INSIGHTS INTO OPTIMIZING THERAPEUTIC APPROACHES FOR T-CELL LYMPHOMAS Integrating Current and...

INSIGHTS INTO OPTIMIZING THERAPEUTIC APPROACHES

FOR T-CELL LYMPHOMAS

Integrating Current and Emerging Agents/Regimens to Develop Evidence-Based Clinical Management Strategies

Faculty

Disclosures

Educational Objectives

After completing this program, participants should be able to:

1. Distinguish between the various T-cell lymphoma subsets, including the molecular, histopathologic, and clinical features that aid in accurate diagnosis and guide treatment decisions

2. Describe current treatment options for peripheral (PTCL) and cutaneous (CTCL) T-cell lymphoma subtypes and how recent clinical trial data with existing and emerging agents can be integrated into evidence-based clinical management strategies

3. Evaluate the efficacy and safety data from studies of current and emerging treatment options to improve outcomes in patients with PTCL and CTCL

4. Summarize new data and possible treatment algorithms that can be used in community practice to achieve the best outcomes for patients PTCL and CTCL

CHARACTERIZATION OF T-CELL LYMPHOMAS

T-cell Lymphomas (TCLs)

• TCLs account for 7%-10% of all Non-Hodgkin Lymphomas in the US

• Most are clinically aggressive

• Heterogeneous in their clinical presentation, features, and prognosis

• Challenges in treatment:

– Increasing number of subtypes, making it very difficult to understand and diagnose these entities

– Each entity is encountered infrequently

– Lack of effective treatmentGisselbrecht C, et al. Blood. 1998;92:76-82. Armitage J, et al. J Clin Oncol. 1998;16:2780–2795.

Mature T-/NK-cell Lymphomas

Adapted from Swerdlow SH, et al. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. 2008.

CTCL

Mycosis Fungoides (MF)

Extranodal LeukemicNodal

Aggressive

Transformed MF

Sézary Syndrome

Primary Cutaneous CD30+ T-cell Disorders

Primary Cutaneous Gamma/Delta TCL

NK/TCL Nasal Type

Enteropathy- associated TCL

Hepatosplenic TCL

Subcutaneous Panniculitis-like TCL

Peripheral TCL-NOS

Anaplastic Large Cell Lymphoma (ALK +/-)

Angioimmunoblastic TCL

Adult T-cell Leukemia/Lymphoma

Aggressive NK-Cell Leukemia

T-cell Prolymphocytic Leukemia

T-cell Large Granular Lymphocytic Leukemia

2008 WHO Classification of TCL


PERIPHERAL T-CELL LYMPHOMA (PTCL) SUBTYPES

Overview of PTCLs

• A rare heterogeneous group of NHL

• Refers to mature “post-thymic” T-cell lymphoma

• Characterized by the proliferation of abnormal T lymphocytes

• Outcomes are poor– Low response rates– 5-year OS ~32%– 5-year failure-free survival ~20%– Most patients relapse within 2-3 years

Gisselbrecht C, et al. Blood. 1998;92:76-82. Armitage J, et al. J Clin Oncol. 1998;16:2780–2795. Weisenburger DD, et al. Blood. 2011;117:3402-3408.

Global Frequencies of PTCL Subtypes• PTCL– not otherwise specified (PTCL-NOS) is the most common

subtype

• Anaplastic large cell lymphoma (ALCL) ALK+/- and angioimmunoblastic lymphoma are also common subtypes

Armitage J, et al. J Clin Oncol. 2008;26:4124–4130.

26%

19%

10%

10%

7%

6%

5%2%1%

1%

3%12% Peripheral T-cell lymphoma NOS

AngioimmunoblasticNatural killer/T-cell lymphomaAdult T-cell leukemia/lymphomaAnaplastic large cell lymphoma ALK+Anaplastic large cell lymphoma ALK-Enteropathy-type T-cellPrimary cutaneous ALCLHepatosplenic T-cellSubcutaneous panniculitis-likeUnclassifiable PTCLOther disorders

PTCL-NOS

Clinical Presentation

• Advanced stage disease with BM, liver, spleen and other extranodal involvement are common

• B symptoms and para-neoplastic symptoms are common

• PTCL-NOS diagnosis is made when other specific entities have been excluded; “waste-basket” of PTCL

• The latter paradigm might be changing based on GEP signature studiesImages courtesy of Dr. Shustov.

AngioimmunoblasticT-cell Lymphoma (AITL)


• Generalized lymphadenopathy, splenomegaly, hepatomegaly, skin and bone marrow involvement are common

• Autoimmune phenomena are common – Pleural effusion, ascites – Arthralgia – Dermatitis– Coomb’s+ hemolytic anemia– Polyclonal hypergammaglobulinemia– Rh+, SMAb+, cold agglutinins– Commonly associated with EBV, however

the neoplastic cells are EBV negative

Images courtesy of Dr. Shustov.

