t cell lymphomas current treatment landscape · other ptcl subtypes – multivariate analysis,asct...

T cell lymphomas –

Current treatment landscape

Tim IllidgeBSc PhD FRCR MCRP FRCPath

University of Manchester

Manchester Cancer Research Centre

The Christie NHS Foundation Trust

Manchester, UK

Disclosures

Speakers bureau:

• Takeda

• BMS

• Roche

Consultancy:

• Takeda

• Kyowa Kirin

• Nordic Nanovector

2 The lecture is sponsored by Takeda

PT/ONC/0918/0034

Provisional entities are listed in italics

*Changes from the 2008 classification.

Mature T/NK-cell neoplasms: WHO 2016 classification

Extranodal CutaneousLeukemic Nodal

Adult T-cell Leukemia/

Lymphoma (ATL/L)

Aggressive NK-cell Leukemia

T-cell prolymphocytic Leukemia

T-cell Large Granular Lymphocytic

Leukemia

Chronic LPD of NK

Systemic EBV+ T-lymphoma of

childhood*

NK/TCL Nasal Type (EBV+)

Enteropathy-associated TCL

(AETL)

Hepatosplenic γ/δ TCL

Hydroa vacciniforme-like LPD*Subcutaneous panniculitis-like TCL

(α/β Type)

Monomorphic epitheliotropic

intestinal TCL*

Indolent T-LPD (GI tract)*

Anaplastic Large Cell Lymphoma

(ALK+)

Peripheral TCL-NOS

Angioimmunoblastic TCL (TFH

phenotype)

Anaplastic Large Cell Lymphoma

(ALK-)*

Breast-implant-associated

ALCL*

Mycosis Fungoides (MF)

Sezary Syndrome

Primary Cutaneous CD30+ LPDs:• Lymphomatoid papulosis

• Primary cutaneous anaplastic large cell lymphoma

(pcALCL)

Primary Cutaneous γ/δ

Primary Cutaneous CD8+ aggressive

epidermotropic TCL

Primary Cutaneous CD4+ small/medium TCL*

Primarycutaneous acral CD8+ TCL*

Nodal PTCL with TFH

phenotype*

Follicular TCL (F-PTCL)

(TFH phenotype)*

CutaneousPeripheral

Indolent Aggressive Swerdlow SH et al. Blood 2016

Frequency of T-cell Lymphoma Subtypes: International PTCL Study 22 centres: 1314 cases over 13 years

ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; NOS, not otherwise specified; AITL, angioimmunoblastic T-cell lymphoma

Other disorders 12.2%

Unclassifiable PTCL 2.5%

Subcutaneous panniculitis-like TCL 0.9%

Hepatosplenic TCL 1.4%

Primary cutaneous ALCL 1.7%

Enteropathy-type TCL 4.7%

ALCL, ALK– 5.5%

ALCL, ALK+ 6.6%

ATLL 9.6%

NK/T-cell lymphoma 10.4%

AITL 18.5%

PTCL-NOS 25.9%

PTCL, AITL, ALCL: ~60% of T-cell NHL

Vose J, et al. J Clin Oncol. 2008;26(25):4124-4130

Vose J, et al. J Clin Oncol. 2008;26(25):4124-4130

The International PTCL and NK/TCL Study: Overall Survival (OS) in PTCL

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Times, years

Ove

rall

surv

ival

, %

Anaplastic large cell lymphoma, ALK+

Anaplastic large cell lymphoma, ALK-

All natural killer/T-cell lymphomasPeripheral T-cell lymphoma, not otherwise specified

Angioimmunoblastic lymphoma (AITL)

Adult T-cell leukemia/lymphoma (ATLL)

P < .001

ALK+ ALCL ALK– ALCL PTCL-NOS AITL NK/TCL ATLL

5-year OS rate 70% 49% 32% 32% 32% 14%

Reasons for Poor Outcomes in T cell Lymphomas

• Diagnosis difficult◦ Needs expert pathology

• Treated like B-cell NHL◦ CHOP or anthracycline-based therapy

◦ Multidrug resistance (MDR)

