8 jason westin

JASON WESTIN, MD

HOUSTON, USA

Assistant Professor at the University of Texas MD

Anderson Cancer Center

Dr Westin’s research focus is on improving therapy

and outcomes for patients with lymphoma. His

specific research interests include: Diffuse Large B-

cell Lymphoma; Development of systems to identify

novel, optimal therapeutic combinations for individual

patients; Drug synergy, additivity, and antagonism;

Scale free networks and their role in cancer therapy;

Development of highly sensitive disease monitoring

methods. Dr. Westin also chairs the Lymphoma Grand

Rounds and is the co-director of the Lymphoma

planning clinic at MD Anderson Cancer Center.

NOVEL TARGETED

THERAPIES IN

T CELL LYMPHOMA:

BEST OF 2014

JASON WESTIN, MD

MD ANDERSON CANCER CENTER

[email protected]

TWITTER: @LYMPHOMA_DOC

In 2014, MDACC saw >1500 new patients with lymphoma

T-cell: 93 (48 treated, 45 untreated)

NHL BREAKDOWN IN US

Armitage JO, Weisenburger DD. J Clin Oncol. 1998;16:2780-2795.

DLBCL, 31%

FL, 22%MALTL, 8%

PTCL, 7%

SLL/CLL, 7%

MCL, 6%

PMLBCL, 2%

ALCL, 2%

BL, 2%

MZL, nodal, 2%

T-ALL, 2%Other, 9%

NHL BREAKDOWN IN CHINA

Yang et al, Diagnostic Pathology 2011

MOST COMMON PTCL SUBTYPES

PTCL-NOS and AITL are the most common

subtypes

Armitage J, et al. J Clin Oncol. 2008

POOR OUTCOME OF

T-CELL LYMPHOMA

Armitage J, et al. J Clin Oncol. 2008

POOR OUTCOME AFTER 1ST

RELAPSE/PROGRESSION

Mak, V et al: J Clin Oncol 31 (16), 2013: 1970-6

Reprinted with permission. © 2013 American Society of Clinical

Oncology. All rights reserved.

FOR MAJORITY OF PTCL…

•Frontline treatment not well defined

• The most commonly used chemotherapy is CHOP

• Role of intensive regimens questioned (MDACC Escalon Cancer 2003)

• Role of doxorubicin questioned (International PTCL project, JCO 2007)

• Role of etoposide undetermined (DSHNHL, Schmitz et al. Blood 2010)

• Upfront transplant controversial (d’Amore JCO2012 and Reimer JCO2009)

•No effective salvage therapy

• Even stem cell transplant is with marginal benefit

• Mechanism oriented targeted therapy is needed

RECENTLY FDA APPROVED DRUGS

FOR RECURRENT/REFRACTORY PTCL

Agent Dose/schedule N ORR (%) CR (%) DOR, Mos PFS

Pralatrexate 30 mg/m2 weekly X 6

111 29 11 10.1 3.5 mo

Romidepsin 14 mg/m2Weekly X 3 Q 28 days

131 25 14 17 4 mo

Belinostat 1000 mg/m² IV on days 1-5

Q21 day cycle

129 26 10% 8.3

Brentuximab Vedotin (ALCL)

1.8 mg/kgQ 21 days

58 86 57 12.6 13.3 mo

ALCL: 12% of all PTCL

3% of adult NHL

Courtesy of Yasuhiro Oki

MUTATIONS VERY FREQUENTLY

OBSERVED IN PTCL

Mutated

Gene

AITL PTCL-NOS EATL

TET2 47-83% 38-49% 20%

IDH2 30-45% 0%

DNMT3A 26% 27%

RHOA 67-68% 0-18%

1. Sakata-Yanagimoto et al. Nat Genetics 2013

2. Palomero et al. Nat Genetics 2013

3. Cairns et al. Blood 2012

4. Lemonnier et al. Blood 2012

FREQUENT COEXISTENCE OF

MUTATION

Sakata-Yanagimoto et al. Nat Genetics 2013

Palomero et al. Nat Genetics 2013

TARGETED THERAPY

BRENTUXIMAB

• Anti-CD30 monoclonal antibody drug conjugate (MMAE)

• CD30 expression is variable, although this may not

correlate with response

• Phase II trial in Mycosis Fungoides / Sezary Syndrome

• 2 skin biopsies, maximum % of CD30 reported

• 32 patients enrolled (30 evaluable)

• Median age 62 (20-87)

• ORR 70% (21/30)

