innovations thérapeutiques avec les anti-cd20 · 2017. 1. 16. · salles g, et al . blood...

Innovations thérapeutiques

avec les Anti-CD20

Franck Morschhauser

Hopital Claude Huriez

University of Lille

France

[email protected]

FcγR

CR3

CD20on B-cell surface

Possible effects of anti-CD20 mAb on B - cells

Type I (Rituximab)

Type II (Tositumomab)

Programmed cell death (PCD)

ADCCComplement

FixationCDC

Both Type I and Type II

Anti-CD20 Antibodies

Name Company Type ADCC CDC Apoptosis

Rituximab Roche/Genentech chIgG1 + + +

Ocrelizumab Roche/Genentech huIgG1 + +/- +

Veltuzumab Immunomedics huIgG1 + + +

90Y ibritumomab Spectrum muIgG1 + + +

131I tositumomab Smithkline muIgG1 + 0 +++

Ofatumumab GenMab/GSK huIgG1 + ++ +/-

AME-133 Lilly huIgG1 ++ + +

PRO131921 Genentech huIgG1 ++ +/- +

GA101 Roche/Glycart huIgG1 +++ 0 +++

EMAB-6 LFB huIgG1 +++ + +

KM3065 Kyowa huIgG1 +++ + +

Biosimilars TEVA, Sanofi ? ? ? ? ?

GA101: A glycoengineered anti-CD20 antibody

Umaña P, et al. Ann Oncol 2008; 19:Abstract 098.Umaña P, et al. Blood 2006; 108:Abstract 229.

Low fucose content

Type II antibody

Elbow hingesubstitution↑ ADCC

Low CDC

↑ Cell death

Clone B-Ly1

ADCC = antibody-dependent cellular cytotoxicityCDC = complement-dependent cytotoxicity

GA101Key PK findings in phase I/II

GAUGUIN NHL Phase I:Study design

• Patients with CD20+ NHL for whom “no therapy of higher priority was available”

• Non-randomized study with an adaptive dose-escalating design

• No pre-medication with corticosteroids for IRR prevention

3 6 9 12 15 18 21 Weeks

Tumor assessment

25

GA101 single agent(total 9 doses)

1

Cohort (n = 3 per group)

GA101 dose (mg)Dose 1/Doses 2–9

1 50/100

2 100/200

3 200/400

4 400/800

5 800/1,200

6 1,200/2,000

7 1,600/1,600/800

Tumor assessment

• Higher doses of GA101 achieve serum concentrations that result in high saturation of the CD20 target

GAUGUIN Phase I (NHL): Higher doses of

GA101 increase target saturation

7

GA101 concentration (µg/ml)

Fra

ctio

n of

free

targ

et

0 500 1,000 1,500 2,000 2,500

0.005

0.050

0.500Loading/induction dose (mg)50/100100/200200/400400/8001,200/2,000

Hourcade-Potelleret F, et al. abstract submitted to Am Soc Pharmacol Clin Therapeutics 2011.

Incr

ea

sin

g b

ase

lin

e t

um

ou

r lo

ad

< P25

P25–P50

P50–P75

> P75

GAUGUIN Phase I/II (NHL): Serum concentrations of GA101 vary by tumour

burden

� Patients were grouped by baseline tumour burden (e.g., P25 = lowest 25%)

� Variability in PK in individual patients was associ ated with higher tumour burden

� This analysis also includes some patients from the GAUDI trial of GA101 plus chemotherapy.Hourcade-Potelleret F, et al. abstract submitted to Am Soc Pharmacol Clin Therape utics 2011.

• Higher doses of GA101 (1,600/800 mg, 1,000/1,000 mg) result in a more rapid and greater reduction in tumour size than lower doses (400/400 mg)

Higher doses of GA101 result in greater

anti-tumour activity

9

Tum

ours

ize

chan

ge

–1.0

–0.5

0.0

0.5

1.0

1.5

2.0

400/400 mg

Tum

ours

ize

chan

ge

–1.0

–0.5

0.0

0.5

1.0

1.5

2.0

1,600/800 mg

Tum

our s

ize

chan

geTime (days) Time (days) Time (days)

0 100 200 300 400 500 0 100 200 300 400 500 0 100 200 300 400 500

–1.0

–0.5

0.0

0.5

1.0

1.5

2.0

1,000/1,000 mg

Hourcade-Potelleret F, et al. abstract submitted to Am Soc Pharmacol Clin Therapeutics 2011.

