Management of Hodgkin Lymphoma: An ASCO/ICML Update

F B Hagemeister, MDProfessor of Medicine

Department of Lymphoma and MyelomaM D Anderson Cancer Center

Bangkok 28 August 2015

Update on Therapy for Hodgkin Lymphoma: ASCO/ICML

1. Brentuximab Trials• Single Agent Therapy• Combination Programs

2. PET-Driven Therapy• Stage I-II Disease• Stage III-IV Disease

3. Novel Agents• Anti-PD-1 for Relapse • Gem/Bu/Mel for SCT

BV Consolidation After Auto SCT for Primary Refractory HL

• 2 yr PFS and 3 Yr OS rates for this group are 40% and 50%, respectively, post autoAST.

• AETHERA: BV vs placebo for Rel/Ref HL after ASCT

Initial Therapy

Relapse

Assess RFs

Primary Refractory

< 12 Mo remission

Relapse > 12 Mo with EN DZ

Salvage Therapy

PD

Off Study

ASCT

BV

Placebo

Moskowitz et al. ICML-13, 2015, #120.

CR PR SD

Treatment Schema

Crossover to BV at PD

BV after ASCT for Primary Refractory HL

Subgroup Feature No. Pts (%) HR RangeEN DZ Yes 53 (27) 0.37 0.18-0.78

No 143 (73) 0.61 0.37-0.98B Symptoms Yes 56 (28) 0.36 0.19-0.72

No 140 (72) 0.63 0.38-1.04# Prior TXs > 2 97 (49) 0.39 0.22-0.71

2 99 (51) 0.79 0.44-1.4# of RFs > 1 196 (100) 0.55 0.37-0.83

> 2 175 (90) 0.47 0.31-0.72> 3 110 (57) 0.4 0.24-0.66

Moskowitz et al. ICML-13, 2015, #120.

• Study of 196 Patients with Primary Refractory HL. • PFS results favor BV in all groups. • The lower the HR, the more significant the difference

Update on Therapy for Hodgkin Lymphoma: ASCO/ICML

1. Brentuximab Trials• Single Agent Therapy• Combination Programs

2. PET-Driven Therapy• Stage I-II Disease• Stage III-IV Disease

3. Novel Agents• Anti-PD-1 for Relapse • Gem/Bu/Mel for SCT

Phase II BV Plus AVD for 34 Non-Bulky Stage I-II HL

• Treatment Schema

Abramson et al. ASCO 2014, Abst 8505.

BV x 21.2mg/kg

q 2 wk

PET CR, PR, SD

Enroll

PD off study

A-AVD X 2

PET CR

PET PR or SD

PD off study

A-AVD X 2

A-AVD X 4

• Patients: Favorable in 68%, unfavorable in 32%.• CR rates: After BV, 18 pt (53%). After 2 A-AVD, 33 pt (97%).

At end of therapy, CR=88%, and 6/8 Pos PETs were false positive (? due to BV).

• Gr 3-4 AEs: FN in 29%, PN in 24%• At med f/u of 14 mo, PFS=90% and OS= 97%.• Randomized study needed to prove benefit of BV

Phase I/II Brentuximab Plus Bendamustine for Relapsed/Refractory HL

• CR rates for Rel/Ref HL with standard agents range 19-60%– Brentuximab vedotin alone: CR 34%– Bendamustine alone: CR 33%

• Treatment Plan: 1.8 mg/m2 BV day 1, Benda 90 mg/m2 days 1,2.– Cycles repeated q 3 wks– Benda de-escalated if DLT (delay of > 2 wk) in > 3/10 pts. 

• Tolerability: No DLT reached• Infusion Reactions before adding Steroids and Antihistamines

LaCasce et al. ASH 2014 # 293; Kuruvilla et al. ICML-13, 2015, # 80.