◦ Doxorubicin and vincristine are substrates

• Outcome of patients who fail front-line therapy is poor

• Not one disease◦ Molecular studies show distinct biological entities

PTCL: Clinical Prognostic Biomarkers

• Prognostic biomarkers - IPI or prognostic index for T-cell

lymphoma (PIT) score

• PIT modified IPI with BM involvement, most effective prognostic

factor

• IPI works less well for AITL and PTCL-NOS

• Modified prognostic index for T-cell lymphoma and alternative

prognostic index for AITL (PIAI)

• None provide a significant improvement over IPI in terms of

impacting treatment strategies.

Gallamini A, et al. Blood. 2004;103:2474-2479. Federico M et al J Clin Oncol.2013 Jan 10;31(2):240-6

Prognostic Index for PTCL-U (PIT)1

Risk factors Prognostic risk

Age >60 years Group 1 0

Serum LDH >normal Group 2 1

PS 2-4 Group 3 2

Bone marrow involvement Group 4 3 or 4

Risk factors Prognostic risk

Age >60 years Group 1 0

Serum LDH >normal Group 2 1

Extra nodal disease Group 3 2

B symptoms Group 4 4

Platelet count 150 x 109/L Group 5 5

Prognostic Index for AITL2

1. Gallamini A, et al. Blood. 2004;103:2474-2479. 2. Federico M et al J Clin Oncol.2013 Jan 10;31(2):240-6

Is There a Favorable Risk PTCL Who Should Be Treated Differently?

• ITCP: 5-year FFS IPI 0,1 risk factors was only 33% and 34% for PTCL-NOS1 and AITL2,

respectively, reduced therapy not validated

• IPI may factor into our treatment recommendations in ALK-positive ALCL; FFS by IPI

risk factor:

– 0/1 = 80%

– 2 = 60%

– 3 = 40%

– 4/5 = 25%

• Suggests that CHOP-based therapy alone may not be adequate for patients with

higher-risk disease

– ALK-positive ALCL over the age of 40: Treat these higher-risk patients similar to

patients who present with the less favorable PTCL entities

1. Vose J, et al. J Clin Oncol. 2008;26(25):4124-4130. 2. Federico M, et al. J Clin Oncol. 2013;31(2):240-246.

PTCL: Putative cellular derivation and known oncogenic pathways

Gaulard P & de Leval L. Semin Hematol 2014; Sabattini E et al. Haematologica 2013.

CD30 expression iscommon in specific PTCLsubtypes and can help withdiagnosis and treatment optimization2

ALK-neg ALCL –Recurrent chromosomal rearrangements with DUSP22 and TP63

1 2

12

Castellar ERP et al. Blood 2014; Hapgood G et al. Br J Haematol 2019.

Approx 30% ALCL -veDUSP22‐IRF4locus on 6p25.3

Striving to improve initial therapy in PTCL

• CHOP provides initial responses for many but… few CRs; even fewer durable remissions; (ALCL >> AITL and PTCL-NOS)

• Alternative strategies:

1. Reimer P, et al. Adv Hematol. 2010;2010:320624.2. Mahadevan D, et al. Cancer 2013;119(2):371-379. 3. Simon A, ete al. Br J Haematol 2010;151(2):159-166.4. Information available on EMA’s website, assessed

12/Nov/2018(https://www.ema.europa.eu/en/medicines)

Adding etoposide to anthracycline-based regimen

• SWOG group Cisplatin, etoposide, gemcitabine, Solu-medrol• ORR only 39% and 2yr PFS of 12%2

• Phase III study GOELAMS group CHOP vs etoposide, ifosfamide, cisplatin alternating with adriamycin, bleomycin, vinblastine, and dacarbazine

• No difference in outcome for the 2 arms ORR of 70% and CR rate of 35% with CHOP3