400/400 mg and 1,600/800 mg data from GAUGUIN Phase II; 1,000/1,000 mg data from GAUSS Phase II

MABTHERA: TOWARD SC ADMINISTRATION

USING A PK-BASED STRATEGY

1 2 3

Innovative enzyme-based delivery system permits subcutaneous administration

of MabThera

Injection of MabThera SC into the skin

Naturally occurring, enzyme-based process temporarily alters the structure of the skin 1

Enzyme-based delivery allows for faster absorption and increases the bioavailability of MabThera 1,2

1. Bookbinder LH, et al. J Control Release 2006; 114:230–241. 2. Roche. Data on file. 2012.

+Highly concentratedMabThera antibody

Innovative enzyme-based delivery system

Effects of enzyme are temporary and fully reversible within 24h of injection

For more information on the mode of action of MabTh era SC, please refer to the MabThera SC mode of act ion video

� Main criteria : Cmin ( stay above Cmin with IV administration)

� Secondary criteria : AUC (exposure)

� Exploratory : Cmax (safety)

MABTHERA: TOWARD SC ADMINISTRATION

USING A PK-BASED STRATEGY

SC route improves rituximab exposure

Salar A, et al. Haematologica 2012; 97 (S1):Abstract 0794. Poster presentation.

Ctrough cycle 7 in induction:

Mab

The

ra S

C(1

,400

mg)

Mean Ctrough (µg/ml)

Intr

aven

ous

(375

mg/

m2 )

Pro

babi

lity

Pro

babi

lity

0.025

0.015

0.0

0.010

0.005

0.020

100 150 200 250

0.020

0.015

0.0

0.010

0.005

100 150 200 250

AUCtau cycle 7 in induction:

Mean AUC tau (µg/ml)

3000 4000 5000 60003500 4500 5500

0.0006

0.0004

0.0002

0.0008

0.0010

0.0

3000 4000 5000 60003500 4500 5500

0.0012

0.0008

0.0002

0.0010

0.00040.0006

0.0014

0.0

95%80%

Lymphome folliculaire

Low tumor burden Follicular Lymphoma

RWW: Time to initiation of new therapy

Ardeshna et al, ICML 2011, Abst 6

Proportion

of patients

with

no new

treatment

initiated

19 19219 8483 187

Events TotalsW+W R4 R4 + M

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Years from randomisation0 1 2 3 4 5

% not requiring Rx at 3yr

W+W=48%

R4=80%

R4+RM=91%

HR (Rituximab vs W+W) = 0.37, 95%CI = 0.25, 0.56, p<0.001

HR (Rituximab + M vs W+W) = 0.20, 95% CI = 0.13, 0.29, p <0.001

HR (Rituximab + M vs Rituximab) = 0.57, 95% CI = 0.29, 1.12, p =0.10

RESORT: Time to treatment failure

Year

Pro

bability

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 1 2 3 4 5 6 7

Rituximab retreatment (n = 134)

Rituximab maintenance (n = 140)

Fail,

n

65

69

Not-fail,

n

69

71

Median TTTF,

years

3.6

3.9

p = 0.80

Median follow-up was 3.8 years.

Kahl et al, ASH 2011, Abstract LBA-6

At 3 years, 86% of RR arm patients remained

untreated and received 3,5 time less of rituximab

Cytotoxic CD8 + T cellEffector CD4 + T cell

TCR

MHC class IMHC class II

Dendritic cell

Tumor peptide

Cross-presentation.