Tming # Pts SAEs Gr 3 Stop Tx

Prior to giving S and A 36 6 8 6

After adding S and A 20 0 2 1

Phase I/II Brentuximab Plus Bendamustine for Relapsed/Refractory HL

• For a total of 54 patients, 48 are evaluable• Features:

• Comparisons of Therapy

• 20 pts went to SCT with good collections,1 relapsed

Disease Status Dur Prior Resp Patients (%)Primary Refractory Not applicable 27 (50)Relapsed < 1 Yr 10 (19)Relapsed > 1 Yr 17 (31)

Studies ORR (%) CR (%) MED PFSBV Alone 75 34 12 mo for CRsBV + Benda 96 83 NR for ORRs

LaCasce et al. ASH 2014 # 293; Kuruvilla et al. ICML-13, 2015, # 80.

Update on Therapy for Hodgkin Lymphoma: ASCO/ICML

1. Brentuximab Trials• Single Agent Therapy• Combination Programs

2. PET-Driven Therapy• Stage I-II Disease• Stage III-IV Disease

3. Novel Agents• Anti-PD-1 for Relapse • Gem/Bu/Mel for SCT

FDG-PET positive16 Patients, prog=112-year PFS 0%

1.0

.08

.06

.04

.02

0.0Perc

ent P

rogr

essi

on-F

ree

PET neg61 Pts, 3 prog2 yr PFS 96%

3210

PET after 2 cycles

P < .001

Years

1.0

.08

.06

.04

.02

0.0Perc

ent P

rogr

essi

on-F

ree CR, PR

2 Pts, 0 prog2 yr PFS 100%

3210

CT after 2 cycles

< PR62 Pts, 11 prog2 yr PFS 82%

P < .554

Years

PET vs CT for Stage I-IV HL: PFS by Radiographs after 2 CT Cycles

Hutchings et al. Blood 107:52-59, 2006

PET ps14 Pts, 11 prog2 yr PFS 0%

Reasons for the “False Positive” PETIntrinsic – hardware

– Improved detectionCriteria for positive

– Visual or SUV– Reader variation

Benign variants– Sarcoidosis– Thyroiditis

Inflammation– Infection– Trauma

Iatrogenic causes– Injections– Post RT– Post Surgery

Type/Location of lymphoma– Marginal Zone/SLL/T-Cell– Bowel, Marrow Disease– Hyperplasia?

Other tumors– Benign

• Warthin’s• Thyroid adenomas• Bowel adenomas

– Malignant (Any)Therapy

– Use of Rituximab– G-CSF

Timing of scan– How many days after last

chemotherapy

Routine Imaging Strategies (RIS) for Classical HL in First Remission

• Three centers: Retrospective comparison of Clinical (CS) and RIS• RIS by NCCN: Imaging Q 6 mo for 2-3 yearsChemotherapy: ABVD - 79%, Stanford V - 15%

Pingali et al, ASCO 2013 # 8505.

Group Mean # scans

% Deaths

% Relapses

Scans per Relapse

CS, n=77 1.14 4.6 6.6 17.6RIS, n=164 4.25 5.3 4.6 122.3

• RIS conferred no OS advantage (p=0.47)• CR rates with relapse therapies were also similar for CS and RIS Suggests that routine imaging after

therapy is completely unnecessary.

IFRT vs None for After 3 ABVD for PET Neg Stage I-IIA HL: The UK NCRI RAPID Trial

602 cases with newly diagnosed, stage IA/IIA HL without bulky med mass after 3 cycles of ABVD

Therapy Choice according to the PET Result, n=571

PET Negative (75%) PET Positive

IF RT (n=209)

No Further Therapy (n=211)

4th ABVD cycle + IF RT (n=145)

Radford et al. NEJM 372: 1598-1607, 2015.

IFRT vs None for PET Negative HL After 3 ABVD: The RAPID Trial

Result IF RT (n=209)

No RT (n=211)

4xABVD + IF RT (n=145)

Progressive DZ 8 20 123 YR PFS 94.5% 90.8% 86%3 YR OS 97.1% 99.5% 94%

Radford et al. NEJM 372: 1598-1607, 2015

From randomization From registrationMedian FU: 48.6 months

There is a 4% improvement by giving RT to those with negative PET, considered “acceptable” for no

RT.