Extranodal NK/T-cell Lymphoma, Nasal Type


• Most prevalent in Asians, Native American population of Mexico, Central America and South America; adult males

• Strong association with EBV

• Most commonly extranodal with typical involvement in the nasal cavity

– Extranasal sites include skin, soft tissue, GI tract, and testis

• Symptoms include nasal obstruction, epistaxis, extensive midfacial destructive lesions, facial pain

• Often localized to upper aerodigestive tract at diagnosis

cCD3-CD2+CD56+cCD3+TIA1+Gr

B+


Anaplastic Large Cell Lymphoma (ALCL)

Clinical Presentation• Two types of ALCL: ALK- and ALK+

• Clinical presentation similar; ALK+ > in younger patients

• Important to distinguish ALK- disease from:– Primary cutaneous ALCL when skin

involvement is present– EATL when GI involvement is present

• Majority of patients present with advanced stage disease, involving both LNs and extranodal sites

• B symptoms are very common; paraneoplastic phenomena are also common (pruritus, rash, arthralgia)


PTCL Prognosis by SubtypeThe International PTCL and NK/TCL Study

PTCL Subtypes

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

5-yr OS rate, % 70 49 32 32 32 14

• Median OS for most subtypes of PTCL is 1–3 years [1,2]

− 5-year OS is approximately 26% [3]

− ALK+ ALCL is an exception, with a 5-year survival of 65%–90% [2]

International T-Cell Lymphoma Project. J Clin Oncol. 2008;26:4124-4130. [1] Armitage JO, et al. Ann Oncol. 2004;15:1447–1449. [2] Savage KJ. Blood Rev. 2007;21:201–216. [3] Rüdiger T, et al. Ann Oncol. 2002;13:140-149.

OS

(%

)

Yrs

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16 18 20

ALCL, ALK+ALCL, ALK-All NK/T-cell lymphomasPTCL-NOSAITLAdult T-cell leukemia/lymphoma


CUTANEOUS T-CELL LYMPHOMA (CTCL) SUBTYPES

Overview of CTCLs

• Characterized by skin lesions with epidermal and dermal involvement

• 3 histological patterns: – Epidermotrophic– Dermal– Subcutaneous

• Classified by their histological, cytogenetic, and immunologic features

• Some subtypes are indolent

• Survival and management varies depending upon clinical presentation and specific subtypeRizvi MA, et al. Blood. 2006;107:1255-1264.

Swerdlow SH. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. 2008.

CTCL Incidence

• CTCL represents 4% of all NHLs

• Aged–adjusted incidence of 6 cases per 1 million

• Twice as common in men as in women

• Incidence is increasing• Incidence increases with age

– Average age of onset is between 50 and 60 years

Criscione VD, Weinstock MA. Arch Dermatol. 2007;143:854-859. Bradford P, Devesa S, Anderson WF, Toro JR. Blood. 2009;113:5064-5073. Figure reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY

CTCL Entities

Category Neoplasm

Extranodal-

cutaneous

• Mycosis fungoides

• Sézary syndrome

• Primary cutaneous CD30+

lymphoproliferative disorders

− Lymphomatoid papulosis

− Primary cutaneous ALCL

• Primary cutaneous T-cell lymphoma

• Subcutaneous panniculitis-like T-cell

lymphoma

Rosen S, Querfeld C. Hematology Am Soc Hematol Educ Program. 2006;2006:323–330.

Most common subtypes

Clinical Features—Mycosis Fungoides (MF)

• Classical – Persistent and progressive skin lesions

– Sun-protected skin

– Large (> 5 cm), pruritic, and multifocal

• Variations – Unusual anatomic sites (palmoplantar,

isolated alopecia)

– Solitary lesion (pagetoid reticulosis)

– Clinical variations (hypopigmented)

– Association with masking clinical conditions (ichthyosis)

• Long clinical course

• Stepwise clinical progression

Kinney MC, Jones D. Am J Clin Pathol. 2007;127:670-686.

Images courtesy of Dr. Foss

Clinical Features—Sézary Syndrome (SS)• Systemic and aggressive variant

• Exfoliative erythroderma, ectropion, alopecia, palmoplantar keratoderma

• Severe pruritus

• Circulating, atypical, malignant T lymphocytes– Sézary cells: CD3+, CD4+, CD5+, CD7+/–, CD8–, CD25+/–, CD26–, CD30-,

CD45RO+, CD52+, CD158+

Querfeld C, et al. Management of Hematologic Malignancies. 2011.