SC route could improve anti-lymphoma imunity

Cartron G et al, Blood 2004; 104: 2634-2642

FcγγγγRIIIa

FcγγγγRIIa

CD11b

FLIRT Trial

Rituximab iv 375 mg/m2

Rituximab sc 1400 mg

J1 J8 J15 J21

J1 J8 J15 J21

M3 M5 M7 M9

Control arm

Experimental arm

E

E

E

E

E Evaluation

R

Endpoint: PFSHypothesis: Control arm: median 23.5 mo vs median 45 mo in experimental arm: Number of patients: 210First patient: Q1-Q2 2014

• Ancillary studies

– FCGRT and FcRn

– Rituximab PK and variability

– Immunity against FL Ag

– Prognostic value of t(14;18)

Ancillary studies

High tumor burden FLPRIMA 6 years follow -up

Progression free survival from randomization

Median follow-up since randomisation : 73 months

6 years = 42.7%

6 years = 59.2%

HR= 0.57P<0001

PRIMA 6 years follow -upProgression free survival from randomization


R-CHOP induction R-CVP induction

HR= 0.538P<.0001

HR= 0.697P=.05

49.7%

38%

62.9%

44.5%

PRIMA 6 years follow -upOverall survival


6 years = 87.4%

6 years = 88.7%

HR= 1.027P=.885

SABRINA (BO22334): Study design

• Stage 1 primary endpoint: MabThera SC:IV Ctrough ratio at Cycle 7 of induction (comparison of serum levels of

MabThera SC compared with IV)

• Stage 1 secondary endpoints: MabThera SC:IV AUC ratio during induction, efficacy (ORR/CR) and safety

23

IV (375 mg/m2)

SC (1,400 mg)

First-line FL

grade 1, 2 or 3a in patients

with an indication for

treatment

Maintenance MabThera IV,

q2m x 2 years

CR/CRu/PR8 x R-CHOP/R-CVP

R

A

N

D

O

M

I

S

E

D

Maintenance MabThera SC,

q2m x 2 years

PR

CR

96 w

eeks

fol

low-u

p

Stage I

N = 127

Davies A, et al. ASH 2012; Abstract 1629 (poster).

The primary endpoint for SABRINA was met


PK endpoint Ratio MabThera SC/IV

Ctrough at Cycle 7 1.62 (90% CI:1.36, 1.94) Primary endpoint

AUC at Cycle 7 1.37 (90%CI:1.24, 1.53) Secondary endpoint

Non-inferior Ctrough for MabThera SC (1,400 mg) compared with MabThera IV (375 mg/m2)

• Secondary PK endpoint: exposure to MabThera after SC administration (area under the curve – AUC)

is at least as high as observed after IV

24

SABRINA Stage 1: Adverse events

MabThera

Number of patients with at least 1 event (%) IV, n (%) SC, n (%)

Adverse events (AEs) 57 (88) 57 (92)

Serious AEs 14 (22) 14 (23)

Grade ≥ 3 AEs 30 (46) 29 (47)

Administration related reactions (ARRs) 21 (32) 31 (50)

• Overall safety profile comparable with the exception of higher incidence of ARRs

• Administration-related reactions (ARRs) with SC were mostly local skin reactions and mild to moderate in intensity

– ARRs were defined as: any events occurring during/within 24 hours of drug administration that were considered treatment-related by the study

investigator

• There were no treatment related deaths

25


SABRINA

SC route of administration delivers comparable efficacy to IV

administration

MabThera

IV

(n = 64)

SC

(n = 63)

Overall response rate 88% 86%

CR/CRu 19% 27%

PR 69% 59%

ORR and CRR indicate that switching to the SC route of administration does not impair MabThera’s anti-lymphoma

activity

26

Davies A, et al. Lancet Oncol vol 15, 2014.