Kim et al, ASH 2014 Abstract #804

BRENTUXIMAB

• CD30 level vs response

• <5%: ORR: 17%

• >5%: ORR: 83%

• Multispectral imaging found +CD30 in 19/20 classified as

CD30 null with immunohistochemistry

• Infiltrating macrophages expressed CD30 - ? Target


• Multispectral imaging found +CD30 in 19/20 classified as

CD30 null with immunohistochemistry

• Infiltrating macrophages expressed CD30 - ? Target

BRENTUXIMAB


BRENTUXIMAB

Fanale et al, JCO 2014

• Phase I trial of Brentuximab and chemotherapy in PTCL

• 2 cycles of BV, followed by CHOP or CHP+B for 6 cycles

• 13 and 26 patients accrued (BV -> CHOP arm closed due to

PD on CHOP treatment portion)

• Median age: 57y (21-82)

• Median prior therapies: 0 (frontline)

• Sequential ORR: 85% (11/13, CR 62%, 2 progressed)

• Combination ORR: 100% (26/26, CR 88%, 0 progressed)

MOGAMULIZUMAB

(KW-0761)

• Defucosylated, humanized, anti-CCR4 monoclonal antibody

• CCR4: C-C Chemokine Receptor Type 4

• G protein-coupled receptor for CCL2, CCL4, CCL5, CCL17, and

CCL22

• Present on Th2, Treg (CD4+ CD25+ FoxP3+), & ~40% of CTCL/PTCL

• Phase I/II trial in relapsed CTCL (MF or SS)

• N=41 (MF=22, SS=19)

• Median age: 66y (35-85), Median prior therapies: 3 (1-17)

• No DLT, MTD not reached, no grade 4

• ORR 37% (SS: 47% vs MF 29%)

• Response may correlate with CCR4 expression

• Phase III trial of Moga vs vorinostat in rel MF/SS ongoing

Duvic et al, Blood 2015

MOGAMULIZUMAB

(KW-0761)

• Phase II trial in relapsed CCR4+ PTCL or CTCL

• N=38 (65 screened, 50 with CCR4+)

• PTCL: 29 (AITL: 12, ALCL Alk- :1)

• CTCL: 8 (MF=7)


• ORR 35% (PTCL: 34%, CTCL: 38%)

• Response vs CCR4 expression

• 1+ ORR 33% n=6

• 2+ ORR 50% n=6

• 3+ ORR 32% n=25

• Grade 3 lymphocytopenia in 73%

• Profound and durable depletion of Treg

Ogura et al, JCO 2014

LENALIDOMIDE

• Immunomodulatory agent (IMiD), targets cereblon, Ikaros,

Aiolos, and IRF4

• Used primarily in Myeloma, MDS (5q-), and B cell lymphoma

• Phase II trial in relapsed T-cell lymphoma

• N= 41


• ORR 26% (10/39), CR 7% (3/39)

• Rash 38%, may correlate with

response

Toumishey et al, Cancer 2014

LENALIDOMIDE

• Phase I/II trial of Lenalidomide + Vorinostat and Dexamethasone

• Vorinostat is HDAC approved for CTCL

• N=8

• ORR: 25% (1 CR, 1 PR, 2 SD, 4 PD)

• Median OS: 6.7m

• Stopped early due to poor response and low accrual

Hopfinger et al, Ann Hematology 2014

ALISERTIB

• Oral selective Aurora A kinase inhibitor

• Aurora kinase is expressed in all actively dividing cells

• Phase II trial in aggressive lymphomas of 50mg twice daily

• 48 patient enrolled, mainly with B-cell

• Median age: 67.5 (32-85)

• Median prior therapies: 3 (1-9)

• 8 patients with aggressive T cell lymphoma

• ORR: 50% (4/8)

Friedberg et al, JCO 2014

SELINEXOR (KPT-330)

• Selective inhibitor of

nuclear export (XPO1)

• Forces retention of tumor

suppressor proteins and

reduces proto-oncogene

• Phase I trial:

5 T cell lymphoma

• 1 CR

• 2 SD

• 2 withdrew

Kuruvilla et al, ASH 2014 abst # 396

ROMIDEPSIN

• Novel class I histone deactylase inhibitor

• FDA approved for relapsed CTCL and PTCL

• Pivotal trial updated for long term survival outcomes

• N:131 patients with relapsed PTCL

• ORR 25% (CR 15%) – unchanged from initial report

• Among CR: 84% had not

progressed at median f/u

of 26 mo

Coiffier et al, J Hematology Oncology 2014

PANOBINOSTAT

Goh, et al, ASH 2014 Abstract # 503

• Oral HDAC inhibitor

• Phase I trials in hematologic malignancies showed responses

• MTD of 20mg 3x weekly

• Phase II trial combined with bortezomib in PTCL or NK cell

• 25 lymphoma pts enrolled (23 evaluable):• AITL n=8, PTCL n=11, ALCL ALK+ n=1, ALK- n=2, NKT n=2,

SPTCL n=1


• ORR: 43% (10/23) CR: 22 (5/23)

• 5 patients underwent alloSCT after response

• Adverse Events:

• ≥ Grade 3

• 68% thrombocytopenia

• 36% neutropenia

• 28% diarrhea

PI3K/Akt/mTOR PATHWAY

OVERVIEW

Phosphatidylinositol-3-kinases

(PI3K) have 3 classes

• Class II and III are ubiquitous

and non-oncogenic

• Class I:

• Class IA and B are

lymphoma therapy targets

PI3K

Class

Isofor

m

Tissue distribution Mouse -/-

Major phenotype

Function

I A p110α Leukocytes

+Ubiquitous

Embryonic lethal Proliferation,

Differentiation,

Survival,

Migration,

Chemotaxis,

Phagocytosis

Metabolism

p110β Leukocytes

+Ubiquitous

Embryonic lethal

p110δ Leukocytes

thymus, breast

Impaired B cell development

I B p110γ Leukocytes,

thymus, heart,

endothelium

Impaired inflammation

(+ p110δ -/-: Severe T cell and

NK cell defect)

Cell migration,

Chemotaxis.

Inflammation

Westin, Status of PI3K/Akt/mTOR Pathway Inhibitors in Lymphoma, Clin Lymph Myel Leuk, 2014

CLINICAL RESULTS OF PI3K/AKT/MTOR PATHWAY-SPECIFIC

INHIBITORS AS SINGLE AGENTS IN UNSELECTED PATIENTS WITH

RELAPSED LYMPHOMA

Target % Response Rate in Different Histologies

DLBCL FL MCL SLL/CLL T-Cell HL

SF1126(65) PI3K-class1 0% 0%

Buparlisib(66) PI3K-class1 * * *

SAR245408(67,69,70) PI3K-class1 25% 50% 50% 0%

BAY 80-6946(68,71) PI3K-class1 11% 40% 83% 67% 50%

Idelalisib(72-74) PI3K-δ 0% 45% 40% 64% 15%

IPI-145(75-77) PI3K-γδ 0% 67% 74% 33%

Rigosertib(78) PI3K-αβ 0% 0% 0%

Everolimus(79-81) mTORC1 30% 38% 32% 18% 42%

Temsirolimus(82-83) mTORC1 28% 54% 38% 11%

Apitolisib PI3K/mTOR * * * * *

GDC-0084 PI3K/mTOR

BEZ235 PI3K/mTOR

GDC-0332 PI3K-αγδ

Pictilisib PI3K-αδ * * * * *

BYL719 PI3K-α

(WT/Mutant)

MK2206 AKT * * * * * *

* Trials ongoing without data No ongoing trials in lymphoma (as of 2014)

Westin, Status of PI3K/Akt/mTOR Pathway Inhibitors in Lymphoma, Clin Lymph Myel Leuk, 2014

PI3K INHBITORS

DUVELISIB (IPI-145)

• Oral PI3K-δ,γ inhibitor

• Phase I trials in hematologic malignancies showed T cell

responses

• MTD of 75mg twice daily

• Disease-specific cohort at MTD for T cell lymphoma:

• 33 patients, 31 evaluable (17 CTCL, 16 PTCL)



• ORR: 42%

• PTCL: ORR 47% (7/15, 2 CR, 5 PR)

• CTCL: ORR 38% (6/16, 0 CR, 6 PR)

• Median OS 36.4 weeks

Horwitz, et al, ASH 2014 Abstract # 803

DUVELISIB (IPI-145)

• Correlative studies:

• By day 8, detection of cytokine alterations suggesting changes in

pharmacodynamic target modulation

• No correlation with response yet

• Cycle 1 Day 22 FDG PET/CT scan:

• Reduction in radiolabeled glucose uptake (SUV) in 6/11 patients

• Adverse Events:

• 26 of 33 patients had ≥ grade 3

• 36% increased liver function tests

• 21% rash

• 15% neutropenia

• 30% discontinued therapy due to toxicity

Horwitz, et al, ASH 2014 Abstract # 803

AKT INHIBITORS

MK2206

Oki et al, ASH 2014 Abstract #3093

• Oral, non-ATP competitive allosteric inhibitor of AKT 1, 2, and 3

• Phase II trials in hematologic malignancies

• MTD 200mg orally once/week (could increase to 300mg)

• 59 patients on Phase II trial – mainly B cell and cHL

• T cell lymphoma:

• 2 patients, 2 evaluable (2 AITL)

• Median age: 68y


• ORR ranged from 14%, with 29% showing tumor reduction

• AITL: ORR 0% (1 with tumor reduction <PR)

• Adverse Events:

• 15% rash

• 5% hyperglycemia

• 2% neutropenia

NOVEL TARGETED

THERAPIES IN

T CELL LYMPHOMA:

BEST OF 2014

JASON WESTIN, MD


[email protected]


QUESTIONS?

JASON WESTIN, MD


[email protected]


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