Alternative to CHOP: attempts at using nonanthracycline-based regimen disappointing

• No randomized clinical trial comparing chemotherapy vs ASCT • Prospective shows benefit, but CR is the most important prognostic factor1

Consideration of transplant as consolidation

• Alemtuzumab, Romidepsin + chemo • Brentuximab vedotin + chemo

Adding novel agents to front-line setting

https://www.ema.europa.eu/en/medicines

Adding etoposide to CHOP:

German prospective high-grade NHL studies

EFS, aged <60 years

PTCL subtype n (%)

ALCL, ALK+ 78 (24.4)ALCL, ALK- 113 (35.3)

PTCL-NOS 70 (21.9)

AITL 28 (8.8)

Other 31 (9.7)

Total 320 (100)

0 10 20 30 40 50 60 70 80

Months

EFS, other subtypes

Non-etoposide (n=29)

80 90 100 110

p=0.057

0 10 20 30 40 50 60 70

100

80

60Etoposide (n=69)

40

20

0

Pat

ien

ts(%

)

0 10 20 30 40 50 60

Months70 80 90 100 110

100 100

80 80

60 60

20 20

0

Non-etoposide (n=12)

40 40

Pat

ien

ts(%

)

p=0.003

6 x CHOP-14/21 (n=41)

6 x CHOEP-14/21 (n=42) Etoposide (n=34)

EFS,ALCL, ALK+

90 100 1100

Pat

ien

ts(%

)

p=0.012

PTCL-NOS,peripheral T-cell lymphoma, not otherwise specified.

Schmitz N et al. Blood 2010

Toxicity with adding etoposide: B1 and B2 studies

*Values in the table represent the percentage of all patients experiencing the respective side effect at least one; **Values represent the percentage of patients who experienced the respective grade 3 and 4 event. CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone;

B1*

CHOEP, cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone. Pfreundschuh M et al. Blood 2004; Pfreundschuh M et al. Blood 2004.

B2**

What Are the Data Supporting ASCT for PTCL?

• No randomized clinical trial comparing chemotherapy vs ASCT

• Retrospective data from prospective randomized trials for aggressive lymphomas

◦ GELA pooled analysis with matched controls no advantage to ASCT1

• Prospective data◦ Variable front-line chemotherapy

◦ Variable preparative regimen for ASCT

◦ Variable inclusion criteria

Mounier N, et al. Ann Oncol. 2004;15(12):1790-1797.

CHOEP -> autoSCT –Nordic trial

CHO(E)P-14 x 6 n=160

ORR 82%CR 51%

BEAM or BEACauto-SCT

n=115 (72%)

5-year OS 51%

PTCL-NOS, peripheral T-cell lymphoma..

5-year PFS 44%

d'Amore F et al. J Clin Oncol 2012

The role of transplant at first remission

• COMPLETE study1

– Patients in CR1

– Median OS: NR with ASCT vs 57.6 months with noASCT(p=0.06)

– ASCT was associated with superior survival for stage III–IV and intermediate-to-high IPI

– ASCT improved OS and PFS with AITL but notother PTCL subtypes

– Multivariate analysis, ASCT was independentlyassociated with improved survival (HR: 0.37; 95% CI 0.15,0.89)

• LYSA study2: Showed no significant difference in PFS or OS in patients with PTCL who received ASCT consolidation (n=134)or noASCT (n=135) following CR on first-line therapy2

– PFS: HR 1.02; 95% CI 0.69, 1.50

– OS: HR 1.08; 95% CI 0.68, 1.69

ASCTmedian PFS: 57.6 months

1.Parks S et al. Cancer 2019; 2.Fossard G et al. Ann Oncol 2018.

Non-transplantmedian PFS: 47.5 months

1ASCTmedian OS: NR

Non-transplantmedian OS: 57.6 months

ASCT in PTCLSummary of Prospective Trials

• ~25%-60% do not get to ASCT due to disease progression during primary therapy

• ~20% relapse within the first year after ASCT

• Additional ~10% relapse by 2 years post ASCT

• Does ASCT as consolidation improve results or just select for healthier people with chemosensitive disease?