Disease-Specific Survival by Stage Risk of Progression by Stage

1. Zackheim HS, et al. J Am Acad Dermatol. 1999;40:418-425. 2. Kim YH, et al. Arch Dermatol. 1996;132:1309-1313.

Skin Stage at Diagnosis 10-Yr Relative Survival,% P Value

T1 100 NS

T2 67 .002

T3 39 < .001

T4 41 < .001

Prognosis by Stage in CTCL—MF/SS

CURRENT THERAPEUTIC OPTIONS FOR PTCL AND CTCL

1ST-LINE TREATMENTS

NCCN Guidelines—Initial Treatment of PTCL

Patient Population

Stage Induction Therapy Consolidation Therapy

ALCL, ALK+ I, II CHOP-21 or CHOEP-21* (3-6 cycles) ± ISRT (30–40 Gy)

Not needed if in remission

ALCL, ALK+ III, IV Multiagent chemotherapy* (6 cycles) Consider consolidation with high-dose therapy and stem cell rescue for all patients except low-risk (aaIPI)

PTCL, NOSALCL, ALK - AITLEATL

I-IV • Clinical trial preferred• Multiagent chemotherapy* (4-6 cycles) ± ISRT (30–40 Gy)

*Suggested regimens: • CHOP-14 or CHOP-21 (cyclophosphamide, doxorubicin, vincristine, prednisone)• CHOEP (cyclophsophamide, doxorubicin, vincristine, etoposide, prednisone)• Dose-adjusted EPOCH (etoposide, prednisone, vincristine,cyclophosphamide, doxorubicin)• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-

dose methotrexate and cytarabine• CHOP followed by IVE (ifosfamide, etoposide, epirubicin) alternating with intermediate-dose methotrexate [Newcastle Regimen] [studied only in patients with EATL]• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with high-dose

methotrexate and cytarabine

NCCN. Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphoma. Version 2.2015.

Standard of Care for PTCL

• Historical approaches– CHOP-based strategies in first-line therapy for patients

with PTCL• ORR: 60%-70%, CR: 40%-60%

– Relapse @ 2 years >70%-80% in most series

• Limited clinical data due to relative rarity and heterogeneity of subtypes

• New approaches– CHOP as platform?– High dose chemotherapy and autologous stem-cell

transplant in PR1/CR1– New agents

NCCN Guidelines—Initial Treatment of CTCL (MF/SS)Patient Population Primary Therapy

Stage IA Skin directed therapies

Stage IB-IIA Generalized skin treatment ± adjuvant local skin treatment

Stage IIB

Generalized tumor, transformed, and/or folliculotropic disease

Limited extent tumor disease ± patch/plaque disease

•Local RT•Systemic therapies (Category A) ± skin directed therapies ±RT

Generalized extent tumor, transformed, and/or folliculotropic disease

•Total skin bean electron therapy (TSBE)•Systemic therapies (Category A, B or C) ± skin directed therapies

Stage IIINo blood involvement Skin directed therapy

Blood involvementSystemic therapies (Category A) ±skin directed therapy

Stage IVSezary Syndrome

•Systemic therapies (Category A)• Combination therapies

Non Sezary or Visceral diseaseSystemic therapies (Category B or C)Multiagent chemotherapy ±RT


Treatment Algorithm—MF/SSIA

(limited patch, plaque)

IB, IIA (generalized patch, plaque)

IIB(tumors)

III(erythroderma)

IVA, B(visceral

involvement)

Topical corticosteroids

(class I)

Bex gel

NM

UVB

Photopheresis ± IFN ± bexAlemtuzumab

Chemotherapy or AlloSCT

PUVA (± IFN or ± retinoid)

Bexarotene capsulesVorinostat

Denileukin diftitox

Spot radiation therapy

Bex capsules

Romidepsin

Standard of Care for CTCL—MF/SS

• Low CR rate (≤ 10%) for all medications approved for MF over the past 15 yrs – Most new drugs for MF expected by the FDA to

achieve 30% ORR (PR + CR)

• Patients require long-term treatment to prevent progression

• As opposed to other areas of oncology, treatments are often used multiple times during the course of the disease– MR or PR not considered failures

RELAPSED/REFRATORY PTCL• Pralatrexate • Belinostat• Romidepsin • Brentuximab

CURRENT THERAPEUTIC OPTIONS FOR PTCL

Candidates forHigh-dose Therapy

Non-candidates for High-dose

Therapy

NCCN Guidelines. Peripheral T-Cell Lymphomas. Version 2.2015

Clinical trial or 2nd-line therapy* or

Palliative RT

Clinical trial or 2nd-line therapy†

Complete or Partial response

No response

Clinical trial orAllogenic transplant or

High-dose therapy w/autologous

transplant

Clinical trial orAlternative 2nd-line or

Best supportive care orPalliative RT

*Alemtuzumab, bendamustine, belinostat, bortezomib, brentuximab vedotin (sALCL excluding primary cutaneous ALCL, sCD30+ PTCL), cyclosporine (AITL), dose-adjusted EPOCH, gemcitabine, pralatrexate, romidepsin

†Bendamustine, belinostat, brentuximab vedotin (sALCL excluding primary cutaneous ALCL, sCD30+ PTCL), DHAP, ESHAP, dose-adjusted EPOCH, GDP, GemOx, ICE, pralatrexate, romidepsin

NCCN Guidelines—R/R PTCL

Relapsed/Refractory PTCL—Single-Agent or Combination Therapies?

