New Drugs In Hematology

Monday, May 9, 2016

2:10-2:25 p.m

Hodgkin Lymphoma Nivolumab

Anas Younes, M.D. Chief, Lymphoma Service

Memorial Sloan-Kettering Cancer Center

immunotherapy modalities

Batlevi, C. L. et al. (2015) Novel immunotherapies in lymphoid malignancies

Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.187

CAR T Cells Bispecific

Immune Checkpoint

Naked antibodies And ADCs

TCR

PD1 T cell

CTLA-4

TIM-3

LAG-3

BTLA

VISTA

OX40

CD137 (4-1BB)

CD27

CD28

HVEM

Inhibitory Receptors Activating Receptors

Blocking

Antibodies

Agonistic

Antibodies

Therapeutic Activation of Autologous T Cells

Targeting Immune Checkpoints

Expression and gene regulation of PDL-1 (CD273) and

PDL-2 (CD274) in Hodgkin Lymphoma

Yamamoto R et al. Blood 2008;111:3220-3224

Expression of PDL1/PDL2

in HL cell lines

LMP1 and LMP2A enhanced the

transcriptional activity of

PDL1/PDL2

LMP1+

PDL1

PDL2

LMP1-

PDL1/PDL2 Expression in

EBV+ and EBV- cHL

9p24.1 amplification and PD-1L cell-surface expression in

HL and MLBCL cell lines.

Green M R et al. Blood 2010;116:3268-3277

PD-1L Copy number

PD-1L Copy number

9p24.1 amplification

EBV Infection

JAK2

PDL1

Hodgkin and Reed Sternberg (HRS) Cells

CD30

HRS Cells Express High Levels of PDL-1

Younes A, ICML, Lugano 2015

HRS Cells Express High Levels of PDL-1

9p24.1 Gene amplification

EBV Infection

JAK2

PDL1

Hodgkin and Reed Sternberg (HRS) Cells

CD30

HRS

PD1

PD-L1

PD-L2 MHC I/II

TCR

T cell

Adapted from Stathis & Younes: Ann Oncology 2015

T-Cells T-Cells

PD1

Nivolumab in Relapsed Hodgkin Lymphoma

Ansell SM et al. N Engl J Med 2015;372:311-319.

-100

-80

-60

-40

-20

0

20

40

60

80

100

Ch

ange

Fro

m B

ase

line

, %

Complete remission

Partial remission

Stable disease

Progressive disease

*

Pembrolizumab (MK-3475) in Patients With Relapsed Classical Hodgkin Lymphoma

Moskowitz C, et al ASH 2014

Nivolumab in Patients (Pts) With Relapsed or Refractory Classical Hodgkin Lymphoma

Clinical Outcomes From Extended Follow-up of a Phase 1 Study (CA209-039)

Stephen M. Ansell, MD, PhD,1 Philippe Armand, MD, PhD,2 John Timmerman, MD,3 Margaret A. Shipp, MD,2 M. Brigid Bradley Garelick, MD,4 Lili Zhu, MS,5

Alexander M. Lesokhin, MD6

1Mayo Clinic, Rochester, MN, USA; 2Dana-Farber Cancer Institute, Boston, MA, USA;

3Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA; 4Bristol-Myers Squibb, Wallingford, CT, USA; 5Bristol-Myers Squibb, Princeton, NJ, USA;

6Memorial Sloan Kettering Cancer Center, New York, NY, USA

ASH 2015

HL Baseline Characteristics

Characteristic cHL (n = 23)

Age, median (range) 35 (20–54)

Histology, n

Nodular sclerosing 22

Mixed cellularity 1

Prior autotransplant, n (%) 18 (78)

Prior brentuximab vedotin, n (%) 18 (78)

Number of prior therapies, median (range) 5 (2–15)

11

Select Treatment-Related Adverse Events

Adverse Event cHL (n = 23)

Any Grade, n (%)

Resolved, %

Gastrointestinal 4 (17)

Diarrhea 3 (13) 100

Colitis 1 (4) 100

Hepatic 2 (9)

ALT increased 1 (4) 100

AST increased 1 (4) 100

Blood alkaline phosphatase increased 1 (4) 0

Pulmonary 1 (4)

Pneumonitis 1 (4) 100

Skin 5 (22)

Rash 4 (17) 100

Pruritus 3 (13) 100

Pruritic rash 1 (4) 100

Skin hypopigmentation 1 (4) 0

Endocrine disorders

Hyperthyroidism 4 (17) 75

Hypersensitivity/infusion reaction 2 (9)

