsquo for escBEACOPP is more for higher risk patients

The ABVD ndash escBEACOPP controversies

bull Should escBEACOPP be reserved for poorer risk patients

bull How should we optimally escalate de-escalate between the two

bull Will the addition of BV to either regimen have a role to play in the UK

Advanced Stage Hodgkin Lymphoma

bull The German escalated BEACOPP journey

HD9

(8 x escB)

10 year f-up 2009

HD15

(6 x escB)

HD18

(4 x escB)

5 year f-up 2017

HD18

bull All patients started with 2 x escalated BEACOPP

bull iPET2 randomised (D12 = negative = 50)ndash PET + variations with rituximab (made no difference)

ndash PET - total 4 cycles vs 6 or 8 cycles

HD18 ndash iPET did not affect outcome

Borchman et al (2017) Lancet

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

EORTCLYSA H10

UnfavourableFavourable

4 x ABVD + ISRT

6 x ABVD

3 x ABVD + ISRT

4 x ABVD

1059 iPET2 negative patients

EORTCLYSA H10

2 x ABVD + 2 x escB + INRT

3 - 4 x ABVD + INRT

361 iPET2 positive patients ndash median 45 years f-up

Early Stage Unfavourable ndash HD14

German trial

bull gt1500 patients

ABVD x 4 + 30Gy IFRT

vs

escalated BEACOPP x 2 + ABVD x 2 + 30Gy IFRT

Early Stage Unfavourable ndash HD14

escB x 2 + ABVD x 2 + IFRT30Gy

ABVD x 4 + IFRT30Gy

N = 1528

bull HD10 ndash 75 years f-upbull 1190 patients 46 second cancers at 75 years median f-up

bull NCIC HD6 ndash 12 years f-up

ndash ABVD only ndash1196 (05) second cancer at 12 years f-up (seems very low)

bull GPOH-HD95 (paediatric trial)ndash No RT - 1165 = second cancer

ndash RT - 20 746 = second cancer (27) 14 of 17 solid cancers in RT field

bull EORTCLYSA H10 ndash 5 years f-upndash No RT ndash 16540 = 30 second cancer

ndash RT ndash 261385 = 19 second cancer

Early stage Second cancers

Early stage HL

bull The facts

ndash Whole cohort survival very good

ndash Young patients death rate very low indeed

ndash Think about ABVD cycle number

ndash Think very carefully about each case where RT is withheld ( Role for including other risk assessments such as TMTV ndash not discussed)

Advanced Stage Hodgkin Lymphoma

bull Choice of chemotherapy

ndash ABVD vs escalated BEACOPP vs others

bull Who should get radiotherapy consolidation

bull Can we use PET to guide decision making for points 1 and 2

The ABVD ndash escBEACOPP consensus

bull ABVD and escalated BEACOPP will both cure the majority of advanced stage HL patients

bull The majority of advanced stage HL patients do not need radiotherapy consolidation

bull Escalated BEACOPP is a more lsquoeffectiversquo HL therapy

bull Escalated BEACOPP is a more lsquotoxicrsquo HL therapy

bull The lsquorelative gainrsquo for escBEACOPP is more for higher risk patients

The ABVD ndash escBEACOPP controversies

bull Should escBEACOPP be reserved for poorer risk patients

bull How should we optimally escalate de-escalate between the two

bull Will the addition of BV to either regimen have a role to play in the UK

Advanced Stage Hodgkin Lymphoma

bull The German escalated BEACOPP journey

HD9

(8 x escB)

10 year f-up 2009

HD15

(6 x escB)

HD18

(4 x escB)

