Immunotherapy with BlinatumomabWhat are the possibilities?

Peter Bader

SBTMO 2018 – ALL Satellite Symposium

“Role of MRD and Immunotherapy in Optimizing ALL Treatment Outcomes”

Rio de Janeiro, August 2nd, 2018

2

Objectives

Refractory ALL

Blinatumomab, Product, clinical development

Blinatumomab in Children and Adults

TOWER Study; BLAST Study, AND RIALTO Study

Own data in 18 children

Present data from TOWER (AllHSCT in adults with R/R ALL from Phase 3

3

Poor Outcome for Patients with r/r pB-ALL

Pediatric patients Adult patients

Standard pB-ALL

CR with frontline chemo 98-99% 85-90%

relapse 15-20% 30-50%

Long-term survival after

early relapses

late relapses

25%

50-60%

8%

24%

r/r pB-ALL

Median OS with chemo only - 4.5-8.4 months

5y-median OS with chemo only - 7-10%

Median OS after chemo only - 10 months

Median OS after HSCT 7.4 months 5.8 months

New agents with reduced toxicity are needed to improve outcomes for patients with r/r pB-ALL

4

Bispecific T-Cell Engager: Blinatumomab

Nagorsen et al. Leuk & Lymph 2009

Baeuerle P.A. et al. Cancer Res. 2009

Bargou R. et al. Science 2008

Topp M.S. et al. Lancet Oncol. 2015

Activation signals promote CTC proliferation

Klinger M. et al.

Blood 2012

Serial lysis of CD19+ B cells

Hoffmann P. et al.

Int J Cancer 2005

5Nagorsen et al. 2012

Blinatumomab – Mode of Action

6

Blinatumomab – Clinical Develpoment

Nagorsen et al. 2012

© Amgen Inc. All Rights Reserved.

A Phase 3, Randomized, Open Label Study

Investigating the Efficacy of the BiTE Antibody

Blinatumomab Versus Standard of Care

Chemotherapy in Adult Subjects With

Relapsed/Refractory B-precursor Acute

Lymphoblastic Leukemia (ALL)

Study (TOWER) – NCT02013167

8

TOWER Study in Adult r/r pB-ALLS

cre

enin

g/P

re-p

hase

Safe

ty f

ollo

w-u

p

Blinatumomab

cIV infusion

4 weeks on

2 weeks off

2 cycles

SOC

chemotherapy

2 cycles

Consolidation3 cycles

Maintenance 12 months

Ra

nd

om

iza

tio

n

© Amgen Inc. All Rights Reserved.

BLAST: A Confirmatory, Single-Arm, Phase 2

Study of Blinatumomab, a Bispecific T-Cell

Engager (BiTE) Antibody Construct, in

Patients with Minimal Residual Disease B-

Precursor Acute Lymphoblastic Leukemia

(ALL)

Study (BLAST) – NCT01207388

10

BLAST Study in Adult r/r pB-ALL, MRD-basedS

cre

enin

g/P

re-p

hase

Safe

ty fo

llow

-up

Long-t

erm

follo

w-u

pBlinatumomab15 μg/m2 cIV infusion

i.th. prophylaxis

4 weeks on

2 weeks off

Up to 4 cycles

HSCT offered to patiens in CR

© Amgen Inc. All Rights Reserved.

Open-label, multicentre, expanded

access study of blinatumomab* in

paediatric and adolescent patients

with relapsed/refractory B-precursor ALL

Study 320 (RIALTO) – NCT02187354

*Blinatumomab is not licensed for use in paediatric patients in the EU

SC-EU-AMG103-00339-06.17

SC-DE-AMG103-00140

12

RIALTO Study in r/r pB-ALLS

cre

enin

g/P

re-p

hase

Safe

ty fo

llow

-up

Long-t

erm

follo

w-u

pBlinatumomab

cIV infusion

4 weeks on

2 weeks off

Up to 5 cycles

HSCT offered to patiens in CR

13

Key Eligibility Criteria

TOWER Study BLAST Study RIALTO Study

Age ≥18 y ≥ 18 y >28 d and <18 y

CD19+ pB-ALL with≥5% blasts in BM

x x

CD19+ pB-ALL with

<5% blasts in BMMRD ≥10E-4 (- ≥10E-3)

x

Ph negative x x x

2nd or later relapse,

any rlps. after HSCT,

refractory disease

1st relapse w remisson

duration <12 months

x

x

x

x

(x) x

x

x

Adequate liver function x x x

ECOG status ≤2 0 or 1

No prior HSCT x

14

Key Exclusion Criteria

TOWER Study BLAST Study RIALTO Study

Clinical relevant CNS

pathology

x x x

Isolated extramedullary

disease

x x

Chemotherapy within

2 wk,

Radiotherapy within

2-4 wk

x

x

x

x

x

x

Immunotherapy x

Immunosuppression

within 2 weeks

x x

Auto HSCT within 6 wk

Allo HSCT within 12 wk

x

x

x

x

Grade 2-4 aGVHD,

Active cGVHD

x

x

x

x

Abnormal liver or

renal function

x

x

x

x

15

Study Endpoints

TOWER Study BLAST Study RIALTO Study

Primary endpoint:

