TERAPIA ANTI-CD20 LA PERSPECTIVA DEL ONCÓLOGO

V SIMPOSIO SEAP-SEOM

BIOMARCADORES EN HEMATOPALOGÍA

Luis de la Cruz Merino Sº Oncología Médica

HUVMacarena (Sevilla)

Índice

1. Introducción: el antígeno CD20 en linfomas

2. Mecanismo de acción de AcMo anti-CD20

3. Impacto clínico de terapia anti-CD20: LBDCG y folicular

4. Perspectiva del patólogo (Dra Mar García. H del Mar, BCN)

5. Radioinmunoterapia y Nuevos AcMo anti-CD20 en desarrollo

6. Conclusiones

Antígeno CD20 como diana para la inmunoterapia

ANTIGEN INDEPENDENT ANTIGEN DEPENDENT

CD20 expression

Neoplasias: Precursor B-cell leukemias B-Cell lymphomas/CLL WM/ Myeloma

Adapted from Longo. Lymphocytic Lymphomas. In: Cancer: Principles and Practice of Oncology. 1993.

Stem

Cell

Pre-Pre-

B Cell Pre-B Cell

Immature

B Cell

Mature

B Cell

Activated

B Cell

Plasma

Cell

IgM

IgG

IgA

sIgM

sIgG

sIgA

sIgM

+ D sIgM

HCR

R/D

HCR

R/D µ HCR HCR

MCL=mantle-cell lymphoma; FL=follicular lymphoma; SLL=small lymphocytic lymphoma; MZL=marginal zone B-cell lymphoma; MALT=mucosa-associated lymphoid tissue; LL=lymphoplasmacytic lymphoma; DLBCL=diffuse large B-cell lymphoma. Armitage et al. J Clin Oncol. 1998;16:2780-2795.

Frecuencia de subtipos LNH en adultos y expresión CD20

El antígeno diana ideal

Expresado SÓLO por las células del tumor

No expresado por células normales de tejidos esenciales para el huésped

No debe producirse toxicidad en el caso de que se eliminen TODAS las células Ag+

Expresado por TODAS las células del tumor

No sometido a mutaciones, variaciones o modulación

El Ag. tiene una función “crítica” para la célula

No internalizable ni secretable

CD20, antígeno asociado a tumor (TAA) tipo antígeno de diferenciación tisular específica

Cang J Hematol&Oncol 2012

Epítopos antígeno CD-20

MECANISMO DE ACCIÓN AcMo Brody J Clin Oncol 2011

Rituximab potencia la actividad “in vitro” de diversos citotóxicos

DTX 50 36 0.0001 Ricin 40 5 0.004 TNF alpha 43 7 0.0015 ADR 53 28 0.0027 CDDP 27 4 0.0456 VP16 8.5 0.6 0.0263

Agente citotóxico + MabThera® – MabThera® P Valor

% Citotoxicidad

Demidem et al. Cancer Biother Radiopharm. 1997;12:177.

H/RS cells

Radiotherapy Chemotherapy

P

PP

Dendritic cell

HMGB1

TLR4

Stimulated

CTL ActivityTumor

microenvironmentcells

CD 20

CD 52

CD 30

AcMo

antiCD20antiCD52

Agents targeting

Immune synapses

AcMo

antiCD30

Lenalidomide

Impacto clínico de la terapia anti-CD20:

difuso de células grandes y folicular

Revised IPI (R-IPI): era Rituximab

Sehn LH, et al. Blood. 2007;109:1857-1861.

Risk Group IPI Factors, n

Very good 0

Good 1-2

Poor 3-5

edad superior a 60 años estadios avanzados III ó IV

PS > 1 LDH elevada

Más de 1 área extraganglionares afectas

Yrs

Perc

ent

Surv

ival

Very good

Good

Poor

P < .0001

Supervivencia global según IPI revisado (R-IPI)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0 0 1 2 3 4 5

Sehn LH, et al. Blood. 2007;109:1857-1861.

* QT BASADA EN R-CHOP

CHOP ± Rituximab en DLBCL: resultados de SG a 7 años (GELA LNH-98.5 Study)

Coiffier B, et al. ASCO 2007. Abstract 8009.

OS (N = 399) Parameter, % Low

Risk

High

Risk

Age, < 70 vs ≥ 70 yrs 58.0 49.0

LDH, NI vs > NI 69.0 45.0*

Stage, I/II vs III/IV 67.0 50.0

Bone marrow, yes vs no 60.0 34.5*

Tumor size, < 10 vs ≥ 10 cm 60.0 36.5

β2-microglobulin, NI vs > NI 64.5 39.0*

Serum albumin, ≥ 35 vs < 35 g/L 60.0 40.0

*P < .05 (multivariate analysis).

