T-Cell Lymphoma and Hodgkin Lymphoma

Steven M. Horwitz M.D. Associate Member Lymphoma Service Memorial Sloan Kettering Cancer Center Disclosures for Steven M. Horwitz, MD

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

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

Rudiger et al. Ann Oncol. 2002;13(1):140-149. CTCL Extranodal Nodal Leukemia T-cell lymphomas are highly heterogenous 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, Monomorphic epitheliotropic Nodal T-cell lymphoma with TFH Aggressive NK-cell leukemia pcALCL) intestinal phenotype*

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

PC CD8+ epidermotropic Breast implant-associated ALCL* ALCL; ALK-neg * cytotoxic

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.

ALK+ ALCL

ALK- ALCL ALK U ALCL AITL TCL-U PTCL NOS

Fredrik Ellin et al. Blood 2014;124:1570-1577 Best outcomes in first-line among participants

5 yr OS 51% 5 yr PFS 44%

d'Amore et al. JCO 2012;30:3093-3099 Brentuximab vedotin, anti-CD30 ADC Approval data in relapsed/refractory setting 100% CD30+, biomarker-driven BCCA N=130 ALCL N=56 PFS 3.7 months

PFS 4 months PFS 13.3 months

Time (months)

>5-10% CD30+ N=109 N=129 PTCL N=21; AITL N=13 6.7 months PFS 3.5 months PFS 1.6 months 1.6 months

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 Clin Oncol. 2012;30:2190-2196, Horwitz SM et al. Blood 2014;123:3095-3100 ECHELON-2 Study Design (NCT01777152)

Key Eligibility Criteria A+CHP • Age ≥18 years N=226 (A) brentuximab vedotin 1.8 mg/kg + • CD30-expression (≥10% cells) (C) 750 mg/m2 + • Previously-untreated PTCL: (H) 50 mg/m2 + o Systemic ALCL (sALCL)* (P) prednisone 100 mg (Days 1-5) R including ALK(+) sALCL with IPI (1:1 + placebo ≥2, ALK(-) sALCL ) o PTCL-NOS, AITL, ATLL, EATL, Q3W for 6 to 8 cycles HSTCL EOT PET CHOP *targeting 75% (±5%) ALCL per EU (C) cyclophosphamide 750 mg/m2 + regulatory commitment (H) doxorubicin 50 mg/m2 + (O) vincristine 1.4 mg/m2 + Stratification Factors N=226 (P) prednisone 100 mg (Days 1-5) • IPI score (0-1 vs. 2-3 vs. 4-5) • Histologic subtype (ALK-positive + placebo brentuximab vedotin sALCL vs. all other histologies) Q3W for 6 to 8 cycles AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large-cell lymphoma; ALK, anaplastic lymphoma kinase ATLL, adult T-cell leukaemia/lymphoma; EATL, Per investigator discretion: enteropathy-associated T-cell lymphoma; EOT, end of treatment; GCSF, granulocyte- colony stimulating factor; HSTCL, hepatosplenic T-cell lymphoma; IPI, international GCSF primary prophylaxis, consolidative RT and SCT prognostic index CD30 Expression in TCL other than ALCL

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)

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 CHOP A+CHP CHOP (N=226) (N=226) (N=226) (N=226) Male, n (%) 133 (59) 151 (67) Disease diagnosis, n (%) Age in years, sALCL 162 (72) 154 (68) 58 (18-85) 58 (18-83) median (range) ALK+ 49 (22) 49 (22) IPI score, n (%) ALK- 113 (50) 105 (46) 0-1 53 (23) 48 (21) PTCL-NOS 29 (13) 43 (19) 2-3 140 (62) 144 (64) AITL 30 (13) 24 (11) 4-5 33 (15) 34 (15) ATLL 4 (2) 3 (1) Stage III/IV, n (%) 184 (81) 180 (80) EATL 1 (0) 2 (1) Progression-free Survival

Events HR (95% CI) P A+CHP 95 (42%) 0.71 0.011 CHOP 124 (55%) (0.54, 0.93)

Median PFS (95% CI) 48.2 mo (35.2, NE) 20.8 mo (12.7, 47.6)

3-yr PFS Median Follow-up 57% 36.2 months 44% Prognosis of early vs advanced stage MF and SS: Appropriate risk-stratification for treatment selection

Stage IA vs. control population: Life-expectancy is not altered in patients with limited patch/plaque disease

Early (IA-IIA) vs Advanced (IIB-IV)

Kim et al, Arch Dermatol 1996;132:1309 F-MF or LCT with worse clinical outcome F-MF not sig independent factor in advanced MF/SS (CLIC Scarisbrick et al, 2015)

Agar et al. J Clin Oncol 2010;28:4730 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 ( or ) in patients with CD30+ CTCL

Screening* Post-treatment Treatment follow-up Up to 48 weeks (16x 21-day cycles)

Inclusion: Brentuximab vedotin: • Diagnosis of CD30+ MF or IV, every 3 weeks pcALCL Every 12 weeks • ≥10% CD30+ for 2 years and • MF patients with ≥1 prior systemic therapy Methotrexate: by mouth weekly then every 6 • pcALCL patients with Randomization or months prior radiotherapy or ≥1 prior systemic therapy Bexarotene: by mouth daily thereafter

* within 28 days of randomization Primary and key secondary endpoint analyses (ITT population)