• Factors (high-risk disease) predict for poor outcome after chemotherapy and ASCT

Novel therapeutic options for T-Cell Lymphomas

Adapted from Savage KJ, et al. Oncology Exchange. 2012;11(3):10-18. Bachy E, et al. Blood. 2014;123(20):3059-3060.

1. Reimer P, et al. Adv Hematol. 2010;2010:320624.2. Mahadevan D, et al. Cancer 2013;119(2):371-379. 3. Simon A, ete al. Br J Haematol 2010;151(2):159-166.4. Information available on EMA’s website, assessed 12/Nov/2018 (https://www.ema.europa.eu/en/medicines)

Pharmacot. Class. Drug EMA Approval Status

Interleukin 2 + C. diphteriae toxin Denileukin diftitoxOrphan designation for CTCL (2001)Not approved

Antifolate PralatrexateNot approved for PTCL (authorization refused)

Histone deacetylase inhibitor

Romidepsin

BelinostatOrphan designation for PTCL(2012)Not approved.

Vorinostat Marketing application for CTCL withdrawnIMiD Lenalidomide Not approved for TCL Anti-CD52 MoAb Alemtuzumab Not approved for TCL

Anti-CD4 MoAb ZanolimumabOrphan designation for PTCL (2007) Not approved.

Anti-CD30 MoAbBrentuximab vedotin

Orphan designation for ALCL (2009); CTCL (2012) Approved for:•relapsed/ refractory sALCL•CD30+ CTCL after ≥prior therapy

Anti-human CCR4 Mogalizumab Not approved

Novel therapeutic options for T-Cell Lymphomas

https://www.ema.europa.eu/en/medicines

Romidepsin in the treatment of PTCL

1. Coiffier B et al. J Hematol Oncol 2014; 2. ClinicalTrials.gov. NCT01796002.

Duration of response with romidepsinin R/R PTCL1

PTCL

Ro + CHOP (Ro D1 & 8)

Placebo+CHOP

RANDOMIZE

RESTAGE C3

F/U Progression

Death

Ongoing Phase III study

Principal Investigators: BertrandCoiffier & Richard Delarue ClinicalTrials identifier: NCT01796002

CD30+ T cell lymphomas

ALCL CD30+

Images kindly provided courtesy of S Pileri

Targeting CD30 with Brentuximab vedotin in T cell lymphomas

• Phase II data relapsed/refractory sALCL (universally express CD30) led to approval in

the US, EU, and Japan

• Across subtypes, approximately 50% of patients express CD30

Variable CD30 expression among other PTCL subtypes4,5

• Encouraging phase 1 study of brentuximab vedotin in combination with CHP as

frontline therapy6

- Manageable safety profile

- At 5 years, 50% of patients remain in remission with no subsequent anticancer

therapy

- Median OS not reached

4. Bossard et al., Blood 124(19):2983-6; 2014

5. Sabattini et al., Haematologica 98(8): e81-82; 2013

6. Fanale MA, et al., Blood 131:2120-4; 2018

1. Savage KJ, et al., Ann Oncol 15(10): 1467-75; 2004

2. Savage KJ, et al., Blood 111(12):5496-504; 2008

3. Simon A, et al., Br J Haematol 151(2): 159-66; 2010

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

Horwitz SM et al. The Lancet 2018

Endpoints and Analysis Populations

Analysis Populations

• Efficacy

◦ Intention-to-treat (ITT)

• Safety

◦ All subjects who received any amount of

brentuximab vedotin or any component of CHOP

Endpoints

Type 1 error control for primary and all key

secondary endpoints

• Primary Endpoint*

◦ Progression-Free Survival (PFS) per BICR

ASCT or RT consolidation not an event

• Secondary Endpoints

◦ Overall survival (OS)