Efficacy

OS

Primary endpoint:

Efficacy

MRD response after 1 cycle(MRD neg with sensitivity of at least 10E-4 by PCR in reference lab)

Primary endpoint:

Safety

Treatment-emergent/related AEs

Secondary endpoint:

Efficacy

EFS

Remission rate

Safety

Incidence and severity of AEs

Secondary endpoint:

Efficacy (w/wo HSCT)

RFS

OS

Duration of MRD response

Safety

Incidence and severity of AEs

Secondary endpoint:

Efficacy

CR within first 2 cycles

MRD neg. within first 2 cycles

RFS

OS

Rate of allo-HSCT after CR

16

TOWER Study

Blinatumomab vs. Chemo in Adult-ALL

Hagop Kantarjiann et al. NEJM 2017

Prospective 2:1 randomized trial: n=405

Blina: 271 Chemo: 134

Median OS

Blina: 7.7 mo Chemo: 4.0 mo

CR/Cri (12 weeks):

Blina: 36/44% Chemo: 16/25%

6 months EFS:

Blina: 31% Chemo: 12%

Longer remission duration

Blina: 7.3 mo Chemo: 4.6 mo

AES grade 3

Blina: 87% Chemo: 92%

Treatment with blina resulted in longer OS

17

Zugmaier et al.

Blood 2015

n=36

BLAST Study

Blinatumomab in MRD Positive Adult-ALL

18

BLAST Study

Blinatumomab in MRD Positive Adult-ALL

Zugmaier et al.

Blood 2015

28% achieved an OS of 30 mo

Survival may be associated

with MRD response

n=36

19

Results

Evaluable 113

Median age 45 (18-76) yrs

In 2nd/later CR: 36%

MolCR: 78%

Median OS: 36.5 mo

- Mol CR y/n: 38.9 vs 12.5 mo

Median RFS: 18.9 mo

- Mol CR y/n: 23.6 vs 5.7 mo

- 1st / later CR: 24.6 vs 11 mo

BLAST Study (Follow-up)

Blinatumomab in MRD Positive Adult-ALL

Gökbuget et al.

Blood 2018

MRD response resulted in improved OS and RFS

20

RIALTO Study: Patient Demographics and

Baseline Characteristics

Locatelli F, et al. ASCO 2017; Abstract 10530 and poster presentation.

Characteristic All patients (N=40)

Male, n (%) 19 (48)

Median (range) age, years 9 (1–17)

Age group, n (%)

1 month to <2 years

2 to <12 years

12 to <17 years

5 (13)

20 (50)

15 (38)

Prior relapses, n (%)

0 (primary refractory)

1

≥2

5 (13)

11 (28)

24 (60)

Prior allogeneic HSCT, n (%) 21 (53)

Bone marrow blasts (local), n (%)

<50%

≥50%

22 (55)

18 (45)

21

RIALTO Study: Response Within first 2

Cycles

Locatelli F, et al. ASCO 2017; Abstract 10530 and poster presentation.

Median number of cycles started and completed: 2 (range, 1−5)

All patients (N=40)

n/N1* % 95% CI

CR during the first two cycles

<50% blasts

≥50% blasts

t(17;19)

25/40

15/22

10/18

2/2

63

68

56

100

46–77

45–86

31–79

NA

MRD response during the first two cycles†

<50% blasts

≥50% blasts

t(17;19)

19/25

12/15

7/10

2/2

76

80

70

100

55–91

52–96

35–93

NA

HSCT realisation‡

Allogeneic HSCT after CR

Allogeneic HSCT without CR

10/25

3/14

40

21

21–61

5–51

22

RIALTO Study: Overall Survival

Locatelli F, et al. ASCO 2017; Abstract 10530 and poster presentation.

