T-Cell Lymphoma and Hodgkin Lymphoma

Steven M. Horwitz M.D.Associate MemberLymphoma ServiceMemorial Sloan Kettering Cancer Center

• Consultancy: ADC Therapeutics, Aileron, Seattle Genetics, Takeda, Kyowa Hakka Kirin, Verastem, Portola, Corvus , Innate, BeiGene

• Research Funding: Aileron, Celgene, Seattle Genetics, Takeda, Kyowa Hakka Kirin, Verastem, ADCT Therapeutics, Spectrum, Forty-Seven

Disclosures for Steven M. Horwitz, MD

Conflict of Interest Disclosure

I hereby declare the following potential conflicts of interest concerning my presentation:

Rudiger et al. Ann Oncol. 2002;13(1):140-149.

T-cell Lymphomas“Heterogeneous and B.A.D”

T-cell lymphomas are highly heterogenousCTCL Extranodal Nodal Leukemia

Mycosis fungoides Extranodal NK/T cell Peripheral T-cell NOS Adult T-cell LL

Sezary Syndrome Enteropathy-associated Angioimmunoblastic T-cell PLL

SPTCL Hepatosplenic T-cell Follicular T-cell T-cell LGL

CD30+ T-cell LPDs (LyP,pcALCL)

Monomorphic epitheliotropicintestinal

Nodal T-cell lymphoma with TFH phenotype*

Aggressive NK-cell leukemia

PC γδ T-cell Indolent T-cell LPD of GI ALCL; ALK-pos Chronic LPD of NK

PC CD8+ epidermotropiccytotoxic

Breast implant-associated ALCL* ALCL; ALK-neg *

PC acral CD8+ TCL* Systemic EBV+ TCL of childhood*

PC CD4+ small/med Hydroa Vacciniforme-like

Swedish National Registry: PFS in 755 patients with PTCL.

Fredrik Ellin et al. Blood 2014;124:1570-1577

ALK+ ALCL

ALK- ALCL ALK U ALCL

PTCL NOSAITL

TCL-U

d'Amore et al. JCO 2012;30:3093-3099

Best outcomes in first-line among clinical trial participants

5 yr OS 51% 5 yr PFS 44%

Pralatrexate N=109

Romidepsin N=130

Mak V et al. JCO 2013;31:1970-1976, O’Connor OA, et al. J Clin Oncol. 2011;29:1182-1189, Coiffier B, et al. J Clin Oncol. 2012;30 :631-636, O’Connor OA et al ASCO 2013, Pro B, et al. J ClinOncol. 2012;30:2190-2196, Horwitz SM et al. Blood 2014;123:3095-3100

Belinostat N=129

PFS 3.7 months

BCCA

PFS 1.6 months

PFS 4 months

PFS 3.5 months

ALCL N=56

PFS 13.3 months

>5-10% CD30+

PTCL N=21; AITL N=13

1.6 months

6.7 months

Approval data in relapsed/refractory setting 100% CD30+, biomarker-driven

Time (months)

Brentuximab vedotin, anti-CD30 ADC

ECHELON-2 Study Design (NCT01777152)

Key Eligibility Criteria

• Age ≥18 years

• CD30-expression (≥10% cells)

• Previously-untreated PTCL:

o Systemic ALCL (sALCL)*

including ALK(+) sALCL with IPI

≥2, ALK(-) sALCL

o PTCL-NOS, AITL, ATLL, EATL,

HSTCL

Stratification Factors

• IPI score (0-1 vs. 2-3 vs. 4-5)

• Histologic subtype (ALK-positive

sALCL vs. all other histologies)

R

(1:1

)

N=226

N=226

EOT

PET

A+CHP

(A) brentuximab vedotin 1.8 mg/kg +

(C) cyclophosphamide 750 mg/m2 +

(H) doxorubicin 50 mg/m2 +

(P) prednisone 100 mg (Days 1-5)