◦ PFS per BICR in sALCL subjects

◦ Complete remission (CR) rate

◦ Objective remission rate (ORR)

◦ Safety

* PFS events = PD, death, or subsequent systemic

therapy to treat residual or progressive disease

* Lymphoma response criteria Cheson 2007


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+ (IPI≥2) 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


Overall Survival

Deaths HR (95% CI) P

A+CHP 51 (23%) 0.66(0.46, 0.95)

0.0244CHOP 73 (32%)

75th Percentile

Not reached 17.5 mo

Median Follow-up 42.1 months


Events HR (95% CI) P

A+CHP 81 (36%) 0.71(0.53, 0.94)

0.017CHOP 111 (49%)

PFS: censored at time of consolidative ASCT or RT

Prespecified Subset Analyses: PFS


Prespecified Subset Analyses: OS


Other Secondary Efficacy Endpoints

A+CHP

(N=226)

CHOP

(N=226) P valueRemission rates in ITT population at EOT

CR rate 68% 56% 0.0066

ORR 83% 72% 0.0032

sALCL subset analysis, n 163 151

Subjects with a PFS event, n (%) 56 (34) 73 (48)

Hazard ratio 0.59 (95% CI: 0.42, 0.84) 0.0031

• All secondary endpoints were statistically significant; type I error controlled


Adverse Events in ≥20% of Subjects


Treatment-Emergent Peripheral Neuropathy

0

10

20

30

40

50

60

70

80

90

100

A+CHP CHOP

Subje

cts

(%

)

Grade 4Grade 3Grade 2Grade 1

A+CHP CHOP

Peripheral Neuropathy (PN)*

*Includes the preferred terms of peripheral sensory neuropathy, paraesthesia, peripheral motor neuropathy, muscular weakness, peripheral sensorimotor neuropathy, hypoaesthesia,

dysaesthesia, areflexia, burning sensation, peroneal nerve palsy, polyneuropathy, autonomic neuropathy, gait disturbance, muscle atrophy, and neuralgia.

Subjects, n (%)

A+CHP

(N=223)

CHOP

(N=226)

Treatment-emergent PN, n 117 124

Resolution† of all PN events 58 (50) 79 (64)

Ongoing PN at last follow-up 61 (52) 45 (36)

Grade 1 44 (72) 32 (71)

Grade 2 15 (25) 12 (27)

Grade 3 2 (1) 1 (1)

†Resolution was defined as resolved/recovered with or without sequelae; or return to baseline or lower

severity as of the latest assessment for pre-existing events


Summary and Conclusions

• A+CHP provided clinically meaningful improvement in PFS and OS versus

CHOP (ECHELON-2 first prospective trial in PTCL to show OS benefit over CHOP)

◦ 34% reduction in the risk of death

• A+CHP has a comparable safety profile to CHOP

• FDA approved brentuximab vedotin in combination with CHP for adults with

previously-untreated sALCL or other CD30-expressing PTCL, including AITL

and PTCL-NOS

Response to A + CHP by CD30 expression in ECHELON-2 trial

• Response rate and durability of response were independent of CD30 expression above vs median and responses were observed amongst patients with the lowest CD30 expression level – 10%.

• The degree of CD30 expression , as measured by IHC does not predict benefit from A+CHP

• Further evaluation of the expression-response relationship in PTCL patients with CD30

Illidge T. et al. Lugano 2019 P#228

BV-CHEP in treating patients with CD30-positive PTCL

ECOG, Eastern Cooperative Oncology Group; NOS, not otherwise specified; PR, partial response; PTCL, peripheral T-cell lymphoma; Q3W, every three weeks; TCL, T-cell lymphoma.ClinicalTrials.gov. NCT03113500.