5 year f-up 2017

HD18

bull All patients started with 2 x escalated BEACOPP

bull iPET2 randomised (D12 = negative = 50)ndash PET + variations with rituximab (made no difference)

ndash PET - total 4 cycles vs 6 or 8 cycles

HD18 ndash iPET did not affect outcome

Borchman et al (2017) Lancet

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

EORTCLYSA H10

2 x ABVD + 2 x escB + INRT

3 - 4 x ABVD + INRT

361 iPET2 positive patients ndash median 45 years f-up

Early Stage Unfavourable ndash HD14

German trial

bull gt1500 patients

ABVD x 4 + 30Gy IFRT

vs

escalated BEACOPP x 2 + ABVD x 2 + 30Gy IFRT

Early Stage Unfavourable ndash HD14

escB x 2 + ABVD x 2 + IFRT30Gy

ABVD x 4 + IFRT30Gy

N = 1528

bull HD10 ndash 75 years f-upbull 1190 patients 46 second cancers at 75 years median f-up

bull NCIC HD6 ndash 12 years f-up

ndash ABVD only ndash1196 (05) second cancer at 12 years f-up (seems very low)

bull GPOH-HD95 (paediatric trial)ndash No RT - 1165 = second cancer

ndash RT - 20 746 = second cancer (27) 14 of 17 solid cancers in RT field

bull EORTCLYSA H10 ndash 5 years f-upndash No RT ndash 16540 = 30 second cancer

ndash RT ndash 261385 = 19 second cancer

Early stage Second cancers

Early stage HL

bull The facts

ndash Whole cohort survival very good

ndash Young patients death rate very low indeed

ndash Think about ABVD cycle number

ndash Think very carefully about each case where RT is withheld ( Role for including other risk assessments such as TMTV ndash not discussed)

Advanced Stage Hodgkin Lymphoma

bull Choice of chemotherapy

ndash ABVD vs escalated BEACOPP vs others

bull Who should get radiotherapy consolidation

bull Can we use PET to guide decision making for points 1 and 2

The ABVD ndash escBEACOPP consensus

bull ABVD and escalated BEACOPP will both cure the majority of advanced stage HL patients

bull The majority of advanced stage HL patients do not need radiotherapy consolidation

bull Escalated BEACOPP is a more lsquoeffectiversquo HL therapy

bull Escalated BEACOPP is a more lsquotoxicrsquo HL therapy

bull The lsquorelative gainrsquo for escBEACOPP is more for higher risk patients

The ABVD ndash escBEACOPP controversies

bull Should escBEACOPP be reserved for poorer risk patients

bull How should we optimally escalate de-escalate between the two

bull Will the addition of BV to either regimen have a role to play in the UK

Advanced Stage Hodgkin Lymphoma

bull The German escalated BEACOPP journey

HD9

(8 x escB)

10 year f-up 2009

HD15

(6 x escB)

HD18

(4 x escB)

5 year f-up 2017

HD18

bull All patients started with 2 x escalated BEACOPP

bull iPET2 randomised (D12 = negative = 50)ndash PET + variations with rituximab (made no difference)

ndash PET - total 4 cycles vs 6 or 8 cycles

HD18 ndash iPET did not affect outcome

Borchman et al (2017) Lancet

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

Early Stage Unfavourable ndash HD14

German trial

bull gt1500 patients

ABVD x 4 + 30Gy IFRT

vs

escalated BEACOPP x 2 + ABVD x 2 + 30Gy IFRT

Early Stage Unfavourable ndash HD14

escB x 2 + ABVD x 2 + IFRT30Gy

ABVD x 4 + IFRT30Gy

N = 1528

bull HD10 ndash 75 years f-upbull 1190 patients 46 second cancers at 75 years median f-up

bull NCIC HD6 ndash 12 years f-up

ndash ABVD only ndash1196 (05) second cancer at 12 years f-up (seems very low)

bull GPOH-HD95 (paediatric trial)ndash No RT - 1165 = second cancer

ndash RT - 20 746 = second cancer (27) 14 of 17 solid cancers in RT field

bull EORTCLYSA H10 ndash 5 years f-upndash No RT ndash 16540 = 30 second cancer

ndash RT ndash 261385 = 19 second cancer

Early stage Second cancers

Early stage HL

bull The facts

ndash Whole cohort survival very good

ndash Young patients death rate very low indeed

ndash Think about ABVD cycle number

ndash Think very carefully about each case where RT is withheld ( Role for including other risk assessments such as TMTV ndash not discussed)

