Venetoclax in multiple myeloma. P-Moreau.pdfMoreau P, et al. Blood 2017;130:2392–2400 Phase 2 Study of Venetoclax Plus Carfilzomib and Dexamethasone in Patients with Relapsed/Refractory

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Venetoclax in multiple myeloma

Pr Philippe Moreau

University Hospital, Nantes, France

Zinc code: PHEM/HEM/1017/0001oDate of preparation: February 2018

Disclosures: P Moreau

This presentation may contain unregistered products or indications of investigational drugs,

please check the drug compendium or consult the company

Research Support/P.I.

Employee

Consultant

Major Stockholder

Speakers Bureau

Honoraria Janssen, Takeda, Celgene, Amgen, Abbvie

Scientific Advisory Board Janssen, Takeda, Celgene, Amgen, Abbvie

Background

Anti-apoptotic proteins BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival1

Venetoclax induces cell death in multiple myeloma (MM) cell lines and primary samples, particularly those positive for the translocation t(11;14), which correlates with higher ratios of BCL2 to MCL1 and BCL2 to BCL2L1 (BCL-XL) mRNA1,2

1. Touzeau C et al. Leukemia 2014

2. Punnoose E et al. Mol Cancer Ther 2016 3

Background





Death signal

Background





Anti-apoptoticprotein

Adapted from Letai et al. Nat Rev Cancer. 2008 ;8(2):121-32.

BCL-2BCL-XL

MCL-1

Venetoclax : the first Bcl-2 specific BH3 mimetic

Background





Souers et al. Nat Med. 2013;19(2):202-8

Venetoclax : the first Bcl-2 specific BH3 mimetic

Bcl-2 is overexpressed in a subset of human myeloma cell lines

Bodet et al. Blood 2011 6;118(14):3901-10

Bodet et al. Blood 2011 6;118(14):3901-10

Can we identify a subgroup of patients with Bcl-2 dependant myeloma and therefore able to respond to

venetoclax ?

Bcl-2 is overexpressed in a subset of human myeloma cell lines

Sensitivity to Venetoclax is restricted to myeloma cells harboring the t(11;14) translocation

CCND1M

AF

MM

SET

OTHER1

10

100

1000

10000

Molecular Subgroups

AB

T-1

99 L

D50

(nM

)

Touzeau et al. Leukemia 2014 ; 28(1):210-2

Preclinical data

Efficacy of venetoclax in a very advanced patient – case report

- 30 year old patient

- Relapsed MM refractory to alkylating agents, bortezomib, lenalidomide, pomalidomide, carfilzomib, bendamustine et daratumumab

- FISH: t(11,14), del17P

Touzeau, Moreau. Haematologica. 2017 ;102(3):e112-e114

Touzeau, Moreau. Haematologica. 2017 ;102(3):e112-e114

Clinical response : Venetoclax (1200 mg/day) + Dex (40 mg/week) (patient progressed after 10 months of therapy)

In-vitro sensitivity to venetoclax

Efficacy of venetoclax in a very advanced patient – case report

- 30 year old patient

- Relapsed MM refractory to alkylating agents, bortezomib, lenalidomide, pomalidomide, carfilzomib, bendamustine et daratrumumab

- FISH: t(11,14), del17P

Kumar S, et al. Blood 2017;130:2401–2409

Dosing and Enrollment

Following a 2-week lead-in period, patients were treated on a 21-day cycle with

daily venetoclax (300 to 1200 mg)

Patients who progressed while receiving monotherapy could have dexamethasone

added to venetoclax and continue on study

N=66

n=6

n=9

n=6

n=9

n=36

Kumar s, et al. Blood 2017;130:2401–2409 + suppl

Pt CharacteristicsN=66

Age, median (range), years 63 (31–79)

ISS stage, n (%)

Stage I

Stage II/III

Unknown

24 (38)

39 (62)

3

Cytogenetic abnormalities, n (%)

t(11;14)

t(4;14)

del(17p)

del(13q)