+ placebo vincristine

Q3W for 6 to 8 cycles

CHOP

(C) cyclophosphamide 750 mg/m2 +

(H) doxorubicin 50 mg/m2 +

(O) vincristine 1.4 mg/m2 +

(P) prednisone 100 mg (Days 1-5)

+ placebo brentuximab vedotin

Q3W for 6 to 8 cycles

*targeting 75% (±5%) ALCL per EU

regulatory commitment

AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large-cell lymphoma; ALK, anaplastic lymphoma kinase ATLL, adult T-cell leukaemia/lymphoma; EATL, enteropathy-associated T-cell lymphoma; EOT, end of treatment; GCSF, granulocyte-colony stimulating factor; HSTCL, hepatosplenic T-cell lymphoma; IPI, international prognostic index

Per investigator discretion:

GCSF primary prophylaxis, consolidative RT and SCT

Series Definition of + Subtype CD30+ % (N)

Sabbatini 2013 > 25% PTCL-NOS 52% (45/87)

AITL 21% (9/42)

ENKTCL 70% (7/10)

MF 13% (4/32)

ALL Types 43% (83/192

Went 2006 > 30% PTCL-NOS 3% (4/145)

AITL 0% (0/42)

CD30 Expression in TCL other than ALCL

Sabbatini et al Haematologica. 2013 August; 98(8): e81–e82

Went et al. J Clin Oncol. 2006 Jun 1;24(16)

Baseline Characteristics

A+CHP

(N=226)

CHOP

(N=226)

Male, n (%) 133 (59) 151 (67)

Age in years,

median (range)58 (18-85) 58 (18-83)

IPI score, n (%)

0-1 53 (23) 48 (21)

2-3 140 (62) 144 (64)

4-5 33 (15) 34 (15)

Stage III/IV, n (%) 184 (81) 180 (80)

A+CHP

(N=226)

CHOP

(N=226)

Disease diagnosis, n (%)

sALCL 162 (72) 154 (68)

ALK+ 49 (22) 49 (22)

ALK- 113 (50) 105 (46)

PTCL-NOS 29 (13) 43 (19)

AITL 30 (13) 24 (11)

ATLL 4 (2) 3 (1)

EATL 1 (0) 2 (1)

Progression-free Survival

3-yr PFS

57%44%

Events HR (95% CI) P

A+CHP 95 (42%) 0.71(0.54, 0.93)

0.011CHOP 124 (55%)

Median PFS (95% CI)

48.2 mo (35.2, NE)20.8 mo (12.7, 47.6)

Median Follow-up 36.2 months

Agar et al. J Clin Oncol 2010;28:4730

Prognosis of early vs advanced stage MF and SS:

Appropriate risk-stratification for treatment selection

Kim et al, Arch Dermatol 1996;132:1309

Stage IA vs. control population:

Life-expectancy is not altered in patients with limited

patch/plaque disease

Early

(IA-IIA)

vs

Advanced

(IIB-IV)

F-MF or LCT with worse clinical outcome

F-MF not sig independent factor in

advanced MF/SS (CLIC Scarisbrick et al, 2015)

Arch Dermatol 146:607, 2010, J Clin Oncol 28:4730, 2010,

Blood 119:1643, 2012, J Clin Oncol 2015;33:3766

ALCANZA: a randomized, open-label, phase 3 trial of brentuximab vedotin vs physician’s choice (methotrexate or bexarotene) in patients with CD30+ CTCL

Inclusion:

• Diagnosis of CD30+ MF or pcALCL

• ≥10% CD30+

• MF patients with ≥1 prior systemic therapy

• pcALCL patients with prior radiotherapy or ≥1 prior systemic therapy

Screening*

Treatment

Ra

nd

om

iza

tio

n

Methotrexate: by mouth weeklyor

Bexarotene: by mouth daily

Brentuximab vedotin: IV, every 3 weeks

Up to 48 weeks (16x 21-day cycles)