Advanced Stage Hodgkin Lymphoma

bull Choice of chemotherapy

ndash ABVD vs escalated BEACOPP vs others

bull Who should get radiotherapy consolidation

bull Can we use PET to guide decision making for points 1 and 2

The ABVD ndash escBEACOPP consensus

bull ABVD and escalated BEACOPP will both cure the majority of advanced stage HL patients

bull The majority of advanced stage HL patients do not need radiotherapy consolidation

bull Escalated BEACOPP is a more lsquoeffectiversquo HL therapy

bull Escalated BEACOPP is a more lsquotoxicrsquo HL therapy

bull The lsquorelative gainrsquo for escBEACOPP is more for higher risk patients

The ABVD ndash escBEACOPP controversies

bull Should escBEACOPP be reserved for poorer risk patients

bull How should we optimally escalate de-escalate between the two

bull Will the addition of BV to either regimen have a role to play in the UK

Advanced Stage Hodgkin Lymphoma

bull The German escalated BEACOPP journey

HD9

(8 x escB)

10 year f-up 2009

HD15

(6 x escB)

HD18

(4 x escB)

5 year f-up 2017

HD18

bull All patients started with 2 x escalated BEACOPP

bull iPET2 randomised (D12 = negative = 50)ndash PET + variations with rituximab (made no difference)

ndash PET - total 4 cycles vs 6 or 8 cycles

HD18 ndash iPET did not affect outcome

Borchman et al (2017) Lancet

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

Early Stage Unfavourable ndash HD14

escB x 2 + ABVD x 2 + IFRT30Gy

ABVD x 4 + IFRT30Gy

N = 1528

bull HD10 ndash 75 years f-upbull 1190 patients 46 second cancers at 75 years median f-up

bull NCIC HD6 ndash 12 years f-up

ndash ABVD only ndash1196 (05) second cancer at 12 years f-up (seems very low)

bull GPOH-HD95 (paediatric trial)ndash No RT - 1165 = second cancer

ndash RT - 20 746 = second cancer (27) 14 of 17 solid cancers in RT field

bull EORTCLYSA H10 ndash 5 years f-upndash No RT ndash 16540 = 30 second cancer

ndash RT ndash 261385 = 19 second cancer

Early stage Second cancers

Early stage HL

bull The facts

ndash Whole cohort survival very good

ndash Young patients death rate very low indeed

ndash Think about ABVD cycle number

ndash Think very carefully about each case where RT is withheld ( Role for including other risk assessments such as TMTV ndash not discussed)

Advanced Stage Hodgkin Lymphoma

bull Choice of chemotherapy

ndash ABVD vs escalated BEACOPP vs others

bull Who should get radiotherapy consolidation

bull Can we use PET to guide decision making for points 1 and 2

The ABVD ndash escBEACOPP consensus

bull ABVD and escalated BEACOPP will both cure the majority of advanced stage HL patients

bull The majority of advanced stage HL patients do not need radiotherapy consolidation

bull Escalated BEACOPP is a more lsquoeffectiversquo HL therapy

bull Escalated BEACOPP is a more lsquotoxicrsquo HL therapy

bull The lsquorelative gainrsquo for escBEACOPP is more for higher risk patients

The ABVD ndash escBEACOPP controversies

bull Should escBEACOPP be reserved for poorer risk patients

bull How should we optimally escalate de-escalate between the two

bull Will the addition of BV to either regimen have a role to play in the UK

Advanced Stage Hodgkin Lymphoma

bull The German escalated BEACOPP journey

HD9

(8 x escB)

10 year f-up 2009

HD15

(6 x escB)

HD18

(4 x escB)

5 year f-up 2017

HD18

bull All patients started with 2 x escalated BEACOPP

bull iPET2 randomised (D12 = negative = 50)ndash PET + variations with rituximab (made no difference)

ndash PET - total 4 cycles vs 6 or 8 cycles

HD18 ndash iPET did not affect outcome

Borchman et al (2017) Lancet

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

bull HD10 ndash 75 years f-upbull 1190 patients 46 second cancers at 75 years median f-up

bull NCIC HD6 ndash 12 years f-up

ndash ABVD only ndash1196 (05) second cancer at 12 years f-up (seems very low)

bull GPOH-HD95 (paediatric trial)ndash No RT - 1165 = second cancer

ndash RT - 20 746 = second cancer (27) 14 of 17 solid cancers in RT field

bull EORTCLYSA H10 ndash 5 years f-upndash No RT ndash 16540 = 30 second cancer

ndash RT ndash 261385 = 19 second cancer

Early stage Second cancers

Early stage HL

bull The facts

ndash Whole cohort survival very good

ndash Young patients death rate very low indeed

ndash Think about ABVD cycle number

ndash Think very carefully about each case where RT is withheld ( Role for including other risk assessments such as TMTV ndash not discussed)