PET Scan Results From the RAPID Trial

Scores Alive without PD (#, %)

Alive with PD (#, %)

Deaths Due to HL (#, %)

Total (#)

PET Score 1 280 (94) 19 (6) 0 299 2 111 (92) 9 (7) 1 (1) 121 3 86 (96) 3 (3) 1 (1) 90 4 30 (94) 2 (6) 0 32 5 15 (65) 5 (22) 3 (13) 23EORTC Fav 284 (92) 25 (8) 1 (0.3) 310 Unfav 172 (92) 9 (5) 4 (2) 185GHSG Fav 299 (91) 24 (7) 4 (1) 327 Unfav 144 (93) 10 (7) 1 (0.6) 327

Radford et al. ICML-13, 2015, #82

PET Scan Results From the RAPID Trial: Prognostic Value of the Positive PET

Radford et al. ICML-13, 2015, #82

• Positive PET after 3 ABVD defined as Deauville score of 3-5

• 145 received a 4th ABVD and IFRT• 88% and 85% had risk criteria to define EORTC

and GHSG favorable HL (66% and 68%, respectively).

• P values by MVA: PET 3-5: 0.001, EORTC: 0.48, GHSG: 0.62

• By Hazard Ratios: PET 5 vs 4- 6.7, vs 3- 9.3, vs 2- 3.2, vs 1- 5.1.

2 ABVD

2 ABVD

2 BEACOPPesc + RT 30

H10 H10 FavFav P

ET

2 ABVD

1 ABVD + RT 30PET+

-

+

2 ABVD

4 ABVD

2 BEACOPPesc + RT 30

H10 H10 UnfavUnfav P

ET

2 ABVD

2 ABVD + RT 30PET+

-

+

RR

RR

EORTC/GELA/IIL HD10 Study of ABVD for Early-Staged HL

Using PET

Raemakers et al. JCO 32: 1-8, 2014

Intergroup H10 Trial of PET Driven Therapy for Stage I/II HL: An Interim Analysis

Favorable: Supradiaphragmatic disease, CS1-2 with 1-3 nodal areas, MTR < .35, Age <50, ESR < 50 with B SX or < 30 with B SXUnfavorable: Any of the above features

Raemakers et al. JCO 32: 1-8, 2014

Feature Therapy No. Pt Relapse 1 Yr PFS % P

Favorable 3 ABVD/RT 188 1 100

4 ABVD 193 9 94.9 0.017

Unfavorable 4 ABVD/RT 251 7 97.3

6 ABVD 268 16 94.7 0.026

Despite these good results, because of the inferior results with only chemotherapy, the chemotherapy-only arms

were closed to patient entry.

The HD10 Trial: BEACOPP for PET Positive HL After Two ABVD

• EORTC-defined Stage I-II HL• PET positive considered Deauville Score 3-5

N=1950 Randomized

UnfavorableN=1196

FavorableN=754

ABVDN=54,14%

BEACOPPN=43,11%

ABVDN=138,23%

BEACOPPN=126, 21%

PET Positive

Raemakers et al. ICML 2015

5 Yr Result ABVD + RT (%) BEACOPP + RT (%) P valuePFS 77 91 0.002OS 89 96 0.062

Update on Therapy for Hodgkin Lymphoma: ASCO/ICML

1. Brentuximab Trials• Single Agent Therapy• Combination Programs

2. PET-Driven Therapy• Stage I-II Disease• Stage III-IV Disease

3. Novel Agents• Anti-PD-1 for Relapse • Gem/Bu/Mel for SCT

ABVD vs BEACOPP vs CEC for Advanced HL: The Fondazione Italiana HD 2000 Trial

ABVD x 6 (N=103)

BEACOPPesc x 4, BEACOPPstd x 2

(N=100)