GAUGUIN iNHL Phase II: End -of-treatment response with GA101 in rituximab -refractory patients (n=24)

†ORR based on evaluable patientsCR, complete response; PR, partial response; SD, st able disease; PD, progressive disease; UNK, unknownSalles G, et al. Blood 2010;116:Abstract 2868, taken from poster presentat ion at ASH, Dec. 201027

Cohort CR PR SD PD UNK ORR †

High dose (n=11)

1 4 3 2 0 50%

Low dose(n=13)

0 1 4 7 0 8%

End of treatment response is defined as 28 days fro m the last GA101 infusion using Cheson 1999 response criteriaRituximab refractory defined as patients who had a response of <6 months or who failed to respond to a rituximab-containing regimen (rituxima b monotherapy or in combination with chemotherapy)

GALLIUM (BO21223) Phase III: Study design

www.clinicaltrials.gov ; NCT01332968

Maintenance rituximab

q2m ×××× 2 years

Maintenance GA101 q2m ×××× 2 years

Rituximab 375 mg/m 2

+ chemotherapy* (n=700)

CR/PR

GA101 1000 mg + chemotherapy* (n=700)

Previously untreated advanced indolent

NHL (n=1400)

Experimental arm GA101 1000 mg d1, d8, d15 cycle 1; d1 cycles 2-8 q21d + CHOP, CVP or cycles 2–6 q28d + bendamustine

Control arm Rituximab 375 mg/m2 on d1 cycles 1-8 q21d + CHOP, CVP or cycles 1-6 q28d + bendamustine

Primary endpoint Investigator-assessed PFS

status - Fully recruited- Final analysis expected in 2017

*FL: Each site to choose 1 of 3 chemotherapy regimens (CHOP, CVP, or bendamustine) which will; then be administered to all patientsNon-FL: CHOP, CVP, or bendamustine selected on a patient-by-patient basis

Optimization of Rituximab ’’’’s efficacy

↑ Affinity↑ ApoptosisTarget

↑ ADCC ↑ CDCFcRnConjugates

Optimizing the mAb itself

Stimulating immune effector cells

Mφ TNK

Optimization of Rituximab ’’’’s

efficacy

Lenalidomide repairs FL T-cell immunologic synapse dysfunction with autologous tumor cells.

Ramsay A G et al. Blood 2009;114:4713-4720

R2 as Frontline therapy in FL: PFS

PFS (months)

Per

cent

sur

viva

l

0 12 24 360

20

40

60

80

100

N=4636 mo PFS: 81%

N=4636 mo PFS: 81%

Fowler, N. et al. ASH 2012.

Study Design

• Stratification: FLIPI (0-1 v 2 v 3-5), Age (>60 v ≤ 60), diameter of largest node (> 6 v ≤ 6 cm)

• R-Chemo arm: Investigator choice of R-CHOP, R-CVP, R-B

R2 maintenance(lenalidomide 1 yr + rituximab 2 yrs)

Rituximab maintenance(2 yrs)

R

24 mos.

R2

R-Chemo

6 mos.

CR, CRu, PR

CR, CRu, PR

1st line

FL

N=1000

GALEN – Phase Ib/II

Phase Ib

Induction

aNHL

(n=88)

FL

(n=90)

R/R CD20+ NHL

GA101 (1000 mg) x 8

+ lenalidomide RD

GA101 q2m x 2 years

+ lenamidomide 1 year

GA101 (1000 mg) x 8

+ lenalidomide RD

GA101 q2m x 2 years

+ lenamidomide 1 year

Phase II

Maintenance

FL

(n=20)

GA101 (1000 mg) x 8

+ lenalidomide

(10, 15, 20, or 25mg q21d)

Confidential – for GA101 investigators’ use in the clinical development programme only

GA101 Development in indolent lymphoma

nPatient

populationTreatments

Primary endpoint

Phase III

GADOLIN (GAO4753g)

~410 Rituximab-refractory indolent

lymphoma

• GA101 + bendamustine(90mg/m 2) �maintenance for 2y

• Bendamustine 120 mg/m 2

PFS

- Events come slower than expected � increase of sample size by additional 50 pts to n = 410

- Final analysis expected in 2017

Lymphome diffus à grandes cellules B

� Randomized study in elderly patients with previously untreated DLBCL

� N = 399

Two different failure concerns in DLBCL

CONFIDENTIAL

Early POD,

toxicity

≥1/3 of patients in CR die of DLBCL

Late relapses

Does dose-dense R -CHOP benefit elderly patients?RCHOP21 vs RCHOP14

CONFIDENTIAL

R-CHOP21

R-CHOP14CHOP14

CHOP21

GELA Ph III/UK Ph III:

No OS advantage with DD Tx

Coiffier, B, et. Al., NEJM 2002; 346 (4):235-242Pfreundschuh, M et. Al, Blood 2004; 104: 634-641Pfreundschuh, M et al. Lancet Oncol 2008; 9(2):105-116R. Delarue, et. Al, ASH 2009

New induction strategies

CONFIDENTIAL

RCHOP x 6-8 cycles

Advanced Stage DLBCL age >60y

observationSecond-line

Improve induction:� Pre-phase therapy� Gender stratified MoAb

dose and schedule� Biologically stratified

therapy (eg GC vs. ABC)

� Anti CD20-CHOP + new agent� R+ New Regimen� CHOP+ New mAb

GOYA (BO21005) Phase III: Study design

CONFIDENTIAL

• Disease-free survival

• Response duration

• Time to next lymphoma treatment

• Safety

• Quality of life

• Medical resource utilisation

• CR, complete response; DLBCL, diffuse large B-cell lymphoma; IPI, international prognostic index; IRC, Independent Review Committee; ORR, overall response rate

• www.clinicaltrials.gov NCT01287741 (May 2012).

Rituximab x 8 cycles + CHOP x

6 or 8

GA101 x 8 cycles +

CHOP x 6 or 8 Previously untreated DLBCL

(N = 1,400)•Age ≥ 18 years

•Low-intermediate, intermediate or high-risk IPI score (low

risk IPI score: IPI 1 irrespective of bulky disease or IPI 0 with

bulky disease)

•ECOG ≤ 2

Randomise

Primary endpoint• Progression-free

survival

Secondary endpoints• Progression-free survival

(assessed by IRC)

• ORR and CR

• ORR and CR (assessed by IRC)

• Overall survival

• Event-free survival

This trial is being conducted in collaboration with the Fondazione Italiana Linfomi (FIL) study group

This trial is currently recruiting

GA101: 1,000 mg d1, d8, d15, cycle 1; d1, cycles 2–8, every 21 daysRituximab: 375 mg/m2 d1, cycles 1–8, every 21 days

LNH 07-3B : Visual assessment / ∆ SUV at interim PET

At 2 cycles At 4 cycles

Casasnovas RO et al. Blood 2011;118:37.

Visual

∆∆∆∆SUV

CHEMO14 according to center decision:- ACVBP14- CHOP14

GAINEDDLBCL, 18-60y, aaIPI = 1-3

Phase III – 2 arms

GA101: 1000mg by injectionD1-D8 cycles 1 -2

MTX BEAM + ASCT

Salvage therapy

∆SUV 0-2

> 66%

2-/4-

PET results

PET 0

∆ SUV0-

≤ 70%

4+

4

According to

randomization arm and CHEMO14 regimen

R

Arm A

Arm B

MTX / GA101-VP-IFOSFAMIDE / Arac

A

BGA101-CHOP-14 x 4

PET 2 PET 4

Induction

∆ SUV0-4

>70%

4-

∆SUV 0-2

≤ 66%

2+/4-

C1 C2 C3 C4

C1 C2 C3 C4

R-CHEMO14

consolidation

MTX / R-VP-IFOSFAMIDE / Arac

R-CHOP-14 x 4

GA101-CHEMO14

Post-induction strategies

CONFIDENTIAL

RCHOP x 6-8 cycles

Advanced Stage DLBCL>60y

observationSecond-line

Maintenance strategies:� Enzastaurin (PRELUDE)� Lenalidomide (REMARC)� mTOR (PILLAR)� Rituximab (ECOG

E4494;NHL13)Consolidation:Y90 ibritumumab tiuxetan(ZEST)

Rituximab maintenance therapy in DLBCL or follicular NHL grade 3

8 x rituximab

plus4–8 x

CHOP-like chemo

Not eligible

CRCRu

REGISTRATION

Stratification*

12 x rituximab375 mg/m 2

q2mo for 2 years

Observation

Induction

Responseevaluation

RANDOMISED

2-year follow-up

Maintenance

* - Type of CHOP-like induction treatment (R-CHOP-14 ,21; R-CHOEP, etc.)- Number of chemotherapy cycles in induction treatme nt (<6 vs. >6)- Geographical region