Advanced Stage Hodgkin Lymphoma

bull Choice of chemotherapy

ndash ABVD vs escalated BEACOPP vs others

bull Who should get radiotherapy consolidation

bull Can we use PET to guide decision making for points 1 and 2

The ABVD ndash escBEACOPP consensus

bull ABVD and escalated BEACOPP will both cure the majority of advanced stage HL patients

bull The majority of advanced stage HL patients do not need radiotherapy consolidation

bull Escalated BEACOPP is a more lsquoeffectiversquo HL therapy

bull Escalated BEACOPP is a more lsquotoxicrsquo HL therapy

bull The lsquorelative gainrsquo for escBEACOPP is more for higher risk patients

The ABVD ndash escBEACOPP controversies

bull Should escBEACOPP be reserved for poorer risk patients

bull How should we optimally escalate de-escalate between the two

bull Will the addition of BV to either regimen have a role to play in the UK

Advanced Stage Hodgkin Lymphoma

bull The German escalated BEACOPP journey

HD9

(8 x escB)

10 year f-up 2009

HD15

(6 x escB)

HD18

(4 x escB)

5 year f-up 2017

HD18

bull All patients started with 2 x escalated BEACOPP

bull iPET2 randomised (D12 = negative = 50)ndash PET + variations with rituximab (made no difference)

ndash PET - total 4 cycles vs 6 or 8 cycles

HD18 ndash iPET did not affect outcome

Borchman et al (2017) Lancet

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

Early stage HL

bull The facts

ndash Whole cohort survival very good

ndash Young patients death rate very low indeed

ndash Think about ABVD cycle number

ndash Think very carefully about each case where RT is withheld ( Role for including other risk assessments such as TMTV ndash not discussed)

Advanced Stage Hodgkin Lymphoma

bull Choice of chemotherapy

ndash ABVD vs escalated BEACOPP vs others

bull Who should get radiotherapy consolidation

bull Can we use PET to guide decision making for points 1 and 2

The ABVD ndash escBEACOPP consensus

bull ABVD and escalated BEACOPP will both cure the majority of advanced stage HL patients

bull The majority of advanced stage HL patients do not need radiotherapy consolidation

bull Escalated BEACOPP is a more lsquoeffectiversquo HL therapy

bull Escalated BEACOPP is a more lsquotoxicrsquo HL therapy

bull The lsquorelative gainrsquo for escBEACOPP is more for higher risk patients

The ABVD ndash escBEACOPP controversies

bull Should escBEACOPP be reserved for poorer risk patients

bull How should we optimally escalate de-escalate between the two

bull Will the addition of BV to either regimen have a role to play in the UK

Advanced Stage Hodgkin Lymphoma

bull The German escalated BEACOPP journey

HD9

(8 x escB)

10 year f-up 2009

HD15

(6 x escB)

HD18

(4 x escB)

5 year f-up 2017

HD18

bull All patients started with 2 x escalated BEACOPP

bull iPET2 randomised (D12 = negative = 50)ndash PET + variations with rituximab (made no difference)

ndash PET - total 4 cycles vs 6 or 8 cycles

HD18 ndash iPET did not affect outcome

Borchman et al (2017) Lancet

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

Advanced Stage Hodgkin Lymphoma

bull Choice of chemotherapy

ndash ABVD vs escalated BEACOPP vs others

bull Who should get radiotherapy consolidation

bull Can we use PET to guide decision making for points 1 and 2

The ABVD ndash escBEACOPP consensus

bull ABVD and escalated BEACOPP will both cure the majority of advanced stage HL patients