Bronchospasm 1 (4) 100

Infusion-related reaction 1 (4) 100

• All AEs were Grade 1/2 except colitis and pneumonitis which were Grade 3

• There were no Grade 4 or Grade 5 AEs and no treatment-related deaths

Patients (n = 23)

Pe

rce

nt

Ch

ange

in T

um

or

Bu

rde

n

CR (22%) PR (65%) SD (13%) 25

0

–25

–50

–75

–100

On treatment, ongoing response Off treatment without disease progressiona

Progressive disease, following response or stable disease

Best Response (PR + CR =87%)

aMaximum clinical benefit, transplant, or toxicity Ansell et al , ASH 2015

Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma

Durability of Response

–100

–50

0

50

100

Time Since First Treatment Date, Weeks

Pe

rce

nt

Ch

ange

Fro

m B

ase

line

in

Tar

get

Lesi

on

s/Tu

mo

r B

urd

en

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114

On treatment, ongoing response

Off treatment without progression

Progressive disease, following response or stable disease

First occurrence of new lesion Ansell et al ASH 2015

Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma

Duration of Response

Median DOR (95% CI): NA (15.5–NA)

Time, Months

Pro

bab

ility

of

Pat

ien

ts in

Res

po

nse

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 21 24 18

PFS

Ansell et al ASH 2015

Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma

Nivolumab for classical Hodgkin lymphoma after autologous stem-cell transplantation and brentuximab vedotin failure: A phase 2 study Anas Younes, MD1, Armando Santoro, MD2, Margaret Shipp, MD3, Pier Luigi Zinzani, MD4, John M Timmerman, MD5, Stephen Ansell, MD6, Philippe Armand, MD3, Michelle Fanale, MD7, Voravit Ratanatharathorn, MD8, John Kuruvilla, MD9, Jonathon Cohen, MD10, Graham Collins, MD11, Kerry J Savage, MD12, Marek Trneny, MD13, Kazunobu Kato, MD14, Benedetto Farsaci, MD14, Susan M Parker, PhD14, Scott Rodig, MD15, Margaretha GM Roemer, MS3, Azra H Ligon, PhD15, Andreas Engert, MD16

April 14, 2016: FDA Grants Nivolumab Priority Review in Hodgkin Lymphoma

Drug Dose/Schedule

N % ORR

% CR ORR in BV treated HL

1st Author

Pembrolizumab (humanized IgG4)

10 mg/kg IV Q 2wks

29 66% 21% 66% (n=19) Moskowitz C

Nivolumab (Fully human IgG4)

3 mg/kg IV Q 2wks

23 87% 17% 70% (n=16) Ansel SM

Results of PD1 Blocking Antibodies in Relapsed HL

Single Agent Activity of PD1 Blocking Antibodies

in Lymphoma

Drug

Antibody 1st Author (s) Hodgkin

Follicular

DLBCL

T-cell

Nivolumab

Fully human IgG4

Ansell Lesokin

Timmerman

87%

(20/23)

40%

(4/10)

36%

(4/11)

17%

(4/23)

Pembrolizumab

Humanized IgG4

Moskowitz Armand

65%

(20/31)

Pidilizumab

Humanized IgG1

Armand 51%

(18/38)

Overa

ll R

esponse R

ate

(%

)

HL

B-N

HL

T-N

HL

Melanom

a

NSCL

C

SCL

C

TNB

C

Ovary RC

C

Hig

h P

D-

L1

Low

PD

-

L1

Urothelia

l

MM

R

deficie

nt

MM

R p

roficie

nt

Colorecta

l

Gastr

ic

Esophageal

HN

SC

C

HC C

Single agent activity of PD-1/PD-L1 axis blockade in

relapsed/refractory Cancer

87 66 28 17 120 556 655 35 129 117 131

292 394 83

144

40 16 27 21 20 26 34 168 39 28 46 38 33 10 18 39 39 23 99 39 No of patients 0

10

20

30

40

50

60

70

80

90

100

MPDL3280A

Pembrolizumab

Nivolumab

Hodgkin

Lymphoma

B and T

NHL

Batlevi,..and Younes: Nat Rev Clinic Oncol 2016

0

25

50

75

100

CR PR

% R

esp

on

se r

ate

Updated from Betlevi and Younes, Hematology Am Soc Hematol Educ Program. 2013 Smith, K et al : Hodgkin Lymphoma, Hoffan Textbook of Hematology 2015 (In Press)

Single agent activity of novel agents in

relapsed cHL

- High response rates - Potentially combinable at full doses