PRSDPD

NHL13

4–12 weeks

CONFIDENTIAL

NHL13: Summary

CONFIDENTIAL

� Rituximab maintenance treatment did not statistically significantly prolong EFS in patients with DLBCL (or FLG3)

� However:

� Trend in favor of R maintenance in EFS (p=0.06)

� Lymphoma relapses reduced by 44% (from 18.7 to 10.7%)

� These signals warrant further exploration of dosing and scheduling (including maintenance) of Rituximab in DLBCL

4646

Study Schema

CONFIDENTIAL

ScreeningDLBCL patients in PET-NEG CR after R-CHEMO

Randomization

Zevalin Study Regimen Follow-up Until Death

Observation Only Follow-up Until Death

Informed Consent signed

*Relapse patients are required to be followed for survival status, information on subsequent lymphoma therapies, and AE/SAEs related to study medication and study conduct for 5 years

• C1-C2: 80% des décès

• Albuminémie > 35g/l

• Survie Globale

• Maladie Curable

Peyrade et al , Lancet Oncol. 2011 May;12(5):460-8.

4-year estimated OS: 50%

[95% CI:40.8-57%]

ASCO 2013, Abs 8536

LNH03-7B/ > 80 ans / R-miniCHOP

LN03-9B / Ofatumumab-miniCHOP

LN03-9B / O-miniCHOP LN03-9B / O-miniCHOP

L’incidence des ABC augmente avec l’âge

3 phases II R2-CHOP (REAL, MAYO CLINIC, LYSA)

Design SENIOR study (I)Design SENIOR study (I)

Hypothèse: OS-2y 59% > 74%, 79 évènements); 250 patients

Design (II)Design (II)

• Phase III

• N = 250 patients

(OS-2y 59% > 74%, 79 évènements)

• Période de recrutement = 2,5 ans

• Durée de l’étude = 4,5 ans

• Début de l’étude = premier trimestre 2014

• « Safety run » pour 20 patients dans le bras expérimental

m2

Diapositive 52

m2 J'indiquerais plutôt "Evaluation de la safety précoce" à la place de "Safety run" pour qu'il n'y ai pas de confusion.marion.bonhomme; 07/10/2013

Lymphome à cellules du manteau

3 ways to improve patients ’outcome in the future

ASCT

INDUCTION CHEMOTHERAPY:

R-CHOP/HD-aracytine

Improve response rate after induction

Maintain response duration

1 2


ASCT


R-CHOP/HD-aracytine

targeted-driven therapies 3


ASCT


R-CHOP/HD-aracytine

New therapies:

Bendamustine

Temsirolimus

Velcade

Revlimid

Ibrutinib

PI3k inhibitors

New antibodies

(SC Rituximab, GA-101, Anti-

CD22, Anti-CD19, zevalin …)

…..

Leucémie lymphoïde chronique

58 58

CLL11 Study design

RANDOMIZE

2:1:2

G-Clb vs. Clb

GA101 + chlorambucilx 6 cycles

R-Clb vs. Clb

Rituximab + chlorambucilx 6 cycles

Chlorambucil x 6 cycles (control arm)

RANDOMIZE

2:1:2

Chlorambucil x 6 cycles (control arm)

G-Clb vs. R-Clb

GA101 + chlorambucilx 6 cycles

Rituximab + chlorambucilx 6 cycles

G-Clb (n=333)%

R-Clb (n=330)%

Male 61 62

Median age, years (range) 74 (39–89) 73 (40–90)

Aged ≥65 years 81 78

Aged ≥75 years 46 42

Median ECOG PS (range) 1 (0-3) 1 (0-3)

Median CIRS score 8.0 8.0

CIRS score >6 78 75

Median CrCl 62.5 62.6

CrCl <70 mL/min 65 64

CrCl <50 mL/min 27 2559

Baseline patient characteristics

ECOG PS, Eastern Cooperative Oncology Group performance status; CIRS, cumulative illness rating scale; CrCl, creatinine clearance

