Key Points

  • Avelumab showed single-agent activity in a subset of patients with relapsed or refractory extranodal natural killer/T-cell lymphoma.

  • The assessment of PD-L1 expression and immune subtyping could help to identify responders to avelumab.

Abstract

This study aimed to assess the efficacy and safety of treatment with avelumab, an anti–programmed death ligand 1 (PD-L1) antibody, in patients with relapsed or refractory extranodal natural killer/T-cell lymphoma (ENKTL). In this phase 2 trial, 21 patients with relapsed or refractory ENKTL were treated with 10 mg/kg of avelumab on days 1 and 15 of a 28-day cycle. The primary end point was the complete response (CR) rate based on the best response. Targeted sequencing and immunohistochemistry were performed using pretreatment tumor tissue, and blood samples were drawn before and after treatment for measurement of cytokines and soluble programmed cell death protein 1 (PD1), PD-L1, and PD-L2. The CR rate was 24% (5 of 21), and the overall response rate was 38% (8 of 21). Although nonresponders showed early progression, 5 responders currently continue to receive treatment and have maintained their response. Most treatment-related adverse events were grade 1 or 2; no grade 4 adverse events were observed. Treatment responses did not correlate with mutation profiles, tumor mutation burden, serum levels of cytokines, or soluble PD1/PD-L1 and PD-L2. However, the response to avelumab was significantly associated with the expression of PD-L1 by tumor tissue (P = .001). Therefore, all patients achieving CR showed high PD-L1 expression, and their tumor subtyping based on PD-L1 expression correlated with treatment response. In summary, avelumab showed single-agent activity in a subset of patients with relapsed or refractory ENKTL. The assessment of PD-L1 expression on tumor cells might be helpful for identifying responders to avelumab. This trial was registered at www.clinicaltrials.gov as #NCT03439501.