Post-treatmentfollow-up

Every 12 weeks for 2 years and

then every 6 months

thereafter

* within 28 days of randomization

Endpoint

Brentuximab vedotin

N=64

Physician’s ChoiceN=64

Difference Between Arms

(95% CI)Statistical

Significance

Primary endpoint

ORR4, n (%) 36 (56.3%) 8 (12.5%) 43.8% (29.1, 58.4) p<0.0001

Key secondary endpoints

CR, n (%) 10 (15.6%) 1 (1.6%) 14.1% (-4.0, 31.5) p=0.0046 adj

Median PFS, months 16.7 3.5

p<0.0001 adj

HR=0.270 (95% CI: 0.169,

0.430)

Mean maximum reduction in Skindex-29 symptom domain, points

-27.96 -8.62 -18.9 (-26.6, -11.2) p<0.0001 adj

Primary and key secondary endpoint analyses (ITT population)

HM Prince et al. Lancet. 2017 Aug 5;390(10094):555-566

• Pi3k-duvelisiib

• Pralatrexate-Romidepsin

• Romidepsin-5-AZA

• Ruxolitinib

• Cerdulatinib syk/jak

• Tipifarnib

• MDM2 inhibitorsEZH1/2 inhibitors

• New ADCs

• Mogamulizumab-Anti CCR4 Ab-CTCL, ATLL-FDA approved CTCL

• Anti CD47 strategies

• Checkpoint inhibitors

• CART

Therapies in Development in TCL/other targets

Amengual et al Blood 2018 131:397-407; Falchi et al ASH 2017; Hamlin et al ASCO 2018Witzig et al ICML 2017; Kim et al Lancet Oncol 2018

PTCL

High unmet need

Upfront CHOP or CHOEP-ASCT

CD30+-BV-CHP

Relapsed-many therapies early in development

CTCL

More Chronic-sequential therapies

T-Cell Lymphoma

HL by the Numbers

Optimal Upfront Treatment8000 pts

Favorable ES

Unfavorable ES

Unfavorable ES with Bulk

Favorable AS Unfavorable AS

1000 2500 1000 2500 1000

100 Fail 300 Fail 200 Fail 500 Fail 300 Fail

700 Pts ≥ 70 yearsNo standard TX

TREATMENT FAILS IN 1400 PATIENTS

RAPID: ≥5cm mass defines group that may need something more…..

PET

IFRT, 30 Gy No further treatment

PET –PET +

ABVD x1 ➡ IFRT Randomization

ABVD x3

PET

Radford J et al, N Engl J Med (2015) 17:1598-607Illidge T et al, ISHL 2018

5-year EFS:

tumor <5cm (n=172) = 93.6%

tumor ≥5cm (n=39) = 79.3%

No further treatment

Johnson et al. ICML 2015

UK RATHL Trial: Interim FDG-PET-adapted therapy for advanced stage cHL

CS II (adverse); CS III and IVIPS 0-7; PS 0-3; Age > 18

BEACOPP-14 x4 ORBEACOPP escalated x4

ABVD x2

PET

Deauville 1-3Deauville 4-5

ABVD x4 AVD x4

R

RT or SLT

No Further RxPET

BEACOPP-14 x1 ORBEACOPP escalated x1

• Primary endpoint

– 3-year PFS of ABVD v AVD

• Non-inferiority design

– 90% power to exclude AVD being > 5%worse than ABVD

RATHL: Outcome in PET-negative radomization ABVD v AVD (@ median follow up 36.3 months)

∆ABVD-AVD = 1.4% (95% CI ‐3.6 - +5.2)

Per Protocol AnalysisIntent to Treat Analysis

HR: 1.11 (0.79-1.54), p = 0.53 3-year PFS:

ABVD 85.4% (95% CI: 81.6-88.5)AVD 84.4% (95% CI: 80.7-87.6)

HR: 1.09 (0.78-1.53), p = 0.59 3-year PFS:

ABVD 85.3% (95% CI: 81.6-88.4)AVD 84.6% (95% CI: 80.8-87.7)

Johnson et al. ICML 2015

3-year OSABVD: 97.1 (94.7-98.4)AVD: 97.4 (95.0-98.6)