Brentuximab Physician’s Difference Between vedotin Choice Arms Statistical Endpoint N=64 N=64 (95% CI) 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 p<0.0001 adj HR=0.270 Median PFS, months 16.7 3.5 (95% CI: 0.169, 0.430)

Mean maximum reduction in Skindex-29 symptom -27.96 -8.62 -18.9 (-26.6, -11.2) p<0.0001 adj

domain, points HM Prince et al. Lancet. 2017 Aug 5;390(10094):555-566 Therapies in Development in TCL/other targets

• Pi3k-duvelisiib • Pralatrexate-Romidepsin • Romidepsin-5-AZA • Ruxolitinib • Cerdulatinib syk/jak • Tipifarnib • MDM2 inhibitors EZH1/2 inhibitors • New ADCs • Mogamulizumab-Anti CCR4 Ab-CTCL, ATLL-FDA approved CTCL • Anti CD47 strategies • Checkpoint inhibitors • CART

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

PTCL High unmet need Upfront CHOP or CHOEP-ASCT CD30+-BV-CHP

Relapsed-many therapies early in development

CTCL More Chronic-sequential therapies HL by the Numbers

Optimal Upfront Treatment 700 Pts ≥ 70 years 8000 pts No standard TX

Favorable Unfavorable Unfavorable Favorable AS Unfavorable AS ES ES ES with Bulk

1000 2500 1000 2500 1000

100 Fail 300 Fail 200 Fail 500 Fail 300 Fail

TREATMENT FAILS IN 1400 PATIENTS RAPID: ≥5cm mass defines group that may need something more….. No further treatment ABVD x3

PET + PET PET –

ABVD x1 ➡ IFRT Randomization 5-year EFS: tumor <5cm (n=172) = 93.6% tumor ≥5cm (n=39) = 79.3% IFRT, 30 Gy No further treatment

Radford J et al, N Engl J Med (2015) 17:1598-607 Illidge T et al, ISHL 2018 UK RATHL Trial: Interim FDG-PET-adapted therapy for advanced stage cHL CS II (adverse); CS III and IV IPS 0-7; PS 0-3; Age > 18 ABVD x2

PET R Deauville 4-5 Deauville 1-3 BEACOPP-14 x4 OR BEACOPP escalated x4 ABVD x4 AVD x4

PET No Further Rx

• Primary endpoint – 3-year PFS of ABVD v AVD BEACOPP-14 x1 OR RT or SLT • Non-inferiority design BEACOPP escalated x1 – 90% power to exclude AVD being > 5% worse than ABVD Johnson et al. ICML 2015 RATHL: Outcome in PET-negative radomization ABVD v AVD (@ median follow up 36.3 months)

Intent to Treat Analysis Per Protocol Analysis

∆ABVD-AVD = 1.4% (95% CI ‐3.6 - +5.2) HR: 1.11 (0.79-1.54), p = 0.53 HR: 1.09 (0.78-1.53), p = 0.59 3-year PFS: 3-year PFS: ABVD 85.4% (95% CI: 81.6-88.5) ABVD 85.3% (95% CI: 81.6-88.4) AVD 84.4% (95% CI: 80.7-87.6) AVD 84.6% (95% CI: 80.8-87.7) can be eliminated if PET-2 is negative

ABVD ABVD AVD P C1-2 C3-6 C3-6 3-year OS Neutropenia 57.3 58.4 57.5 0.78 ABVD: 97.1 (94.7-98.4) Thrombocytopenia 1.3 1.3 3.2 0.045 AVD: 97.4 (95.0-98.6) 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 Johnson et al. ICML 2015 % of patients experiencing grade 3-4 events RATHL: Outcome in PET-positive patients (@ median follow up 36.3 months)

PFS OS

3-year PFS: 3-year OS: BEACOPP-14 66.0% (95% CI 55.0-74.9%) BEACOPP-14 89.6% (95% CI 80.0%-94.7%) escBEACOPP 71.1% (59.0%-80.2%) escBEACOPP 82.2% (70.5%-90.2%)

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

Johnson et al. ICML 2015 ECHELON-1: Phase 3 Study of BV+AVD Versus ABVD in Newly Diagnosed, Advanced cHL1

218 study sites in 21 countries worldwide Follow-up ABVD x 6 cycles (n = 670) every 3 R months for 36

1:1 EOT BV+AVD x 6 cycles (n = 664) months, then

Screening Screening N = BV 1.2 mg/kg IV infusion CT/PET CT/PET scan CT/PET CT/PET scan every 6 1,334 Days 1 and 15 months until study closure Inclusion Criteria End-of-cycle-2 PET scan • Deauville 5; could receive alternate therapy per • cHL stage III or IV physician’s choice (not an mPFS event) • ECOG PS 0, 1, or 2 • Age ≥18 years • Measurable disease • Adequate liver and renal function

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

Number of Events BV+AVD ABVD Time (n = 117) (n = 146) Progression 90 102 Death 18 22 Modified progression 9 22 • 7 15 • Radiotherapy 2 7

mPFS Estimates BV+AVD ABVD Time (95% CI) (95% CI) 82.1 77.2 2-year (78.7-85.0) (73.7-80.4)

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

• 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

Moskowitz CH, et al. Lancet 2015;385:1853-62 Moskowitz CH, et al. ISHL 2018 Other active agents in Rel/Ref HL

Drug n ORR Reference 36 53% Moskowitz AJ, et al. JCO 2013 Everolimus 57 42% Johnston, et al. ASH 2012 129 27% Younes, et al. JCO 2012 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 Hodgkin Lymphoma 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