REFERENCES

1.
Kim
WS
,
Song
SY
,
Ahn
YC
, et al
.
CHOP followed by involved field radiation: is it optimal for localized nasal natural killer/T-cell lymphoma?
Ann Oncol
.
2001
;
12
(
3
):
349
-
352
.
2.
Au
WY
,
Weisenburger
DD
,
Intragumtornchai
T
, et al;
International Peripheral T-Cell Lymphoma Project
.
Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project
.
Blood
.
2009
;
113
(
17
):
3931
-
3937
.
3.
Fox
CP
,
Civallero
M
,
Ko
YH
, et al
.
Survival outcomes of patients with extranodal natural-killer T-cell lymphoma: a prospective cohort study from the international T-cell Project
.
Lancet Haematol
.
2020
;
7
(
4
):
e284
-
e294
.
4.
Yamaguchi
M
,
Kwong
YL
,
Kim
WS
, et al
.
Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: the NK-Cell Tumor Study Group study
.
J Clin Oncol
.
2011
;
29
(
33
):
4410
-
4416
.
5.
Kim
SJ
,
Kim
K
,
Kim
BS
, et al
.
Phase II trial of concurrent radiation and weekly cisplatin followed by VIPD chemotherapy in newly diagnosed, stage IE to IIE, nasal, extranodal NK/T-cell lymphoma: Consortium for Improving Survival of Lymphoma study
.
J Clin Oncol
.
2009
;
27
(
35
):
6027
-
6032
.
6.
Jaccard
A
,
Gachard
N
,
Marin
B
, et al;
GELA and GOELAMS Intergroup
.
Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study
.
Blood
.
2011
;
117
(
6
):
1834
-
1839
.
7.
Kim
SJ
,
Yoon
DH
,
Jaccard
A
, et al
.
A prognostic index for natural killer cell lymphoma after non-anthracycline-based treatment: a multicentre, retrospective analysis
.
Lancet Oncol
.
2016
;
17
(
3
):
389
-
400
.
8.
Jeong
SH
,
Song
HN
,
Park
JS
, et al
.
allogeneic stem cell transplantation for patients with natural killer/T cell lymphoid malignancy: a multicenter analysis comparing upfront and salvage transplantation
.
Biol Blood Marrow Transplant
.
2018
;
24
(
12
):
2471
-
2478
.
9.
Lim
SH
,
Hong
JY
,
Lim
ST
, et al
.
Beyond first-line non-anthracycline-based chemotherapy for extranodal NK/T-cell lymphoma: clinical outcome and current perspectives on salvage therapy for patients after first relapse and progression of disease
.
Ann Oncol
.
2017
;
28
(
9
):
2199
-
2205
.
10.
Chen
L
,
Flies
DB
.
Molecular mechanisms of T cell co-stimulation and co-inhibition [published correction in Nat Rev Immunol. 2013;13:542]
.
Nat Rev Immunol
.
2013
;
13
(
4
):
227
-
242
.
11.
Chen
BJ
,
Chapuy
B
,
Ouyang
J
, et al
.
PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies
.
Clin Cancer Res
.
2013
;
19
(
13
):
3462
-
3473
.
12.
Kwong
YL
,
Chan
TSY
,
Tan
D
, et al
.
PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase
.
Blood
.
2017
;
129
(
17
):
2437
-
2442
.
13.
Kim
SJ
,
Hyeon
J
,
Cho
I
,
Ko
YH
,
Kim
WS
.
Comparison of efficacy of pembrolizumab between epstein-barr virus‒positive and ‒negative relapsed or refractory non-Hodgkin lymphomas
.
Cancer Res Treat
.
2019
;
51
(
2
):
611
-
622
.
14.
Cho
J
,
Kim
SJ
,
Park
WY
, et al
.
Immune subtyping of extranodal NK/T-cell lymphoma: a new biomarker and an immune shift during disease progression
.
Mod Pathol
.
2020
;
33
(
4
):
603
-
615
.
15.
Gaiser
MR
,
Bongiorno
M
,
Brownell
I
.
PD-L1 inhibition with avelumab for metastatic Merkel cell carcinoma
.
Expert Rev Clin Pharmacol
.
2018
;
11
(
4
):
345
-
359
.
16.
Zhang
J
,
Medeiros
LJ
,
Young
KH
.
Cancer immunotherapy in diffuse large B-cell lymphoma
.
Front Oncol
.
2018
;
8
:
351
.
17.
Suh
C
,
Kim
WS
,
Kim
JS
,
Park
BB
.
Review of the clinical research conducted by the Consortium for Improving Survival of Lymphoma of the Korean Society of Hematology Lymphoma Working Party
.
Blood Res
.
2013
;
48
(
3
):
171
-
177
.
18.
Cheson
BD
,
Fisher
RI
,
Barrington
SF
, et al;
United Kingdom National Cancer Research Institute
.
Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification
.
J Clin Oncol
.
2014
;
32
(
27
):
3059
-
3068
.
19.
Nagato
T
,
Ohkuri
T
,
Ohara
K
, et al
.
Programmed death-ligand 1 and its soluble form are highly expressed in nasal natural killer/T-cell lymphoma: a potential rationale for immunotherapy
.
Cancer Immunol Immunother
.
2017
;
66
(
7
):
877
-
890
.
20.
Simon
R
.
Optimal two-stage designs for phase II clinical trials
.
Control Clin Trials
.
1989
;
10
(
1
):
1
-
10
.
21.
Schemper
M
,
Smith
TL
.
A note on quantifying follow-up in studies of failure time
.
Control Clin Trials
.
1996
;
17
(
4
):
343
-
346
.
22.
Takahara
M
,
Kis
LL
,
Nagy
N
, et al
.
Concomitant increase of LMP1 and CD25 (IL-2-receptor alpha) expression induced by IL-10 in the EBV-positive NK lines SNK6 and KAI3
.
Int J Cancer
.
2006
;
119
(
12
):
2775
-
2783
.
23.
Song
TL
,
Nairismägi
ML
,
Laurensia
Y
, et al
.
Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma
.
Blood
.
2018
;
132
(
11
):
1146
-
1158
.
24.
Zhu
X
,
Lang
J
.
Soluble PD-1 and PD-L1: predictive and prognostic significance in cancer
.
Oncotarget
.
2017
;
8
(
57
):
97671
-
97682
.
25.
Kinter
AL
,
Godbout
EJ
,
McNally
JP
, et al
.
The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands
.
J Immunol
.
2008
;
181
(
10
):
6738
-
6746
.
26.
Murakami
M
,
Hashida
Y
,
Imajoh
M
, et al
.
PCR array analysis of gene expression profiles in chronic active Epstein-Barr virus infection
.
Microbes Infect
.
2014
;
16
(
7
):
581
-
586
.
27.
Hu
X
,
Ivashkiv
LB
.
Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases
.
Immunity
.
2009
;
31
(
4
):
539
-
550
.
28.
de Mel
S
,
Hue
SS
,
Jeyasekharan
AD
,
Chng
WJ
,
Ng
SB
.
Molecular pathogenic pathways in extranodal NK/T cell lymphoma
.
J Hematol Oncol
.
2019
;
12
(
1
):
33
.
29.
Ratner
L
,
Waldmann
TA
,
Janakiram
M
,
Brammer
JE
.
Rapid progression of adult T-cell leukemia-lymphoma after PD-1 inhibitor therapy
.
N Engl J Med
.
2018
;
378
(
20
):
1947
-
1948
.
30.
Rauch
DA
,
Conlon
KC
,
Janakiram
M
, et al
.
Rapid progression of adult T-cell leukemia/lymphoma as tumor-infiltrating Tregs after PD-1 blockade
.
Blood
.
2019
;
134
(
17
):
1406
-
1414
.
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