Bleomycin can be eliminated if PET-2 is negative

ABVDC1-2

ABVDC3-6

AVDC3-6

P

Neutropenia 57.3 58.4 57.5 0.78

Thrombocytopenia 1.3 1.3 3.2 0.045

Neutropenic fever 2.1 4.7 2.2 0.032

Infection 6.3 14.5 10.1 0.040

Thromboembolism 1.4 4.9 2.6 0.061

Respiratory AE 0.7 3.6 0.6 0.002

Any non-heme AE 16 31 21 <0.001

% of patients experiencing grade 3-4 events

RATHL: Outcome in PET-positive patients (@ median follow up 36.3 months)

Johnson et al. ICML 2015

OSPFS

3-year PFS: BEACOPP-14 66.0% (95% CI 55.0-74.9%)

escBEACOPP 71.1% (59.0%-80.2%)

3-year OS: BEACOPP-14 89.6% (95% CI 80.0%-94.7%)

escBEACOPP 82.2% (70.5%-90.2%)

Outcome of PET-2 positive patients improved compared to historical controls

ECHELON-1: Phase 3 Study of BV+AVD Versus ABVD in Newly Diagnosed, Advanced cHL1

1. Connors JM et al. 60th American Society of Hematology Annual Meeting & Exposition (ASH 2017). Abstract 6.

Scr

ee

nin

g

CT

/PE

T s

can

ABVD x 6 cycles (n = 670)

BV+AVD x 6 cycles (n = 664)BV 1.2 mg/kg IV infusion

Days 1 and 15

EO

TC

T/P

ET

sca

n Follow-up every 3

months for 36 months, then

every 6 months until study closure

218 study sites in 21 countries worldwide

1:1R

N = 1,334

End-of-cycle-2 PET scan• Deauville 5; could receive alternate therapy per

physician’s choice (not an mPFS event)

Inclusion Criteria• cHL stage III or IV• ECOG PS 0, 1, or 2• Age ≥18 years• Measurable disease• Adequate liver and renal function

mPFS Per Independent Review

TimeBV+AVD(95% CI)

ABVD(95% CI)

2-year82.1

(78.7-85.0)77.2

(73.7-80.4)

TimeBV+AVD(n = 117)

ABVD(n = 146)

Progression 90 102

Death 18 22

Modified progression• Chemotherapy• Radiotherapy

972

22157

Number of Events

mPFS Estimates

Median follow-up (range): 24.9 mo (0.0-49.3)

1. Connors JM et al. ASH 2017. Abstract 6.

Post-transplant brentuximab vedotin maintenance

Moskowitz CH, et al. Lancet 2015;385:1853-62Moskowitz CH, et al. ISHL 2018

• AETHERA: Phase III study evaluating post-transplant maintenance BV for higher risk patients

• Risk factors: Relapse within 1 year of initial treatment, primary refractory disease, extranodal disease

• 329 patients received brentuximab vedotin (BV) (n=165) or placebo (n=164)

5-Year PFS Rates

BV=59% Placebo=41%

HR=0.521

Other active agents in Rel/Ref HL

Drug n ORR Reference

Bendamustine 36 53% Moskowitz AJ, et al. JCO 2013

Everolimus 57 42% Johnston, et al. ASH 2012

Panobinostat 129 27% Younes, et al. JCO 2012

Entinostat 38 12% Batlevi, et al. Haematologica 2016

Mocetinostat 51 33% Younes, et al. Lancet Oncol. 2011

Lenalidomide 36 19.5% Fehniger, et al. Blood. 2011

ADCT-301 (Cami-T) 60 69% Hamadani et al. ASH 2018

CD30 CARTs Ramos/Grover ASH 2018

Frontline

Early stage Short course ABVD

Advanced stage : ABVD vs BV-AVD

Relapsed-standard

BV if not given upfront

Nivo/Pembro

Relapsed-investigational

CART

ADCT-301

Hodgkin Lymphoma