Censored at time of

allogeneic HSCT N

Median OS,

months

95% CI,

months

Not censored 40 9.8 7.1–NE

Censored 40 8.3 5.4–9.8

181614121086420

0

0

1

0

1

0

1

0

3

1

7

1

12

4

12

4

15

7

16

8

17

9

22

12

30

18

33

25

33

30

37

37

39

39

40

40

0.0

0.2

0.4

0.6

0.8

1.0

Time (months)

Surv

ival pro

babili

ty

Number of subjects at risk:

Median follow-up: 11.8 months

Not censored Censored

Frankfurt Patients (N=18)

N (%) N (%)

Sex

Male

Female

14

4

(78)

(22)

Age

median [range]

13 years

[2 - 20]

Diagnosis

ALL

B-NHL

17

1

(94)

(6)

Number of SCTs before

treatment

0

1

2

7

10

1

(39)

(56)

(6)

Number of relapses before

treatment

1

2

3

4

9

6

2

1

(50)

(33)

(11)

(6)

Number of Blinatumomab

cycles

1

2

11

7

(61)

(39)

Duration of Blinatumomab

cycle

median [range]

28 days

[2-36]

Course after Blinatumomabmedian post treatment observation period: 1.6 years [25 days – 5.5 years]

Response to

BlinatumomabSCT after treatment

Total Yes (%) No (%)

CR (MRD+/-)8 6 (75) 2 (25)

NR10 7 (70) 3 (30)

Total18 13 (72) 5 (28)

Outcome in Patients with SCTs after

Blinatumomabmedian post SCT observation period: 2.5 years [83 days – 5.4 years]

Response to

BlinatumomabOutcome

Total CR (%) Relapse (%) TRM (%)

CR (MRD+/-)6 2 (33) 2 (33) 2 (33)

NR7 3 (43) 3 (43) 1 (14)

Total13 5 (39) 5 (39) 3 (23)

Outcome of patients without SCT (n=5)

Response to

BlinatumomabOutcome

Total CR (%) Lost to

follow-up

(%) Death (%)

CR (MRD+/-)2 2 (100) 0 (0) 0 (0)

NR3 0 (0) 2 (66) 1 (33)

Total5 2 (40) 2 (40) 1 (20)

Outcome of all patients (n=18)median post treatment observation period: 1.6 years [25 days – 5.5 years]

Response to

BlinatumomabOutcome

Total CR (%) Relapse (%) NRM (%) Lost

to FU

(%)

CR 8 4 (50) 2 (25) 2 (25) 0 (0)

NR10 3 (30) 4 (40) 1 (10) 2 (20)

Total18 7 (39) 6 (33) 3 (17) 2 (11)

Overall survival of patients since begin of

treatment with Blinatumomab

Time since begin of treatment (years)

Ove

rall s

urv

iva

l (%

)

0

20

40

60

80

100

2-y-p= 54.6%, 95%-CI: 32.4% - 92.1%

0 1 2 3 4 5 6

Overall survival of patients with CR vs.

patients with NR after treatment with

Blinatumomab

CR includes CR MRD+

Time since end of treatment (years)

Ove

rall s

urv

iva

l (%

)

0

20

40

60

80

100

0 1 2 3 4 5 6

CR: 2-y-p= 71.4%, 95%-CI: 44.7% - 100%

NR: 2-y-p= 45.7%, 95%-CI: 20.3% - 100%

30

Summary Allogeneic SCT remains the gold standard (highest risk, relapsed patients)

Children and adolescents with ALL

CR1: ultra high risk features, persistent MRD

CR2: - late relapses with pers. MRD- early, very early relapse

>CR2: all patients

Level of MRD prior to transplant is a major predictor for outcome

Antibody treatment Remission induction and improvement; reduce toxicity and clear MRD

post transplant

Adult Patients with r/r ALL

High risk for relapse and TRM irrespective of treatment

Patients with persistent remission after Blinatumomab

Efforts are focusing on minimizing the relapse risk by intensifying therapy upfront and by eradicating MRD using the new available immunotherapies e.g. Blinatumomab

Combining all these modalities (new therapies, conventional chemotherapy and HCT) is challenging.