CEC x 6 (alternating

COPP/EBV/CAD) (N=102)

R

Merli et al. ASH 2014 # 499

RT in

130

305 Pts cHL

Stages IIB, III, IV

10 Yr Results ABVD BEACOPP CEC PPFS (%) 69 74 74 0.64OS 84 84 86 0.88# MDS/AML 0 1 1 -# NHL 0 1 1 -# Solid Tumors

1 4 2 -

2nd Ca Risk 0.9 6.7 4.4 ** P = 0.027 for BEACOPP vs ABVD• Early data had better PFS with BEACOPP than ABVD• With longer follow-up, PFS advantage of BEACOPP is

diminished by deaths due to second cancers

ABVD vs BEACOPP vs CEC for Advanced HL: The HD 2000 Trial

Merli et al. ASH 2014 # 499

GITIL HD0607 Study of BEACOPP + R After 2 ABVD for PET Positive Stage II-IV 497 HL

PET

IIB-IVB, IIA with >3 nodal sites, ESR >

50, or bulky dz

PET positive, n=41, 15% PET negative, n=222, 84%

Gallamini et al, ASCO 2010 # 8006 Gallamini et al, ASH 2012 #.550

CR n=212/222CR n=30/41 REF n=6REF n=8

Primary endpoint: 3 Yr FFS

ABVD x2

ABVD x4 RT

PR n=1

4 escBEACOPP vs 4 escBEACOPP

+ R

PR n=2

If PET Neg after 4 ABVD, RT randomized

BEACOPP + R for PET Pos Stage II-IV HL After 2 ABVD: The GITIL/FIL HD0607 Study

Gallamini et al, ASCO 2010 # 8006 Gallamini et al, ASH 2012 # 550

PET Neg

PET Pos

All Patients

(Comparison Data)

Failure Free Survival Results

Updated 1 YR PFS Results:

97.3, 94.7, 80.5%

BEACOPP + R for PET Positive PET After Two ABVD: ICMLTreatment Outcomes

Response PET2 Neg % PET2 Pos % Total

CR 520 96 89 75 605PR 4 0.7 3 2.6 7

SD 4 0.7 1 0.9 5PD 6 1.1 13 11 19Relapse 4 0.7 7 6 11

Gallamini et al. ICML-13, 2015

2 Yr FFS PET Neg

ABVD + RT (%) ABVD No RT (%) P value88 94 0.063

2 Yr FFS PET Pos

R-BEACOPP (%) BEACOPP (%)62 72 0.27

2 Yr OS by PET Pos, 91% Neg, 99% <0.001

Phase II ASCT for PET Positive HL After Two ABVD: A FIL HD0801 Trial

1. 512 patients with Untreated Stage IIB-IV HL2. Therapy: 2 ABVD then a PET

• Negative PET (Deauville 1-2) receives 4 ABVD 1) If Pos at end, off study 2) If Neg at end, randomize RT

• Positive PET (Deauville 3-5) receives 4 IGEV1) If Pos at end, and no donor, receives M/BEAM

and ASCT2) If Pos at end, with donor, receives M and AlloSCT3) If Neg at end, receives BEAM and SCT

Zinzani et al. ICML-13, 2015.

Result All (%) Pos (%) Neg (%) P value2 Yr PFS from PET2 79 76 81 NS2 Yr OS from Start 96 - - -

Update on Therapy for Hodgkin Lymphoma: ASCO/ICML

1. Brentuximab Trials• Single Agent Therapy• Combination Programs

2. PET-Driven Therapy• Stage I-II Disease• Stage III-IV Disease

3. Novel Agents• Anti-PD-1 for Relapse • Gem/Bu/Mel for SCT

PD-1 is Inactivated by PD-L1 and PD-L2 on Tumor Cells

• PD-1 is a protein on T-Cells that dampens the normal immune response•Tumor cells can evade normal T-cell attack• Inactivate T-cell function by activation of PD-1 via PD-L1 and PD-L2