• Factors to consider: patient specific – Performance score, comorbidities– Goals of therapy: palliative vs curative intent

• Factors to consider: regimen specific– Toxicities of the regimen– ORR if transplant candidate– Meaningful endpoints: PFS, response rate, and

duration– Relevant targets if targeted therapies are available

NCCN Guidelines. Peripheral T-Cell Lymphomas. Version 2.2015

Relapsed/Refractory PTCL—FDA Approved Agents

AgentRegimen N ORR, % CR, % Response

Duration, Mos

Pralatrexate[3]

(Pivotal)30 mg/m2 weekly x 6

of 7 wks 111 29 11 10.1

Romidepsin[1] (NCI)

14 mg/m2 weekly x 3 every 28 days 47 38 18 8.9

Romidepsin[2] (Pivotal)

14 mg/m2 weekly x 3 every 28 days 131 25 14 17.0

Brentuximab vedotin[4] (ALCL) 1.8 mg/kg every 21 days 58 86 57 12.6

Belinostat[5]

1,000 mg/m2 once daily on days 1-5 of a 21-day

cycle120 25.8 10.8 8.4

1. Piekarz RL, et al. Blood. 2011;117:5827-5834. 2. Coiffier B, et al. J Clin Oncol. 2012;30:631-636. 3. O’Connor OA, et al. J Clin Oncol. 2011;29:1182-1189. 4. Pro B, et al. J Clin Oncol. 2012;30:2190-2196. 5. O’Connor OA, et al. J Clin Oncol. 2015; 33:2492-2499.

PRALATREXATE—Antineoplastic Folate Analog

RFC-1

Cell membrane

Extracellular

Cytosol

DNA

10-formyl

THF

5.10-methenyl

THF

PDX

THF

Folate

DHF

PRPPGARFT

PDX-Glu(n)

IMP

AICARFT

AMP

GMP

dUMP

dTMP

DHFR

RNADNA

TS

FPGS

Pralatrexate>>>MTXRFC-1

FDA granted accelerated approval in September 2009 for R/R PTCL

Pralatrexate [package insert]. Westminster, CO: Allos Therapeutics, Inc. Revised 9/2009.

PRALATREXATE—R/R PTCL

• Most common grade 3/4 AEs (n=111 evaluable):– Thrombocytopenia (32%)– Mucositis (22%)– Neutropenia (22%)– Anemia (18%)

O’Conner OA, et al. J Clin Oncol. 2011;29:1182-1189.

Outcome Patients (N=109 evaluable)

ORR 29%

• CR 11%

• PR 18%

Median DOR 10.1 months

Median PFS 3.5 months

Median OS 14.5 months3 6 9 12 15 180

0.25

0.50

1.00

0.75

Months

Pro

po

rtio

n

Permanently censored (eg, transplant) (n = 8)Continue in follow-up for response (n = 8)

ROMIDEPSIN—HDAC Inhibitor

Activation of apoptosis[4]

Caspase 3

Caspase 8

PARP

BAX

BAK

HDI – +

HAT

HDAC

Control HDI

Cell cycle arrest[4]

100806040200

Co

un

ts

FL2-A

FL2-A0

10

20

30

Co

un

ts

FL2-A

Gene regulation[1]Protein acetylation[3]

Anti-angiogenesis[5]

Histone acetylation/Transcription induction[2]

Romidepsin

Hsp70

Hsp70AcAc

+ HDI

Proteasome

Hsp70 acetylation andclient protein degradation

1. Peart MJ, et al. Proc Nat Acad Sci. 2005;102:3697-3702. 2. Bolden JE, et al. Nat Rev Drug Discov. 2006;5:769-784. 3. Wang Y, et al. Biochem Biophys Res Commun. 2007;356:998-1003. 4. Celgene Corp. Data on file. 5. Kwon HJ, et al. Int J Cancer. 2002;97:290-296.