60

Baseline disease characteristics

G-Clb (n=333)%

R-Clb (n=330)%

Binet stage

A 22 22

B 43 41

C 35 37

FISH cytogenetics

17p– 7 7

11q– 16 17

+12 16 16

13q– 29 30

Other 7 8

Normal 25 22

IGHV status

Unmutated 62 61FISH, fluorescence in situ hybridization; IGHV, immunoglobulin heavy chain variable region

G-Clb (n=336) a

%R-Clb (n=321) a

%

Any AE grade ≥ 3b 70 55

Infusion-related reaction 20 4

Neutropenia 33 28

Anemia 4 4

Thrombocytopenia 10 3

Infection 12 14

Pneumonia 4 5

a Safety population for G-Clb includes 5 patients randomized to R-Clb who received one infusion of GA101 in errorb Incidence rate of ≥3% in any treatment arm 61

Adverse events of interest

G-Clb (n=333)%

R-Clb (n=329) a

%

Response rate

ORR 78 65

p <0.0001

CRb 21 7

PRc 58 58

SD 5 15

PD 4 11

Not evaluable d 13 9

62

End-of-treatment response

a Assessment not reached by data cut-off in 1 patient in R-Clb arm; as assessed by iwCLL criteria 3 months after end of treatmentb Confirmed by imaging and bone marrow, and includes incomplete CRc Includes nodular PRd Due to missing data or withdrawal from study treatment prior to response assessmentORR, overall response rate; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease

As measured by central laboratory assessment (ASO-RQ-PCR) at 3 months after end of treatment;bone marrow samples were usually only taken from patients thought to be in CR 63

Minimal residual disease (MRD)

Median observation time: G-Clb, 18.8 months; R-Clb, 18.6 monthsType 1 error controlled through closed test procedure; P value of the global test was <0.0001Independent Review Committee-assessed progression-free survival (PFS) was consistent with investigator-assessed PFS 64

0 3 6 9 12 15 18 21 24 27 30 33 36 39

330 317 309 259 163 114 72 49 31 14 5 2 0 0330 307 302 278 213 156 122 93 60 34 12 4 1 0

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Pro

gres

sion

-fre

e su

rviv

al

Time (months)

G-Clb:R-Clb:

No. at risk

Progression -free survival (Head-to-Head)

Median observation time: G-Clb, 23.2 months; Clb, 20.4 monthsType 1 error controlled through closed test procedure; P value of the global test was <0.0001Independent Review Committee-assessed PFS was consistent with investigator-assessed PFS 65

0 3 6 9 12 15 18 21 24 27 30 33 36 39

118 101 89 68 36 18 11 6 4 3 1 0 0 0238 220 218 207 188 156 122 93 60 34 12 4 1 0

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Pro

gres

sion

-fre

e su

rviv

al

Time (months)

G-Clb:Clb:

No. at risk

Progression -free survival (GA101)

Median observation time: G-Clb, 18.8 months; R-Clb, 18.6 monthsNo multiplicity adjustment was done for secondary endpoints

Total number of deaths: G-Clb, 28 (8%); R-Clb, 41 (12%)

66

0 3 6 9 12 15 18 21 24 27 30 33 36 39

330 320 314 305 255 203 169 138 105 61 27 8 0 0333 316 310 303 261 214 170 144 115 71 34 14 2 0

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Ove

rall

surv

ival

Time (months)

G-Clb:R-Clb:

No. at risk

Overall survival (Head-to-Head)

• L’innovation en matière d’anti CD20 passe par une meilleure connaissance des relations structures/fon ctions et de la PK

• GA101 est l’anti CD20 le plus prometteur dans les différents sous-types de lymphome (FL, DLBCL and MC L) mais sa supériorité au rituximab reste à démontrer

• GA101-Clb est le traitement de première ligne des L LC avec comorbidités

• La voie sous-cutanée des anti CD20 mérite d’être ex plorée hors aspects économiques

67

Conclusion

innovations thérapeutiques avec les anti-cd20 · 2017. 1. 16. · salles g, et al . blood...

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