Hyperdiploid

30 (46)

6 (9)

12 (18)

32 (48)

27 (41)

No. of prior lines of therapy,a median (range)

Autologous stem cell transplant, n (%)

Bortezomib/refractory, n (%)

Lenalidomide/refractory, n (%)

Bortezomib and lenalidomide refractory, n (%)

Refractory to last prior therapy, n (%)

5 (1–15)

50 (76)

62 (94)/46 (70)

62 (94)/51 (77)

40 (61)

52 (79)

aPercentages based on total study population Data cutoff of 19Aug2016Kumar S, et al. Blood 2017;130:2401–2409

Summary of Adverse Events (AEs)

n (%) Any Grade Grade 3/4

Total 66 (100) 45 (68)

Hematologic

Thrombocytopenia 21 (32) 17 (26)

Neutropenia 18 (27) 14 (21)

Anemia 15 (23) 9 (14)

Leukopenia 15 (23) 9 (14)

Lymphopenia 12 (18) 10 (15)

Non-hematologic

Nausea 31 (47) 2 (3)

Diarrhea 24 (36) 2 (3)

Fatigue 18 (27) 3 (5)

Back pain 14 (21) 5 (8)

Vomiting 13 (20) 2 (3)

AEs for ≥20% of patients for any grade AE or for ≥10% with grade 3

or 4 AEs.Data cutoff of 19Aug2016

Two patients had dose-limiting

toxicities at 600 mg of abdominal

pain and nausea

Serious AEs (≥2% of patients):

pneumonia (8%), sepsis (5%), pain,

pyrexia, cough, and hypotension

(3% each)

No events of TLS were reported

MTD was not reached


Objective Response Rates in All Patients

and by t(11;14) Status

0

1 0

2 0

3 0

4 0

5 0

Pe

rc

en

ta

ge

o

f P

atie

nts

sC R C R V G P R PR

A ll P a t ie n ts

N = 6 6

t (1 1 ;1 4 )

n = 3 0

O R R 2 1 %

O R R 4 0 %

n o n - t (1 1 ;1 4 )

n = 3 6

O R R 6 %

6%

8%

13%

4%

10%

13%

3%

3%

3%

4%

Data cutoff of 19Aug2016

020

40

60

80

100

B O R T /L E N /C A R F /P O M

L E N /C A R F /P O M

B O R T /C A R F /P O M

B O R T /L E N /P O M

B O R T /L E N /C A R F

C A R F /P O M

L E N /P O M

L E N /C A R F

B O R T /P O M

B O R T /C A R F

B O R T /L E N

P o m a l id o m id e (P O M )

C a rfi l z o m ib (C A R F )

L e n a l id o m id e (L E N )

B o rte z o m ib (B O R T )

L a st l in e o f th e ra p y

t(1 1 ;1 4 ) M M

O v e ra ll re s p o n s e ra te (% )

R e fr a c to r y to :

N

30

26

22

23

11

19

20

7

16

7

15

9

6

14

7

7

6


Time to porgressionTime to Progression and Duration of Response

Data cutoff of 19Aug2016 10

0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4

0

2 5

5 0

7 5

1 0 0

M o n th s s in c e f irs t d o s e

% N

ot

Pro

gre

ss

ed

t (1 1 ;1 4 )

n o n - t(1 1 ;1 4 )

N o . a t r is k 6 6 3 3 2 7 2 0 1 6 9 3 1 1 1 1 1

N o . a t r is k 3 0 2 0 1 9 1 7 1 3 7 2 1 1 1 1 1

N o . a t r is k 3 6 1 3 8 3 3 2 1

T im e to P ro g re s s io n

A ll P a tie n ts

0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4

0

2 5

5 0

7 5

1 0 0

M o n th s s in c e f ir s t re s p o n s e

t (1 1 ;1 4 )

n o n - t(1 1 ;1 4 )