bull The majority of advanced stage HL patients do not need radiotherapy consolidation

bull Escalated BEACOPP is a more lsquoeffectiversquo HL therapy

bull Escalated BEACOPP is a more lsquotoxicrsquo HL therapy

bull The lsquorelative gainrsquo for escBEACOPP is more for higher risk patients

The ABVD ndash escBEACOPP controversies

bull Should escBEACOPP be reserved for poorer risk patients

bull How should we optimally escalate de-escalate between the two

bull Will the addition of BV to either regimen have a role to play in the UK

Advanced Stage Hodgkin Lymphoma

bull The German escalated BEACOPP journey

HD9

(8 x escB)

10 year f-up 2009

HD15

(6 x escB)

HD18

(4 x escB)

5 year f-up 2017

HD18

bull All patients started with 2 x escalated BEACOPP

bull iPET2 randomised (D12 = negative = 50)ndash PET + variations with rituximab (made no difference)

ndash PET - total 4 cycles vs 6 or 8 cycles

HD18 ndash iPET did not affect outcome

Borchman et al (2017) Lancet

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

The ABVD ndash escBEACOPP consensus

bull ABVD and escalated BEACOPP will both cure the majority of advanced stage HL patients

bull The majority of advanced stage HL patients do not need radiotherapy consolidation

bull Escalated BEACOPP is a more lsquoeffectiversquo HL therapy

bull Escalated BEACOPP is a more lsquotoxicrsquo HL therapy

bull The lsquorelative gainrsquo for escBEACOPP is more for higher risk patients

The ABVD ndash escBEACOPP controversies

bull Should escBEACOPP be reserved for poorer risk patients

bull How should we optimally escalate de-escalate between the two

bull Will the addition of BV to either regimen have a role to play in the UK

Advanced Stage Hodgkin Lymphoma

bull The German escalated BEACOPP journey

HD9

(8 x escB)

10 year f-up 2009

HD15

(6 x escB)

HD18

(4 x escB)

5 year f-up 2017

HD18

bull All patients started with 2 x escalated BEACOPP

bull iPET2 randomised (D12 = negative = 50)ndash PET + variations with rituximab (made no difference)

ndash PET - total 4 cycles vs 6 or 8 cycles

HD18 ndash iPET did not affect outcome

Borchman et al (2017) Lancet

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

The ABVD ndash escBEACOPP controversies

bull Should escBEACOPP be reserved for poorer risk patients

bull How should we optimally escalate de-escalate between the two

bull Will the addition of BV to either regimen have a role to play in the UK

Advanced Stage Hodgkin Lymphoma

bull The German escalated BEACOPP journey

HD9

(8 x escB)

10 year f-up 2009

HD15

(6 x escB)

HD18

(4 x escB)

5 year f-up 2017

HD18

bull All patients started with 2 x escalated BEACOPP

bull iPET2 randomised (D12 = negative = 50)ndash PET + variations with rituximab (made no difference)

ndash PET - total 4 cycles vs 6 or 8 cycles

HD18 ndash iPET did not affect outcome

Borchman et al (2017) Lancet

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

Advanced Stage Hodgkin Lymphoma

bull The German escalated BEACOPP journey

HD9

(8 x escB)

10 year f-up 2009

HD15

(6 x escB)

HD18

(4 x escB)

5 year f-up 2017

HD18

bull All patients started with 2 x escalated BEACOPP

bull iPET2 randomised (D12 = negative = 50)ndash PET + variations with rituximab (made no difference)

ndash PET - total 4 cycles vs 6 or 8 cycles

HD18 ndash iPET did not affect outcome

Borchman et al (2017) Lancet

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

HD18

bull All patients started with 2 x escalated BEACOPP

bull iPET2 randomised (D12 = negative = 50)ndash PET + variations with rituximab (made no difference)

