Nivolumab in Hodgkin Lymphoma

Stephen M. Ansell, MD, PhD Professor of Medicine

Chair, Lymphoma Group

Mayo Clinic

Conflicts of Interest

• Research Funding from – – Bristol Myers Squibb

– Celldex Therapeutics

– Seattle Genetics

– Merck

– Affimed

A. B.

C. D.

1. Exhausted intratumoral T-cells are poorly functional

Yang et al. J Clin Invest 2012;122(4):1271-82.

2. Increased PD-L1 and PD-L2 expression in Hodgkin Lymphoma

Ansell et al. N Engl J Med. 2015;372:311-319 Roemer et al. ASH 2015 abstract #176

PD-L1 Negative PD-L1 Positive

Moskowitz et al. ASH 2014, abstract 290

• PD-1 ligands are overexpressed in inflammatory environments and attenuate the immune response via PD-1 on immune effector cells.1

• PD-L1 expressed on malignant cells and/or in the tumor microenvironment suppresses tumor infiltrating lymphocyte activity.2

MHC

PD-L1

PD-1

PD-1

T-cell receptor

PD-L2

T cell

NFκB Other

PI3K

IFNγ

IFNγR

Shp-2

Anti-PD-1

Tumor cell

1Francisco LM et al. J Exp Med 2009;206:3015-29. 2Andorsky DJ et al. Clin Cancer Res 2011;17:4232-44

Does Immune Checkpoint Blockade work? Blocking PD-1 using nivolumab

42 year old female – Hodgkin lymphoma 26 year old male – Hodgkin lymphoma

Does Blocking PD-1 with nivolumab work?

Courtesy of SM Ansell, Mayo Clinic

Hodgkin Lymphoma – Phase 1 data with nivolumab

PR (70%) CR (17%) SD (13%)

Ansell et al. N Engl J Med. 2015;372(4):311-9.

Nivolumab - 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, abstract 583

Retreatment With Nivolumab

Pretreatment 6 weeks posttreatment Progression when therapy stopped

6 weeks post-second course of therapy

Ansell et al. Haematologica 2016; 101(s5): P090

Nivolumab for classical Hodgkin's

lymphoma: a multicentre, multicohort, single-arm phase 2 trial (Cohort B).

Younes et al. Lancet Oncol. 2016 2016 Sep;17(9):1283-94.

80 patients – failed ASCT and BV

66% ORR

Duration of Response by Best Response Cohort B: Nivolumab After BV Post-ASCT

OR

CR

PR

0 3 6 9 12 15

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

ba

bil

ity o

f re

sp

on

se

Months

6 5 5 3 2 0

48 39 31 22 10 0

54 44 36 25 12 0

No. of patients at risk

CR

PR

OR

Database lock Oct 2015

Apr 2016

Median follow-up, mo (range)

9

(2–12)

15

(2–19)

ORR, n (%) 53 (66) 54 (68)

Median DOR, mo (95% CI)

8 (7, NR)

13 (9, NR)

Median DOCR, mo (95% CI)

5

(NR,

NR)

NR

(5, NR)

Median DOPR, mo (95% CI)

8

(7, NR)

13

(8, NR)

Timmerman et al. ASH 2016 abstract #1110

Best Overall Response Cohort A: Nivolumab in BV-Naïve Post-ASCT Patients

Cohort A (n = 63)

IRRC assessed

ORR, n (%)

95% CI

43 (68)

55, 79

CR, n (%) 14 (22)

PR, n (%) 29 (46)

SD, n (%) 13 (21)

PD, n (%) 7 (11)

Timmerman et al. ASH 2016 abstract #1110

Duration of Response by Best Response Cohort A: Nivolumab in BV-Naïve Post-ASCT Patients

PR

CR

OR

18 0 3 6 9 12 15

Months

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

ba

bil

ity o

f re

sp

on

se

0 14 13 12 9 3 1

0 29 24 16 10 3 0

0 43 37 28 19 6 1

CR

PR

OR

No. of patients at risk

Durable responses in both complete and partial responders

Database lock Jun 2016

Median duration

of

follow-up, mo

(range)

14

(1–20)

Median DOR, mo

(95% CI)

NR

(NR, NR)

Timmerman et al. ASH 2016 abstract #1110

Nivolumab and Ipilimumab Mechanism of Action

CTLA-4 blockade (ipilimumab) PD-1 blockade (nivolumab)

APC–T-cell

interaction

Activation

(cytokine secretion,

lysis, proliferation,

migration to tumor)

Tumor

microenvironment

Dendritic cell T cell Tumor cell

MHC TCR TCR

PD-L1

PD-L2

MHC

PD-1

PD-1

B7

B7 CD28

CTLA-4

anti-CTLA-4

+++

---

+++ T

cell

+++

---

---

anti-PD-1

CTLA-4 is expressed on T cells and

inhibits T-cell activation1

PD-1 expression on tumor-infiltrating lymphocytes

is associated

with decreased cytokine production and effector

function Ipilimumab disrupts the CTLA-4

pathway,

thus inducing anti-tumor immunity1

Nivolumab disrupts PD-1 pathway

signaling and

restores anti-tumor T-cell function2–4

Ansell et al. ASH 2016 abstract #183

Nivolumab + Ipilimumab – Hodgkin Lymphoma

15

100

0 12 24 36 48 60 72 84 96

−50

−75

100

−25

0

25

50

75

Time since first treatment date (weeks)

Change in tumor burden, HL

Responders (n = 23)

Non-responders (n = 8)

Ch

ange

fro

m b

ase

line

in t

arge

t le

sio

ns

tum

or

bu

rde

n (

%)

aResponse was not reported for 2 (6%) patients with HL bTransplant-naïve patients are a subset of the total number of patients with HL; a total of 13 transplant-naïve patients were chemoresistant and 3 were

ineligible for the procedure NR = not reached; + = censored value

HL (N = 31)

ORR, n (%)a 23 (74)

Complete response 6 (19)

Partial response 17 (55)

Stable disease 3 (10)

Relapsed or progressive disease

3 (10)

Median duration of OR, months (range)

NR (0.0+, 13.4+)

Transplant naïveb (n = 18)

ORR, n (%) 12 (67)

Ansell et al. ASH 2016 abstract #183

Change in SPD from baseline

Nivolumab + Brentuximab vedotin

5-Point Score n (%) Total

CmR 1 8 (28) 18 (62)

2 6 (21)

3 3 (10)

Missing 1 (3)

PmR 4 6 (21) 8 (28)

5 2 (7)

NmR 5 1 (3) 3 (10)

PmD 5 2 (7) 2 (7)

a Cycle 2 SPD reported for 1 patient

a

Change in max SUV from baseline

Deauville score (N=29)

ORR (26/29) = 90%

95% CI: 72.6, 97.8

CmR (18/29) = 62%

95% CI: 42.3, 79.3

Herrera et al. ASH 2016 abstract #1105

BV and Nivolumab is Highly Active

Evaluable Patients (n = 12) ORR

ORR 12/12 (100%)

CR 8/12 (66%)

PR 4/12 (34%)

2 of 2 patients with prior BV evaluable= CR

Diefenbach et al. ASH 2016 abstract #1106

Conclusions

• Optimizing immune function is the new therapeutic “frontier” in Hodgkin lymphoma

• Immune checkpoint inhibitors such as nivolumab hold real promise in Hodgkin lymphoma.

• Incorporating promising immunologic agents such as nivolumab into combination approaches will be the next clinical challenge.