Phase II, open-label, single-arm, interventional study

Key inclusion criteria:• ECOG status ≤2• Histologically

confirmed previously untreated PTCL or NK-cell lymphoma*

• CD30 expression ≥1%• Measurable disease• Adequate kidney and

liver function

Induction:BV-CHEP ×6 cycles

Consolidation: BV Q3W ×10cycles

Received between 30–60 days post-ASCT or when achieving CR or PRafter 6 cycles of induction therapy

Principal Investigator:Alex F. Herrera ClinicalTrials identifier: NCT03113500

Mycosis

Fungoides

MF or T-MF

Secondary

Cutaneous

ALCL

PTCL-NOS

HTLV-1

ATL

Hodgkin

Lymphoma

HL

CD30+ Cutaneous T cell lymphomas

Primary Cutaneous

ALCLc-ALCL

Lymphomatoid

Papulosis

LyP

Primary cutaneous

Anaplastic T-cell

Lymphoma

Lymphomatoid Papulosis

Transformed CD30+

Mycosis Fungoides

CD30+ Lymphoproliferative Disorders

ALCANZA: Brentuximab vedotin vs physician's choice of methotrexate or bexarotene, in previously treated patients with CD30-expressing CTCL (NCT01578499)

• 131 patients were enrolled between 13/Aug/2012-31/July/2015

• Final Analysis: 10 months from LPI

Kim et al. ASH 2016; Abstract #182 ;Prince HM et al. Lancet 2017;390:555-566.

• Median follow-up for PFS was 33.9m

• With 46 and 51 patients having progressed (39 and 46 patients) or died (7 and 5 patients), respectively, median PFS with

brentuximab vedotin versus physician’s choice was 15.8 versus 3.6 months

• Kaplan-Meier estimates demonstrated improved PFS rates with brentuximab vedotin versus physician’s choice at

1 year (63.9% vs 15.6%) and 2 years (28.8% vs 8.4%)

Progression-free survival Updated at 34 month follow up (ITT)

Horwtiz S et al. Blood 2017 130:1509

Time to next treatment (TTNT)

• At a median follow-up of 33.9 months, 47 (73%) and 48 (75%) of patients in the brentuximab vedotin and physician’s choice arms,

respectively, had received ≥1 subsequent antineoplastic therapy

• Median TTNT was significantly longer with brentuximab vedotin versus physician’s choice (14.2 vs 6.1 months; HR 0.335; 95% CI, 0.218–0.515; p<0.001)

• In the brentuximab vedotin versus physician’s choice arms, the probability of patients not requiring subsequent antineoplastic therapy was greater at 1 year

(65.5% vs 15.3%) and 2 years (24.6% vs 4.4%) post-randomizationP

rob

abili

ty o

f su

bse

qu

ent

anti

neo

pla

stic

th

erap

y

Horwtiz S et al. Blood 2017 130:1509

ALCANZA Summary

• Brentuximab vedotin demonstrated improved, durable responses compared

with physician’s choice across subgroups defined by disease

stage/compartment in patients with CD30-positive CTCL requiring systemic

therapy

• ORR4 (primary endpoint) was consistently higher with brentuximab vedotin in

both MF and pcALCL, irrespective of disease stage and compartment

Prince HM et al. Lancet 2017;390:555-566.; Horwtiz S et al. Blood 2017 130:1509

Mogamulizumab - Mechanism of Action

Chemokines and chemokine receptors orchestrate cell migration and homing in the body1; C-C chemokine receptor 4 (CCR4) is the receptor for two CC chemokine ligands (CCLs)—CCL17 (also called thymus- and activation-regulated chemokine, TARC) and CCL22 (macrophage-derived chemokine, MDC) 1

Mogamulizumab, a humanized anti-CCR4 mAb, binds to CCR4-positive malignant T cells, and elicits anti-tumour activity mediated by antibody-dependent cellular cytotoxicity (ADCC).2

Selective targeting of CCR4+ malignant T cells by mogamulizumab (a) activates immune effector cells (natural killer cells and monocytes) (b)3-5

The effector cells bind to mogamulizumab (b), triggering release of cytotoxic molecules that kill the CCR4+ malignant T cell via ADCC (c)3-5