Surv

ival

Pro

bab

ility

Yrs

0

0.2

0.4

0.6

0.8

1

0 1 3 5 7 8 2 4 6

CHOP

R-CHOP

P = .0004

R-CVP vs CVP en linfoma folicular sin tratamiento previo

•Follicular NHL (IWF B,C, D) •Stage III-IV •> 18 yrs. •No prior Rx •Measurable Dz •Central histology review

R A N D O M I Z E

CVP x 4 cycles (q 3 weeks)

R-CVP x 4 cycles (q 3 weeks)

R estaging

CVP x 4 cycles (q 3 weeks)

R-CVP x 4 cycles (q 3 weeks)

SD,PD off treatment

CR, PR

rituximab 375 mg/m2 IV d1

cyclophosphamide 750 mg/m2 IV d1

vincristine 1.4 mg/m2 IV d1

prednisone 40 mg/m2 PO d1–5

Tiempo al fallo del tto. y tiempo hasta la progresión (mediana de seguimiento 25 meses)

Event-free probability

0.0 3 6 9 12 15 18 21 24 27 30 42

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0

Study month

33 36 39 0.0

3 6 9 12 15 18 21 24 27 30 42

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0

Study month

Event-free probability

33 36 39

TTF TTP

R-CVP: median 30m R-CVP: median 27m

CVP: median 7m CVP: median 15m

P<0.0001 P<0.0001

All deaths, n (%) 22 (13.8) 15 (9.3) Death from lymphoma 15 (9.4) 9 (5.6)

CVP R-CVP

Marcus R et al. Proc ASH 2003.

CHOP

rituximab en primera línea de linfoma folicular

R A N D O M I S A T I O N

CHOP x 4–6

CHOP x 4–6 +

MabThera

CR, PR

R A N D O M I S A T I O N

Peripheral blood stem cell transplant

2 x CHOP +/- MabThera + standard IFN-maintenance

2 x CHOP +/- MabThera + intensive IFN-maintenance

2 x CHOP +/- MabThera + standard IFN-maintenance

CR, PR

Hiddemann W, et al. Blood 2003;102:104a (Abstract 352)

Patients > 60 years

Patients < 60 years

OR

CHOP

rituximab en primera línea de linfoma folicular: tiempo hasta el fracaso de tratamiento

Years after start of therapy

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0 0 1 2 3

Pro

po

rtio

n o

n t

reat

me

nt

MabThera + CHOP (143/159)

CHOP (102/143)

Hiddemann W, et al. Blood 2003;102:104a (Abstract 352)

Bendamustine-Rituximab

CHOP-Rituximab

Follicular G I-II

Waldenströms

Marginal zone

Small lymphocytic

Mantle cell

R

StiL NHL 1-2003

Bendamustine 90 mg/m2 day 1+2 + R day 1, max 6 cycles, q 4 wks. CHOP-R, max 6 cycles, q 3 wks.

# Abst 3. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R)

as first-line treatment in patients with indolent and mantle cell lymphomas (MCL):

Updated results from the StiL NHL1 study. Mathias J. Rummel. ASCO 2012

Supervivencia libre de progresión (45 meses seguimiento)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 12 24 36 48 60 72 84 96 m

Hazard ratio, 0.58 (95% CI 0.44 - 0.74)

p = 0.0000148

Median (months)

B-R 69.5

CHOP-R 31.2

Radioinmunoterapia y Nuevos AcMo anti-CD20

AcMo anti-CD20, además de Rituximab….

Brody J Clin Oncol 2011

Elección del isótopo

Properties 90Yttrium 131Iodine

Half-life 64 hours 192 hours

Energy emitter Beta

(2.3 MeV)

Gamma (0.36 MeV)

Beta (0.6 MeV)

Path length 90 5 mm 90 0.8 mm

Urinary

excretion

Minimal

7% in 7 days

Extensive/variable

46 - 90% in 2 days

Dosing

Based on

weight and

platelet count

Clearance based

dosing using whole

body dosimetry

Administration Outpatient

Inpatient or

restrictions to

protect family/public

131I

Zevalin en linfoma indolente

Cheson BD. Blood 2003; 101: 391-398.