• T-Cells are “exhausted”• Cannot attack tumor cells• Inactivation is reversible

PD-L1 is Upregulated in Tumor cells• Chromosome 9p24.1 amplification upregulates

PD-L1, as can EBV infection• Multiple tumor types utilize the PD-L1 and PD-L2

interaction with PD-1 to escape immune surveillance– Breast, NSCLC, Kidney, Colon, Melanoma,

Hematologic Malignancies overexpress PD Ligands– Pembrolizumab FDA-approved for Metastatic

Melanoma– Nivolumab recently approved for Metastatic

Melanoma– Ongoing studies in many other tumors

Phase I Nivolumab in Rel/Ref HL: Preliminary Safety, Efficacy and Biomarker Results

• 23 Hodgkin lymphoma patients from larger study in hematologic malignancies– Dosing: 1-3 mg/kg with no MTD reached in Phase I– Expansion cohort 3 mg/kg chosen, week 1, 4 and q 2

wk for maximum 2 years• Drug-related adverse events (> 10%, all reversible)

Armand et al. ASH 2014 # 289; Timmerman et al. ICML-13, 2015, # 10.

Event Any Gr, # (%) Gr 3, # (%)

Any 18 (78) 5 (22)

Rash 5 (22) 0

Platelets 4 (17) 0

Fatigue, fever, diarrhea, nausea, pruritis

3 each (13) 0

Armand et al. ASH 2014 # 289; Timmerman et al. ICML-13, 2015, #10.

Phase I Nivolumab in Rel/Ref HL: Preliminary Safety, Efficacy and Biomarker Results

Response Pts, N =24

(%)

SCT Fail, BV Fail N=15, %

SCT Naïve, BV Fail N=3, %

BV Naïve N=5,%

Overall 20 (87) 87 100 80

Best Resp CR 4 (17) 7 0 60

PR 16 (70) 80 100 20

SD 3 (13) 13 0 20

6 MO PFS % 86 85 n/c 801st evaluation at 8 weeks of therapy

Median follow-up – 40 weeks

Phase Ib Pembrolizumab (MK-3475) for HL after Brentuximab Failure: KEYNOTE-013

• 31 with Rel/Ref HL: Path NS or MC– All relapsed from or failed BV therapy – 3 or more prior therapies in 28 (97%) – Prior ASCT = 20 (69%)

• Pembrolizumab given 10mg/kg every 2 weeks– Evaluation based on response at 12 weeks (6 doses)

• Tolerability: 16 (55%) of pts experienced one or more treatment-related Aes, but no Gr 4-5 events.

• Results at med follow-up at 38 weeks– 29 Cases evaluable – ORR 66%, CR 21%, PR 45%, SD 21%

Moskowitz, ASH 2014 # 290

Phase Ib Pembrolizumab (MK-3475) for HL after Brentuximab Failure: KEYNOTE-013

Moskowitz, ASH 2014 # 290

Response Rate

SCT ineligible or refused* N=9

SCT failed N=29

Total N=9

Overall 44 75 66CR 22 20 21PR 22 55 45SD 33 15 21“Clinical Benefit”

78 90 86

PD 22 10 14

*1 refused SCT

Update on Therapy for Hodgkin Lymphoma: ASCO/ICML

1. Brentuximab Trials• Single Agent Therapy• Combination Programs

2. PET-Driven Therapy• Stage I-II Disease• Stage III-IV Disease

3. Novel Agents• Anti-PD-1 for Relapse • Gem/Bu/Mel for SCT

Gem/Bu/Mel SCT for Refractory or High-Risk HL: Comparison with Other Regimens

Nieto et al. Biol Blood Marrow Transplant 19: 410-417, 2013.

EFS Results

P=0.01

OS Results P=0.04

Management of Hodgkin Lymphoma: An ASCO/ICML Update

F B Hagemeister, MDProfessor of Medicine

Department of Lymphoma and MyelomaM D Anderson Cancer Center

Bangkok 28 August 2015