Coiffier BD, et al. J Clin Oncol.2012;30:631-636

• Grade 3/4 AEs (> 10%): neutropenia, thrombocytopenia, anemia, infections• FDA granted accelerated approval in June 2011 for treatment of patients with

PTCL who have received ≥ 1 prior therapy• Ro-CHOP vs CHOP ongoing in Europe

N= 131• PTCL (MF or SS excluded) • Failed ≥1 prior systemic therapy• ECOG PS ≤2

Romidepsin 14 mg/m2 IVDays 1,8, and 15 q28d

ROMIDEPSIN—R/RPTCL

Outcome Patients

ORR 25%

• CR/CRu 15%

• PR 11%

• SD 25%

Response by Primary Diagnosis Patients

PTCL-NOS 29%

AITL 30%

ALK-ALCL 24%

BELINOSTAT—HDAC Inhibitor

Belinostat

Belinostat [package insert]. Irvine, CA: Spectrum Pharmaceuticals, Inc. Revised 7/2104.

FDA granted accelerated approval in July 2014 for R/R PTCL

BELINOSTAT— R/R PTCL

Response Efficacy Analysis Set

n=120; n(%)CR+PR 31 (26) [95% CI, 18-35]

CR 13 (11) [95% CI, 6-18]PR 18 (15)SD 18 (15)PD 48 (40)NE 23 (19)

O’Connor O. et al. ASCO 2013. Abstract 8507.

• Median OS (n=120): 7.9 months • Grade 3-4 AEs (≥ 5%): thrombocytopenia (13%), neutropenia (13%), anemia (10%),

dyspnea (6%), pneumonia (6%), and fatigue (5%)

BELIEF Study• PTCL (N=129)• Failed ≥1 prior systemic therapy• Platelets ≥ 50,000/µL• No prior HDACi therapy

Belinostat1000mg/m2

Day 1-5 x 21 day cycle

BRENTUXIMAB VEDOTIN—Antibody-drug Conjugate

FDA-approved in 2011 for:• HL after failure of ASCT or after failure of ≥ 2 multiagent chemotherapy regimens

in patients who are not ASCT candidates• Systemic ALCL after failure of at least 1 prior multiagent chemotherapy regimen

Brentuximab vedotin [package insert]. Bothell, WA:Seattle Genetics, Inc. Revised 9/2011.

BRENTUXIMAB—R/R HL

Pivotal Study• R/R HL • Age > 12 years• Measurable disease FDG-avid• ECOG 0-1

Brentuximab vedotin• 1.8 mg/kg IV every 21 days• Max 16 cycles for SD or better• Restage * at cycles 2, 4, 7, 10,

13, 16

Clinical Response N=58

ORR (95% CI) 86% (75, 94)

CR rate (95% CI) 59% (45, 71)

Median Duration Months

OR (95% CI) 13.2 (5.7, NE)

Response in patients with CR (95% CI) Not reached (13, NE)

Pro B, et al. J Clin Oncol. 2012;30:2190-2196

• Kaplan-Meier estimated 4-year survival rate: 64% (95% CI, 51%-76%)• Grade 3/4 AEs (>10%): neutropenia (21%), thrombocytopenia (14%), and

peripheral sensory neuropathy (12%)

BRENTUXIMAB—R/R PTCL

• Phase II• R/R AITL, R/R PTCL-NOS • Median of 2 prior therapies (1-9)• 63% refractory to most recent

therapy

Brentuximab vedotin 1.8 mg/kg IV every 21 days until

progression or unacceptable toxicity

Clinical Response,

n(%)

AITL (n=13)

PTCL-NOS

(n=22)Total

ORR 7 (54) 7 (33) 14 (41)

CR 5 (38) 3 (14) 8 (24)

PR 2 (15) 4 (19) 6 (18)

SD 3 (23) 3 (14) 6 (18)

PD 3 (23) 11 (52) 14 (41)

Horwitz SM, et al. Blood. 2014;123:3095-3100.

• Grade 3/4 AEs: neutropenia (14%), peripheral sensory neuropathy (9%), and hyperkalemia (9%)

PFS

RELAPSED/REFRATORY CTCL• Romidepsin • Pralatrexate• Vorinostat • Brentuximab

CURRENT THERAPEUTIC OPTIONS FOR CTCL

NCCN Guidelines—R/R CTCL

• Patients who relapse may respond when retreated with the same regimen• Patients with relapse or persistent disease after primary treatment should

be considered for clinical trial


Suggested Treatment Regimens for Second-line Therapy of CTCL (in alphabetical order)

CR/PR or Inadequate Response Refractory Disease or Progression

•Retreatment with initial therapy •Alemtuzumab•Allogenic transplant•Clinical trial•Combination therapy•Multiagent chemotherapy•Systemic chemotherapy •Systemic therapy•Systemic therapy ± skin-directed therapy•TSEBT