1 4 1 4 1 3 1 3 9 3 2 1 1 1 1

1 2 1 2 1 1 1 1 8 3 2 1 1 1 1

2 2 2 2 1

D u ra t io n o f O v e ra ll R e s p o n s e

A ll P a tie n ts

Median duration of response = 10 months

Kumar et al. Blood 2018

Ratio Bcl-2/ Bcl-XL as biomarker of response

Kumar et al. Blood 2018

Ratio Bcl-2/ Bcl-XL as biomarker of response

Moreau P, et al. Blood 2017;130:2392–2400

Background

Anti-apoptotic proteins BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival

Venetoclax is a selective, orally available small molecule BCL-2 inhibitor1 and bortezomib can indirectly inhibit MCL-12

When combined, venetoclax can enhance the activity of bortezomib in MM cell lines and xenograft models2

1. Roberts AW et al. N Engl J Med 2016;374:311-322;

2. Punnoose E et al. Mol Cancer Ther 2016;15(5):1132-44

Dosing and Enrollment

Patients received 50–1200 mg venetoclax per designated dose escalation cohorts

Enrollment by Dose Cohort

Dose

(mg)50 100 200 300 400 500 600 800 1000 1200

Total

DESE

Total

DE +

SE

n 3 6 5 7 6 7 5 3 3 9 54 12 66

Day 1 2 4 5 8 9 11 12 1 8 15 22

Cycles 1 – 8

Designated

Cohort Dose

Cycles 9 – 11

Designated

Cohort Dose

Cycles 12+

Days 1 – 35 at

Monotherapy

Dexamethasone and bortezomib (1.3 mg/m2 SC)

Dexamethasone (20 mg, PO)

Dosing cycle – 21 days for cycles 1 – 8 and 35 days for cycles 9+

Moreau P, et al. Blood 2017;130:2392–2400 and Suppl

Patient Characteristics

N = 66

Age, median (range), years 64 (38–79)

ISS stage, n (%)

Stage I

Stage II/III

Unknown

21 (35)

39 (65)

6

Cytogenetic abnormalities, n (%)

t(11;14)

t(4;14)

del(17p)

del(13q)

Hyperdiploid

9 (14)

5 (8)

15 (23)

30 (45)

30 (45)

No. of prior lines of therapy, median (range)

Stem cell transplant, n (%)

Prior bortezomib/refractory, n (%)

Prior lenalidomide/refractory, n (%)

Refractory to last prior therapy

3 (1–13)

39 (59)

53 (80)/26 (39)

48 (73)/35 (53)

40 (61)Moreau P, et al. Blood 2017;130:2392–2400





Phase 2 Study of Venetoclax Plus Carfilzomib and Dexamethasone in Patients with

Relapsed/Refractory Multiple Myeloma--Dosing

Costa L, at. 2018 ASCO Annual Meeting

Phase 2 Study of Venetoclax Plus Carfilzomib and Dexamethasone in Patients with

Relapsed/Refractory Multiple Myeloma—ORRs

Costa L, at. 2018 ASCO Annual Meeting

Venetoclax : a hope for plasma cell leukemia patients?

De Larrea, Leukemia 2013Royer, J Clin Oncol 2016

The prognosis of PCL remainsvery poor despite the use of novel agents

t(11;14) is found in up to 50%of PCL patients

Venetoclax : a hope for AL-amyloidosis patients?

t(11;14) is found in up to 50%of patients with AL-amyloidosis

Leung et al

Venetoclax: clinical development in myeloma

Touzeau, Moreau. Leukemia 2018 (review)

Venetoclax: clinical development in myeloma

Touzeau , Moreau. Leukemia 2018 (review)

Conclusions

- Venetoclax: first (?) targeted-therapy in MM

- Combination with Pis

- AL-amyloidosis, plasma cell leukemia

Documents

Venetoclax in multiple myeloma. P-Moreau.pdfMoreau P, et al. Blood 2017;130:2392–2400 Phase 2 Study of Venetoclax Plus Carfilzomib and Dexamethasone in Patients with Relapsed/Refractory