Cooperations

Halvard BönigGerman Red Cross Blood Donor Service Frankfurt/Main, Germany

Winfried S. WelsGeorg-Speyer-Haus, Frankfurt/Main, Germany

PhysiciansMichael MerkerShahrzad BakhtiarEva RettingerAndre WillaschAndrea JarischJan Sörensen

Graft Manipulation,Cell Therapeutics Sabine Huenecke Melanie BremmClaudia CappelVerena PfirrmannSibylle Wehner

Mesenchymal Stroma CellsZyrafete KuçiSelim Kuçi

CIK / T Cell TherapyEva RettingerVerena PfirrmannMichael MerkerLisa-Marie PfeffermannSarah OelsnerVida Meyer Molecular Biology

Andre WillaschChristlinde MauracherGitta NozadFariba SoltaniMiriam StaisHermann Kreyenberg

Pediatric Stem Cell Transplantation & Immunology: Peter Bader / Evelyn Ullrich / Thomas Klingebiel

Clinical Trial OfficeVerena PfirrmannBettina SteinmetzTina Homrighausen

OfficeKirsten Schäfer

NK cells / ExperimentalSara TognarelliJuliane WagnerJochen FrühKatja Thoma

Bio MathematicsEmilia Salzmann-Manrique

Participating Institutions

Düsseldorf, Germany

Roland Meisel

Florian Babor

Friedhelm Schuster

Frankfurt/Main, Germany

Hubert Serve

Gesine Bug

Mainz, Germany

Matthias Theobald

Eva Wagner

Hauptrock Beate

Heidelberg, Germany

Johann Greil

32

Can allogeneic HSCT in ALL be

replaced by antibody therapy?

33

Principal Considerations Treatment of acute leukemia

Multimodal chemotherapy protocols Adults

Children and adolescents

Considerable improvement Leukemia free survival:

90% in children and adolescents with ALL

Indications for SCT CR1 only in high risk patients for ALL

Slow response, hypodiploidy, pers. MRD

CR2 Only high risk patients in children and adolescents with ALL

Early, very early relapses and slow MRD clearance in late relapses

CR3 All patients

34

Stem-Cell Transplantation in Children With Acute Lymphoblastic Leukemia: A Prospective

International Multicenter Trial Comparing Sibling Donors With Matched Unrelated Donors—

The ALL-SCT-BFM-2003 TrialChristina Peters, Martin Schrappe, Arend von Stackelberg, André Schrauder, Peter Bader, Wolfram Ebell,Peter Lang, Karl-Walter Sykora,

Johanna Schrum, Bernhard Kremens, Karoline Ehlert, Michael H. Albert,Roland Meisel, Susanne Matthes-Martin, Tayfun Gungor, Wolfgang

Holter, Brigitte Strahm, Bernd Gruhn,Ansgar Schulz, Wilhelm Woessmann, Ulrike Poetschger, Martin Zimmermann, and Thomas Klingebiel

C. Peters et al.

J Clin Oncol 2015

MSD: 71%

MUD: 69%

MSD: 3%

MUD: 10%MSD: 24%

MUD: 22%

MSD: 79%

MUD: 73%

35

Patient with ALL from 2005-2014n=99 in complete remission at the time of first transplantation

N % N %

Sex

Male

Female

60

39

61

39

Age

< 10 years

> 10 years

35

64

35

65

Remission

CR1

≥ CR2

54

45

55

45

Donor

MSD

MUD

Haploidentical

21

67

11

21

68

11

Phenotype

pB-ALL

T-ALL

bi-pheno ALL

82

12

5

83

12

5

Immunotherapy

(WD of CSA or DLI)

Yes

No

29

70

29

71

Frankfurt Experience

S. Bahktiar, submitted

36

n Events 4-y TRM P

━ 49 7 0.14 ±0.05 .129

━ 50 2 0.04±0.02

Ov

era

ll s

urv

iva

l

0 10 20 30 40 50 60

0.0

0.2

0.4

0.6

0.8

1.0

Outcome for ALL2005-2009 versus 2010-2014

months after SCT

TR

M

0 10 20 30 40 50 60

0.0

0.2

0.4

0.6

0.8

1.0

months after SCT

CIR

0 10 20 30 40 50 60

0.0

0.2

0.4

0.6

0.8

1.0

pE

FS

0 10 20 30 40 50 60

0.0

0.2

0.4

0.6

0.8

1.0

n Events 4-y EFS P

━ 49 18 0.63 ±0.07 .365

━ 50 10 0.77±0.06

2010-2014 (n=50) = 87%

2005-2009 (n=49) = 71%

2010-2014 (n=50) = 77%

2005-2009 (n=49) = 63%

n Events 4-y OS P

━ 49 14 0.71 ±0.06 .198

━ 50 6 0.87±0.05

n Events 4-y CIR P

━ 49 11 0.22 ±0.06 .958

━ 50 8 0.19±0.06

S. Bahktiar, submitted

37

CIBMTR Study. Period 2000-2011: Patients n=1458

2y: 50%

Segal et.al: Cancer 2017