Relapsed/Refractory CTCL—Select Systemic Agents

Agent Regimen N ORR, % Response Duration, Mos

Romidepsin[1] • 14 mg/m2 on days 1, 8, and 15 of a 28-day cycle. 167 35 11-15

Vorinostat[2] • 400 mg once daily• Could be reduced for toxicity to 300

mg orally daily or 300 mg orally five days a week

74 30 5

Pralatrexate[3] • 15 mg/m2 weekly for 3 weeks of a 4-week cycle 54 41 NR

Brentuximab[4

]• 1.8 mg/kg every 21 days.• Patients achieving CR received 2

additional doses • PR after 8 cycles could receive up

to 16 doses

48 71 9-10 (MF)

1. FDA Approval for Romidepsin. Available at http://www.cancer.gov/about-cancer/treatment/drugs/fda-romidepsin. 2. FDA Approval for Vorinostat. Available at http://www.cancer.gov/about-cancer/treatment/drugs/fda-vorinostat. 3. Horwitz SM, et al. Blood. 2012;119:4115-4122. 4. Duvic M, et al. Blood. 013, 122 : 367.

HDAC INHIBITORS IN MF/SS

Romidepsin

GPI Study[1] NCI Study[2]

Stage N ORR, % N ORR, %

All stages 96 34 71 34

IB-IIA 28 25 8 62.5

IIB 21 43 15 47

III 23 39 6 33

IV 24 33 41 22

Vorinostat[3]

Stage N ORR, %

All stages 74 29.7

IB-IIA 13 30.8

≥ IIB 61 29.5

SS 30 33.3

1. Whittaker SJ, et al. J Clin Ocol. 2010;28:4485-4491. 2. Piekarz RL, et al. J Clin Oncol. 2009;27:5410-5417. 3. Olsen EA, et al. J Clin Oncol. 2007;25:3109-3115.

• Romidepsin: FDA-approved in 2009 for use in patients with CTCL who have received ≥ 1 prior systemic therapy

• Vorinostat: FDA-approved in 2006 for use in patients with of CTCL who have progressive, persistent, or recurrent disease on or following two systemic therapies

Horwitz SM, et al. Blood. 2012;119:4115-4122.

PRALATREXATE—R/R CTCL

• ORR: 41% (22/54)• Grade 3-4 AEs: mucositis (17%), thrombocytopenia (3%)

Cohort >15 mg/m2 N=41Median PFS: 388 days

• Phase I• R/R CTCL (n = 54)• Failed ≥ 1 prior therapy

Pralatrexate15 mg/m2 weekly for 3 weeks of a

4 week cycle

BRENTUXIMAB—R/R CTCL

Primary Diagnosis

Total pts Response

(ORR: 71%) Time to Response

(wks) Median DOR

(wks) MF 28 12PR, 2 CR 50% 10.5 13.5 LyP 9 5 CR, 4 PR 100% 3 23 pc-ALCL 2 2 CR 100% 3 18 LyP/MF 7 6 CR, 1 PR 100% 3 18 ALCL/LyP 2 2 CR 100%

Duvic M, Tetzlaff M, Clos AL, et al. 2013 ASH Annual Meeting. Abstract 367. Duvic M, et al. Blood . 2013;122:367.

• Phase II; N = 48• Primary cutaneous CD30+

including LyP and pc-ALCL or CD30+ MF

• Failed ≥ 1 prior therapy

Brentuximab• Infused at 1.8 mg/kg every 21 days• Patients achieving CR received 2

additional doses • PR after 8 cycles could receive up

to 16 total doses

• The most common AE of any grade was peripheral neuropathy (60%)• Grade 3/4 AEs: neutropenia (n=5), nausea (n=2), chest pain (n=2), deep vein

thrombosis (n=1), transaminitis (n=1) and dehydration (n=1).

EMERGING TREATMENT STRATEGIES FOR

PTCL AND CTCL

• Alisertib • Mogamolizumab

• IPI-145 (duvelisib) • Tipifarnib• Crizotinib •

Combination trials

.

ALISERTIB—Aurora A Kinase Inhibitor• Leads to mitotic arrest

– Abnormal spindles, unseparated centrosomes– Cells undergo apoptosis

• Ongoing studies in TCL:

– International randomized phase III trial comparing alisertib to investigator’s choice1

– Phase I: combination with romidepsin2

– Phase I: combination with vorinostat3

– Preclinical: combination with PI3K inhibition

Friedberg J, et al. J Clin Oncol. 2014;32:44-50 . ClinicalTrials.gov. [1] NCT01482962,[2] NCT01897012 [3] NCT01567709.

Untreated Treated Treated

ALISERTIB—R/R PTCL, Transformed MF

Barr, et al. J Clin Oncol. 2015;33:2399-2404.