• The first type II, glycoengineered,

humanised anti-CD20 monoclonal

antibody (mAb)

– Designed to provide an

advancement in antibody

technology

• In preclinical studies comparing it

to rituximab, GA101 showed:

– Increased direct cell death

induction

– Enhanced antibody-dependent cell-

mediated cytotoxicity (ADCC)

• GA101 is being evaluated in an

extensive clinical trial program in

B-cell malignancies

GA101: AcMo anti-CD20 tipo II

Mössner E, et al. Blood 2010;115:43934402; Niederfellner G, et al. Blood 2011; 118:358−367

Heavy chain CD20 peptide

Glycoengineering

Light chain

GA101: mecanismos de acción

Mössner E, et al. Blood 2010;115:43934402

Lower CDC activity Type II versus Type I antibody

B-cell

Effector

cell

Increased direct cell death Type II versus Type I antibody

Enhanced ADCC Glycoengineering for increased

affinity to FcγRIIIa

CD20 FcγRIIIa

Complement GA101

CDC, complement-dependent cytotoxicity

90

80

70

60

50

40

30

20

10

0

GA101 induce muerte celular directa

Alduaij W et al. Blood 2009; 114:Abstract 725, taken from oral presentation at ASH 2009

GA101 induced increased cell death on a panel of B-lymphoma cell lines compared with rituximab

Raji Daudi Granta 519 SU-DHL4

Ce

ll d

eat

h (

% a

nn

exin

V/P

I +ve

)

Control GA101 Rituximab

P<0.03

Compared with rituximab:

Increased direct cell death induction due to Type II mode of binding

Increased ADCC due to glycoengineering (stronger affinity for FcγRIIIa)

Superior B-cell depletion compared with rituximab in whole-blood assay as well as lymphoid tissue in cynomolgus monkeys

Complete tumour remissions in various NHL xenograft models

Induced anti-tumour activity in combination with chemotherapy

Resumen datos preclínicos GA101:

anti-CD20 AcMo

Mössner E, et al. Blood 2010;115:43934402 Herting F, et al. Blood 2010;116:Abstract 3915, taken from poster presentation at ASH, Dec. 2010

GA101

CDC

Cell death/ proliferation

ADCC

Cell death/ proliferation

CDC

ADCC

CDC

Cell death/ proliferation

ADCC

CDC

Cell death/ proliferation

ADCC

Rituximab

Cell death/ proliferation

CDC

ADCC

Rituximab

Cell death/ proliferation

CDC

ADCC

n Patient

population

Treatments Primary

endpoint

Phase I

GAUGUIN (BO20999) 34 CD20+ • GA101 Safety

GAUSS (BO21003) 22 CD20+ • GA101 Safety

JO21900 (Japan) 24 CD20+ • GA101 Safety

GAUDI (BO21000) 56

80

R/R fNHL

First-line fNHL

• GA101 + CHOP

• GA101 + FC

• GA101 + CHOP

• GA101 + bendamustine

Safety

GALTON (GAO4779g) 40 First-line CLL • GA101 + FC

• GA101 + bendamustine

Safety

Phase II

GAUGUIN (BO20999) 100 R/R iNHL, aNHL, CLL • GA101 ORR

GAUSS (BO21003) 180 Relapsed iNHL • GA101 vs rituximab ORR

Source: www.clinicaltrials.gov

GA101 estudios completados y en marcha(Fase I/II)

Note: dark blue shaded studies are ongoing

n Patient

population

Treatments Primary

endpoint

Phase III

CLL-11 (BO21004) 780 First-line CLL with

comorbidities

• GA101 + chlorambucil

• Rituximab + chlorambucil

• Chlorambucil

PFS

GADOLIN (GAO4753g) 360 Rituximab-refractory iNHL • GA101 + bendamustine

• Bendamustine

PFS

GOYA (BO21005) 1400 First-line DLBCL • GA101 + CHOP

• Rituximab + CHOP

PFS

GALLIUM (BO21223) 1400 First-line iNHL • GA101 + chemotherapy

• Rituximab + chemotherapy

PFS

Source: www.clinicaltrials.gov

GA101 estudios completados y en marcha (Fase III)

Note: all studies are ongoing

Rituximab 375 mg/m2 + CHOP x 6 or 8 (n=700)

GA101 1000 mg + CHOP x 6 or 8 (n=700)

Previously untreated CD20+ DLBCL (n=1400)

GOYA (BO21005) fase III: diseño

DFS, disease-free survival; DOR, duration of response; OS, overall survival; TTNLT, time to next lymphoma treatment www.clinicaltrials.gov; NCT01287741

Experimental arm GA101 1000 mg d1, d8, d15 cycle 1; d1 cycles 2–8 q21d + CHOP

Control arm Rituximab 375 mg/m2 on d1 q21d cycles 1–8 + CHOP

Primary endpoint Investigator-assessed PFS

Secondary endpoints OS, EFS, ORR, DFS, DOR, TTNLT, medical resource utilisation

Conclusiones

Antígeno CD20, cumple criterios de “antígeno ideal” Mecanismo de acción citotóxico directo e inmunológico Terapia anti-CD20 ha cambiado la historia natural de la mayor parte de LNH: incremento en SG, cambios en índices pronósticos y nuevos estándares de tratamiento Radioinmunoconjugados y nuevos anti-CD20 en desarrollo Incertidumbres anti-CD20: forma admon, duración, estrategias de combinación, resistencias…..