ndash PET - total 4 cycles vs 6 or 8 cycles

HD18 ndash iPET did not affect outcome

Borchman et al (2017) Lancet

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

HD18 ndash iPET did not affect outcome

Borchman et al (2017) Lancet

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

HD18 ndash 4x eBEACOPP as good as 68 if iPET neg

Borchman et al (2017) Lancet

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

Subsequent analysis iPET D3 probably neg

3y estimate

Deauville 1-3 942

Deauville 4 876

Difference -66

Hazard ratio 227 (135-384)) p=0002

Borchman et al ndash ASH 2017

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

If an HD18 approach is taken

bull frac34 of patients finish within 12 weeks with only 5 relapse risk

bull frac14 patients take 18 weeks with 10-15 relapse risk

bull Fertility fatigue second cancers

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

RATHL

bull All patients start with ABVD x 2

bull iPET2 negative (D1-3) randomised B or no B

bull iPET2 positive ALL move to escBEACOPP

ndash No RT mandated (was this incorrect)

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

RATHL ndash median FU 52mo

PFS

5yr PFS of 816 (79 ndash 84)

OS

5yr OS 951 (93-96)

Trotman et al ICML 2017

ABVD - AVD = 12 (-37 to +48)within pre-defined non-inferiority margin of

5

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

855 783 717 647 425 200

163 121 104 91 63 35

iPET2 POS

iPET2 NEG

16 of patients were iPET+ (DS 45) and intensified to eBEACOPP14

Prog

ress

ion-

free

sur

viva

l (

)

RATHLTRIALPFS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

0 1 2 3 4 5Years

5y PFS () 95 CI

iPET2 NEG 831 802ndash856

iPET2 POS 684 603ndash752

Total 813 786ndash836

Median follow-up 58 months

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

144 135 114 74 39163

Ove

rall

surv

ival

(

)

Years0 1 2 3 4 5

iPET2 POS

iPET2 NEG

832 803 738 481 221855iPET2 NEGiPET2 POS

RATHLTRIALOS stratified by iPET2 result1 0 8 8 P A T I E N T S 1 8 5 9 Y E A R S

0

100

80

60

40

20

at risk

Median follow-up 58 months

5y OS () 95 CI

iPET2 NEG 980 946ndash975

iPET2 POS 872 803ndash918

RATHL 18ndash59 951 934ndash964

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

EECN vs RATHL (18ndash59)

Years

PFS whole cohort

Prog

ress

ion-

free

sur

viva

l (

)

EECN ABVD EECN eBEACOPP

RATHL

RATHL

escB EECN

1088944849765507244 85 17 0 0 0 0 ndash

44 36 26 18 11 3 0 0 0 0 044 ndash

158140124119110 92 78 57 45 28 12177 ndashABVD EECN

0 1 2 3 4 5 6 8 9 10 12

0

100

80

60

40

20

C O M PARIS ON H R ( 9 5 C I ) p - v alue

EECN ABVD vs RATHL 113 (079ndash162) 0 4 9 0

EECN eBEACOPP vs RATHL 025 (006ndash100) 0 0 5 0

EECN eBEACOPP vs EECN ABVD 022 (005ndash091) 0 0 1 9

at risk

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

Within the RATHL 18ndash59 cohorthellip

221 of IPS 3 + patients were iPET2

positive

129 of IPS 0-2 patients were iPET2

positive

mdash and were escalated to

eBEACOPP14

endpoint5 year rate

EECNA B V D

RATHL18 59

EECNeBEACOPP

PFS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 7 9 2 (177 723ndash845) 8 1 3 (1088 786ndash836) 9 5 5 (44 830ndash988)

IPS 0-2 8 4 7 (106 762ndash903) 8 3 8 (728 807ndash864) 9 0 9 (11 508ndash987)

IPS 3+ 7 1 9 (69 595ndash811) 7 6 2 (359 710ndash807) 9 7 0 (33 804ndash996)

Stage IV 7 3 6 (59 600ndash832) 7 6 6 (305 709ndash814) 9 6 9 (32 798ndash996)

OS ( n 9 5 C I ) ( n 9 5 C I ) ( n 9 5 C I )

Whole cohort 9 2 9 (177 878ndash959) 9 5 1 (1088 934ndash964) 9 7 2 (44 819ndash996)

IPS 0-2 9 8 1 (106 925ndash995) 9 6 3 (728 943ndash976) 8 5 7 (11 334ndash979)