Category N = 37 (%)

PTCL response rate 30%

Transformed MF response rate 0%

Complete response 2 (5)

Partial response 21 (57)

Stable disease 7 (19)

• S1108: Phase II• R/R PTCL or transformed MF

Alisertib• 50 mg po BID x 7 days, 21–day

cycle• Dose reduction to 40 g BID, 30

mg BID for toxicity

Grade 3/4 AEs (≥ 5%): neutropenia (32%), anemia (30%), thrombocytopenia (24%), febrile neutropenia (14%), mucositis (11%), and rash (5%)

50

ALISERIB—R/R PTCL

• LUMIERE: Phase III• R/R PTCL or transformed MF

Alisertib• 5×10-mg twice daily orally on

days 1-7 in a 21-day cycle

Investigators Choice (single agent)

• Pralatrexate− 30mg/m2 once weekly

for 6 weeks of 7-week cycle

• Gemcitabine − 1,000 mg/m2 on days 1,

8, and 15 of a 28-day cycle

• Romidepsin− 14mg/m2 on days 1,8,&

15 of a 28-cycle Clinicaltrials.gov ClinicalTrials.gov Identifier:NCT01482962.

Results available soon

1. Shinkawa T, et al. J Biol Chem. 2003;278:3466-3473. 2. Ishii T, et al. Clin Cancer Res. 2010;16:1520-1531. 3. Ishida T, et al. Clin Cancer Res. 2003;9:3625-3634.

MOGAMULIZUMAB—Defucosylated Humanized Anti-CCR4 Antibody

• CCR4 is highly expressed

(~ 90%) in ATLL[3]

• Significantly associated with skin involvement (P < .05) and unfavorable outcomes[3]

• Mogamulizumab has enhanced ADCC due to defucosylated Fc region[1,2]

Extracellular regions

N-terminal

Slide courtesy of T. Ishida

KW-0761

Asn297

Fucose

MOGAMULIZUMAB—TCL

• Active in phase II study in patients with ATLL (N = 28)1

– ORR: 50% (13/26); 8 CR– Median PFS: 5.2 mos– Median OS: 13.7 mos– AEs: infusion reactions (89%), skin rash (63%)

• Mycosis fungoides/Sezary syndrome (N = 38)2

– ORR: 37% (MF: 29%; SS: 47%)

• Approved in Japan for the treatment of ATLL

• Ongoing multicenter, randomized phase III clinical trial of mogamulizumab vs vorinostat in patients with MF/SS3

1. Ishida T, et al. J Clin Oncol. 2012;30:837-842. 2. Duvic M, et al. 2012 ASH. Abstract 3697. 3. ClinicalTrials.gov. NCT01728805.

IPI-145 (DUVELISIB)—A PI3K-δ,γ Inhibitor

• Potent oral inhibitor of PI3K-δ and PI3K-γ isoforms

– Selective for PI3K over other protein and lipid kinases

• Inhibits malignant B-cell and T-cell survival

– Direct effects on tumor cells

– Disrupting tumor cell interactions within the microenvironment

IPI-145

DiNitto J, et al. Keystone Symposia 2013. Abstract 1032. Palombella V, et al. Keystone Symposia 2013. Horwitz S, et al. ASCO 2013. Abstract 8518.

CI O

N

N

N

HNN

NH

PI3K Isoform PI3K-δ PI3K-γ

ExpressionPrimarily

LeukocytesPrimarily

Leukocytes

Biochemical Activity (KD) 23 pM 243 pM

Whole Blood Assay (IC50)

96 nMAnti-FcƐR1

1028 nM fMLP

IPI-145-02 (DUVELISIB)—Advanced Hematologic Malignancies

Horwitz S, et al. ASH 2014. Abstract 803.

• Phase I• 33 patients with R/R TCL

Duvelisib• Orally BID in 28-day cycles• 25 mg (n=1), 50 mg (n=1), 60 mg

(n=4), 75 mg (MTD; n=27), 100 mg (n=2)

Population

Best Response, n (%)Median Time to

Response, months(Range)

n CR PR SD PD ORR

All TCL 33 2 (6) 12 (36) 7 (21) 12 (36) 14 (42) 1.9 (1.5, 3.8)

PTCL 15 2 (13) 6 (40) 1 (7) 6 (40) 8 (53) 1.9 (1.5, 3.5)

CTCL 18 0 6 (33) 6 (33) 6 (33) 6 (33) 2.4 (1.6, 3.8)• Clinical activity observed across PTCL and CTCL subtypes• Most AEs were Grade 1 or 2 • Grade 3 ≥ AEs : ALT/AST increase, rash, and pneumonia

Witzig T, et al. Blood. 2011;118;4882-4889.