Mogamulizumab is glycoengineered (defucosylation) for enhanced antibody-dependent mediated cellular cytotoxicity (ADCC).4,5

CCR4+ T cell

Effector cell

mogamulizumab

T cell lysis CCR4+ T cell

Effector cell

a b c

1 Niwa R, et al. Clin Cancer Res. 2005;11(6):2327-36; 2 Ishii T, et al. Clin Cancer Res. 2010;16(5):1520-1531; 3 Ishida T, et al. Clin Cancer Res. 2004;10(22):7529-39; 4 Duvic M, et al. Ther Adv Hematol. 2016;7(3):171-174; 5 POTELIGEO [package insert]. Kyowa Kirin Inc., Bedminster, NJ USA.

MAVORIC (NCT01728805): Open-Label, Randomized, International, Phase 3 Study of Mogamulizumab Versus Vorinostat in Patients With MF/SS

Inclusion:• Stage IB – IVB histologically

confirmed MF or SS• Failed ≥1 prior systemic TxExclusion:• Patients with large cell

transformation

1:1

Ran

do

miz

atio

n Mogamulizumab1.0 mg/kg IV

Weekly for the first 5 weeks,then every 2 weeks

Vorinostat400 mg PO daily

One-way crossover after PD

• 372 patients were randomized at 61 centers across 11 countries• Tx was administered on an outpatient basis• Vorinostat (FDA-approved HDACi) was administered in accordance with US

prescribing information • Patients could remain in the Tx phase up until progression or intolerable toxicity

Kim YH, et al. Lancet Oncol. 2018;19(9):1192-1204.

Primary Endpoint: Progression-Free Survival (Investigator Assessment)

PFS: 7.70 vs 3.10 months (HR 0.53 [95% CI: 0.41, 0.69], P<0.0001)ORR: 28.0% vs 4.8%, P<0.0001Among patients crossing over from vorinostat to MOGA, n=133, due to progression/intolerance, 31% achieved ORR

CI, confidence interval; HR, hazard ratio; MOGA, mogamulizumab; ORR, overall response rate; PFS, progression-free survival.

Kim YH, et al. Lancet Oncol. 2018;19(9):1192-1204.

NK/T-cell lymphoma preferential sensitivity to checkpoint

blockade in contrast to other TCL ?

Pembrolizumab in NK/T-cell lymphoma1 Rapid progression of ATL with nivolumab3

Sintilimab, human anti-PD-1 mab in NK/T-cell lymphoma2

N=28; ORR 68%1-year OS rate was 82.1%

Phase II study of the PD1-inhibitor pembrolizumab forTCL4•

Response rate was 27% (4/15 patients; all 4 respondersachieved a CR)

Nivolumab5

•

•

PTCL 40% (2/5) PRs, 1 durableMF 15% (2/13) PRs, both ongoing

1. Kwong Y-L et al. Blood 2017; 2. Tao R et al. J Clin Oncol 2019; 3. Ratner et al. N Engl J Med 2018; 378:1947-1948; 4. Barta SK et al. J Clin Oncol 2018; 5. Lesokhin AM et al. J Clin Oncol 2016.

TELLOMAK: T cell lymphoma anti-‐KIR3DL2 Therapy: An open label, multi-cohort, multicenter, international Phase II study evaluating the efficacy and safety of IPH4102 alone or in combination with chemotherapy in patients with advanced T cell lymphoma

• Background: KIR3DL2 is a killer immunoglobulin‐like receptor that is expressed by tumor

cells across different subtypes of T‐cell lymphomas (> 85% of Sézary Syndrome (SS), ~50%

of mycosis fungoides (MF), and ~50% in peripheral T‐cell lymphomas (PTCL)).

• IPH4102 is a humanized first‐in‐class anti‐KIR3DL2 monoclonal antibody designed to deplete

KIR3DL2‐expressing cells via antibody‐dependent cell‐cytotoxicity (ADCC) and phagocytosis.