IPS 3+ 8 4 5 (69 729ndash914) 9 2 6 (359 891ndash951) 1 0 0 (33 NA)

Stage IV 9 2 6 (59 813ndash972) 9 2 1 (305 881ndash948) 1 0 0 (32 NA)

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

Escalated BEACOP with dacarbazine

bull Appealing ndash as per the BRECADD protocol

bull Paediatric data suggests equivalence between dacarbazine and procarbazine (but we canrsquot be certain)

bull Toxicity is likely to be less

bull First 10 patients completed All well in PET negative remission No radiotherapy

ndash iPET2 D2=3 D3=5 D4 =2

ndash 5 patients stopped at 4 cycles

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

Will BV impact on frontline Rx -ECHELON-1

bull Inclusion criteriandash cHL stage III or IVndash ECOG PS 0 1 or 2ndash Age ge18 years ndash Measurable diseasendash Adequate liver and renal function

218 study sites in 21 countries worldwide

Scre

en

ing

CT

PE

T s

can

11

ran

do

miz

ati

on

(N=

1334)

EO

T C

TP

ET

Follow-up

Every 3 months for

36 months then

every

6 months until

study closure

End-of-Cycle-2 PET scanbull Deauville 5 could receive alternate

therapy per physicianrsquos choice (not a modified PFS event)

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

ABVD x 6 cycles

(n=670)

A+AVD x 6 cycles (n=664)

Brentuximab 12 mgkg IV infusion

Days 1 amp 15

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

Follow-up

Primary EP ndash a controversy beginshellipbull Primary endpoint modified PFS per IRF

ndash A modified PFS event was defined as the first of PD Death OR

Dx Tx Follow-upPET6 = D1 2

Dx Tx Follow-upPET6 = D3 4 5

Dx Tx Follow-upPET6 = D3 4 5

No event

No eventDx Tx PET6 = D1 2 Tx

No event

Event Tx wo ldquoChesonrdquo progression

bull PET6 = D3-5 after completion of frontline therapy followed by subsequent anticancer Tx

Per IRF

Event

Dx Tx Follow-up

PDdeath at any time

PET6 = D1ndash5

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

Baseline characteristics

Percentages do not total 100 due to rounding daggerUnknownmissing data for 5 and 4 in the A+AVD and ABVD groups respectively IPS International Prognostic Score

Baseline disease characteristicsA+AVDN=664

ABVDN=670

Ann Arbor stage IIIIV

3664

3763

IPS risk factors 0ndash12ndash34ndash7

215325

215227

ECOG PS 012

57394

57394

B symptoms 60 57

Bone marrow involvement 22 23

Sites of extranodal involvement dagger

None1gt1

333329

343329

Baseline patient characteristicsA+AVDN=664

ABVDN=670

Male 57 59

Not Hispanic or Latino 86 86

White 84 83

Median age years (range) 35 (18ndash82) 37 (18ndash83)

Age years lt4545ndash5960ndash64ge65

681949

632269

Median time since initial diagnosis months

092 089

Region Americas Europe Asia

395011

395011

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

mPFS per independent review

10

08

06

04

02

00 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

Time from randomization (months)

Pro

ba

bil

ity o

f m

od

ifie

d P

FS

HR 077 (95 CI 060ndash098)

Log-rank test p-value 0035

A+AV

D

ABVD

Censored

Censored

09

07

05

03

01

TimeA+AVD

(95 CI)ABVD

(95 CI)

2-year 821

(787ndash850)

772

(737ndash804)

Median follow-up (range) 249 months (00ndash493)

Modified PFS estimates

Connors JM et al (2017) NEJM

Connors JM et al ASH 2017 Abstract no 0006

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

Many difficult issues

bull Small difference in mPFS (really an EFS)

bull Very short f-up for a HL trial

bull More toxicity

bull If we accept more toxicity why not escB

bull Long term effects

bull Cost

Trial design (no response adaptive therapy)

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM

FUTURE TRIALS

bull Exploring prognostic tools

bull Reducing chemotherapy and radiotherapy exposure

bull Early recognition of the poorest prognostic patients to change therapy early

Many complex designs are possible - ASK GRAHAM