• Phase II• R/R NHL

• Aggressive B-NHL (n = 42)• Indolent B-NHL (n = 15)• T-NHL and HL (n = 36)

Tipifarnib• 300 mg bid 21 days of

28-day cycles`

Disease Type Number ORR

Cohort 3 (TCL and HL) 11/36 (6 CRs; 5 PRs) 31%

HL 4/19 21%

MF 2/4 50%

PTCL-NOS 4/8 (3 CRs, 1PR) 50%

ALCL 1/5 (1 CR cutaneous) 20%

• DOR: median 7.5 months• OS: median 19.7 months• Grade 3/4 AEs: neutropenia (37%), thrombocytopenia (32%), anemia (11%)

TIPIFARNIB—Farnesyl Transferase Inhibitor: R/R TCL and HL

CRIZOTINIB—Tyrosine Kinase Inhibitor of ALK• Competitive binding to ATP binding pocket • Inhibits c-Met/Hepatocyte growth factor receptor tyrosine

kinase• Approved for late-stage ALK expressing NSCLC

– EML-ALK fusion

• 11 ALK+ relapsed NHL patients (9 ALCL)– Median of 3 prior therapies

– Clinical responses in 10 of 11• All 9 ALCL pts achieved complete remissions lasting 2-40+ months

• Negative for NPM/ALK by PCR

• 2 -yr PFS 64%

– Non-cross resistant with brentuximabXALKORI® (crizotinib) [package insert]. NY, NY: Pfizer Inc; Revised 11/13. Gambacorti Passerini et al. J. Natl. Cancer Inst. 2014;106:djt378.

BRENTUXIMAB + CHP—Combination Therapy in R/R NHL

16 total cycles

Fanale M, et al. J Clin Oncol. 2014;32:3137-3143.

Single agent 1.8 mg/kg Brentuximab vedotin every

3 weeks for 10 cycles

• Phase I• R/R NHL

1.8 mg/kg Brentuximab + Standard-dose CHP every 3

weeks for 6 cycles

sALCL(n=19)

Other diagnoses(n=7)

Total(N=26)

Objective response rate, n (%) 19 (100) 7 (100) 26 (100)

CR 16 (84) 7 (100) 23 (88)

PR 3 (16) -- 3 (12)

Median PFS (95% CI) -- -- -- (4+, 13+)

Median OS (95% CI) -- -- -- (4+, 13+)

• Following these assessments, 10 of 26 patients continued therapy with single-agent brentuximab vedotin

− At the end of Cycle 12, ORR=12/13 (92%), CR rate=11/13 (85%)− At the end of Cycle 16, ORR=4/4 (100%), CR rate=4/4 (100%)

Agents in Clinical Trials—Anticipated Frontline Treatments

Agent(reference) Phase Number of patients Response

Romidepsin + CHOPNCT01796002, (Delarue 2013)

3• Currently recruiting• Goal of 420 pts

Romidepsin + CHOPRo-CHOP Study(Dupuis et al, 2014)

1b/2 37ORR = 69%CR = 51%PR = 17%

Brentuximab vedotin +CHOP or CHP(Fanale 2014)

1 26 CD30+ PTCL

CR = 88%Estimated PFS= 71%

Pralatrexate alternating with CEOP(Advani 2013)

2 33PTCL

ORR = 70%CR = 52%

PTCL—Ongoing Phase-3 Trials

Intervention Patient Population

Primary Endpoints

Status

CHOP14 + G-CSF + alemtuzumab vs CHOP14 + G-CSF

Newly diagnosed

PTCLEFS Active

Alisertib vs pralatrexate or gemcitabine or romidepsin [2] R/R PTCL ORR, PFS Active

Brentuximab vedotin + CHP vs CHOP [3]

CD30+ TCL

PFS Recruiting

Romidepsin + CHOP vs CHOP* [4]

Newly diagnosed

PTCLPFS

Recruiting

1. ClinicalTrials.gov NCT00646854. 2. ClinicalTrials.gov NCT01482962. 3. ClinicalTrials.gov NCT01777152 4. ClinicalTrials.gov NCT01796002

*European study

CTCL—Ongoing Phase-3 Trials

Intervention Patient Population Primary Endpoints

Status

Brentuximab vedotin vs Methotrexate or Bexotrexate [1]

CD30+ CTCL ORR Recruiting

Mogamulizumab vs Vorinostat [2]

Relapsed/Refractory CTCL

PFS Recruiting

1. ClinicalTrials.gov NCT01578499. 2. ClinicalTrials.gov NCT01728805.

Clinical Trials—To Enroll or Not

• Advantages:– Receive therapy that potentially is better then

standard of care– Access to agents that are not yet available– Enhanced monitoring

• Risks– Receive therapy that is not effective– Unexpected side effects – Leak of personal information

DISCUSSION

QUESTIONS & ANSWERS

INSIGHTS INTO OPTIMIZING THERAPEUTIC APPROACHES FOR T-CELL LYMPHOMAS Integrating Current and...

Documents

Transcript of INSIGHTS INTO OPTIMIZING THERAPEUTIC APPROACHES FOR T-CELL LYMPHOMAS Integrating Current and...