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.