P. Porcu et al. Lugano 2019


• A first‐in‐human study including 44 patients with relapsed/refractory cutaneous

T‐cell lymphoma (CTCL) showed that the drug is safe and has very robust

clinical activity.

• The majority of the patients enrolled had relapsed/refractory SS (n=35).

IPH4102 produced an overall response rate (ORR) of 42.9%, and median

progression free survival (PFS) of ~1 year leading to FDA fast track

designation in January 2019.

• IPH4102 has not been previously investigated in PTCL.

• Preclinical studies have shown that gemcitabine and oxaliplatin can

upregulate KIR3DL2 expression on T‐cell lymphoma cell lines.



• Open‐label, multi‐cohort, multi‐center, international phase II trial.

• Patients will be allocated to one of five cohorts:

◦ Cohort 1: SS,

◦ Cohorts 2&3: MF stratified according to KIR3DL2 expression,

◦ Cohorts 4&5: PTCL stratified according to KIR3DL2 expression.

• In the PTCL cohorts, IPH4102 will be administered using the same

schedule in combination with gemcitabine and oxaliplatin

(GEMOX), which will be administered every 2 weeks for a

maximum of 8 cycles.


Summary and conclusions

1. ECHELON-2 : First phase 3 A+CHP 34% reduction in death for PTCL

Practice changing for use of Brentuximab Vedotin in ALCL.

2. ALCANZA: First phase 3 trial against approved standard of care (methotrexate/bexarotene),

practice-changing for the use of BV in clinical management of CD30+ CTCL patients requiring

systemic therapy. NICE approved

3. MAVORIC: Phase 3 MAVORIC trial (anti-CCR4; Mogamulizumab (POTELIGEO®) the largest phase

3 randomised study of systemic therapy in CTCL and the first to show clinically meaningful

advantage in SS and advanced advantage e systemic therapies using progression-free survival as a

primary endpoint. Awaiting NICE appraisal

4. TELLOMAK: T cell lymphoma anti-‐KIR3DL2 Therapy IPH4102 ORR of 42.9%, and median

progression free survival (PFS) of ~1 year leading to FDA fast track designation in January 2019.

Subtype-specific approaches: Conclusions

Speaker opinion

ALCL: ECHELON-2 practice changing

– ALCL ALK+: BV-CH-P > CHOP (?) > CHOEP

– ALCL ALK-: BV-CH-P > CHOP (?) > CHOEP

– Consolidation? ECHELON-2 doesn't really address this

– DUSP22 rearranged- analysis in ECHELON-2 is pending

PTCL-NOS, AITL: Beyond BV-CHP, CHOEP-still room for improvement

– BV-CHEP, ASCT

– Others targets –CHOP + X strategy +/-

• Lenalidomide – no clear advantage

• HDAC, hypomethylating – awaiting data

– JAK/STAT, PI3K, checkpoint inhibitors, others

– Likely subtype specific or tumor/target specific factors (NK/T)

CTCL and SS: Brentuximab Vedotin and Mogamulizumab approved

Remaining unmet needs in PTCL: Conclusions

• More effective options as initial treatment

• ALCL

– DUSP22 rearranged- analysis in ECHELON-2 is pending

• ASCT

– Unresolved without a clinical trial and clinical trial unlikely to be done

– Hopefully better initial therapy will remove the question

• PTCL-NOS, AITL – beyond BV-CHP, CHOEP, BV-CHEP, ASCT

– Others targets –CHOP + X strategy +/-• Len, HDAC, hypomethylating – awaiting data

– JAK/STAT, PI3K, checkpoint inhibitors, others– Immunotherapy/CAR-T

• Subtype specific or tumor/target specific factors most likely

Speaker opinion

Acknowledgements : Steve Horwitz, Owen O’Connor, Barbara Pro

Thank you for your attention

Questions

t cell lymphomas current treatment landscape · other ptcl subtypes – multivariate analysis,asct...

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