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Update on Merkel cellcarcinoma(MCC)
Céleste Lebbé
Hospital Saint Louis
Paris, France
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COI
• Advisory boards, participation to clinical trials:
Merck Serono, Merck, BMS, Roche, Novartis, Pierre Fabre, Amgen
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Rationale for targeting PD1/anti-PD-L1 therapy in MCC
• PD-L1 is expressed by MCC tumor cells and by adjacent immune cell infiltrates1
• MCPyV-specific T cell dysfunction2
• CD8 T cell levels increase with larger tumor burden
• Exhausted phenotype (PD-1+, Tim-3+)
• MCPyV-negative tumors have higher mutation and neoantigen burden3
1. Lipson EJ, et al. Cancer Immunol Res. 2013;1(1):54-63; 2. Afanasiev O, et al. Clin Cancer Res.
2014;19(19):5351-60; 3. Goh G, et al. Oncotarget. 2016;7(3):3403-15. 4 4. Wong Cancer Res; 75(24)
December 15, 2015 3. Nghiem PT et al., N Engl J Med 2016
PD-L1+Tumor cells
PD-1+ lymphs
J.Taube, JHU
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Treatment of MCC stage I-III
immune check point inhibitors trial adjuvant/neoadjuvant
therapyDrug/trial Target n stage Median follow
up
outcome
Ipilimumab adjuvant
NCT02196961 ADMEC (DECOG)
Ph II , open, controlled vs
observation
CTLA-4 40 I-IV 22 mo Negative
(futility analysis
: no difference
in PFS
Nivolumab adjuvant
NCT02196961 ADMEC-0
(DECOG)
Ph II , open, controlled vs
observation
PD1
Avelumab adjuvant
NCT03271372
Ph III blinded, controlled vs placebo
PD-L1
Nivolumab neo-adjuvant
NCT02488759 phase II open single
arm
PD-1Adapted from Ugurel ASCO 2018
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Treatment of MCC stage I-III
immune check point inhibitors trial adjuvant/neoadjuvant therapy
Drug/trial Target n stage Median follow
up
outcome
Ipilimumab adjuvant
NCT02196961 ADMEC (DECOG)
Ph II , open, controlled vs
observation
CTLA-4 40 I-IV 22 mo Negative
(futility analysis
: no difference
in PFS
Nivolumab adjuvant
NCT02196961 ADMEC-0 (DECOG)
Ph II , open, controlled vs
observation
PD1 ac
cru
ing
I-IV pending pending
Avelumab adjuvant
NCT03271372
Ph III blinded, controlled vs placebo
PD-L1 ac
cru
ing
III pending pending
Nivolumab neo-adjuvant
NCT02488759 phase II open single
arm
PD-1
Adapted from Ugurel ASCO 2018Do not duplica
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Nivolumab as Neoadjuvant Therapy in Patients With Resectable Merkel Cell Carcinoma in CheckMate 358
Suzanne L. Topalian,1 Shailender Bhatia,2 Ragini R. Kudchadkar,3 Asim Amin,4
William H. Sharfman,1 Celeste Lebbé,5 Jean-Pierre Delord,6 Michi M. Shinohara,2
Shrujal S. Baxi,7 Christine H. Chung,8 Uwe M. Martens,9 Robert L. Ferris,10
Julie E. Stein,1 Ibrahima Soumaoro,11 Ricardo F. Zwirtes,11 Tian Chen,11
Christopher Harbison,11 Janis M. Taube,1 Paul Nghiem2
1Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center, Baltimore, MD, USA; 2University of Washington, Seattle Cancer Care Alliance, Seattle, WA, USA; 3Winship Cancer Institute of Emory University, Atlanta, GA, USA; 4Levine Cancer Institute, Atrium Healthcare, Charlotte, NC, USA; 5APHP University St. Louis Hospital, Paris, France; 6IUCT-Oncopole, Toulouse, France; 7Memorial Sloan Kettering Cancer Center, New York, NY, USA; 8H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 9SLK-Clinics, MOLIT Institute, Heilbronn, Germany; 10University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; 11Bristol-Myers Squibb, Princeton, NJ, USA
Suzanne L. Topalian
Abstract 9505
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CheckMate 358
Study Design
7
Treatment Follow-upScreening
• ≥12 weeks
• Optional SOC
adjuvant Rx
• Resume NIVO if
PD within 1 year
• PFS
• OS
Assessments
• Twenty-nine patients with resectable MCC were enrolled on a multiple cohort, phase 1/2 study of nivolumab (NIVO) in advanced virus-positive and virus-negative solid tumors (NCT02488759).
• Enrollment January 2016 - January 2018; data analysis March 2018.
• Resectable Rx-
naive MCC
• AJCC stage IIA–IV
• Age ≥18 years
• ECOG PS 0–1
• Archival or fresh
tumor biopsy
• NIVO 240 mg
Q2W × 2
doses (D1 &
D15)
• Surgery (D29)
• Radiographic
pre/post NIVO
• Pathologic
• Tumor MCPyV
(IHC)
• Tumor PD-L1
(IHC)Do not duplicate or d
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CheckMate 358
Baseline Characteristics of Treated Patients (N = 29)
Age, median (range),
years69.0 (22–88)
Male, n (%) 20 (69.0)
Region, n (%)
US/Canada
Europe
22 (75.9)
7 (24.1)
ECOG PS, n (%)
0
1
25 (86.2)
4 (13.8)
AJCC stage, n (%)
II
III
IV
8 (27.6)
20 (69.0)
1 (3.4)
8
MCPyV status,a n (%)
Evaluable
Positive
Negative
Unknown
21 (72.4)
15 (71.4)b
6 (28.6)b
8 (27.6)
Tumor PD-L1 expression, n (%)
Evaluable
≥1%
<1%
Unknown
20 (69.0)
6 (30.0)b
14 (70.0)b
9 (31.0)
aViral status investigator-assessed bPercent among evaluable patients Do not duplica
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CheckMate 358
Treatment and Follow-up
9
• Median follow-up after first dose of NIVO: 67.1 weeks (range: 2.3–106.3 weeks)
Surgery (n=27)
AE and/or
consent
withdrawn (n=2)
All treated patients (N = 29)NIVO 2 doses (n=26)
NIVO 1 dose (n=3)
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CheckMate 358
100
75
50
Radiographic Tumor Reduction
• 40% of 25 CT-evaluable patients had target lesion reductions >30%.
• Radiographic response and tumor MCPyV status were investigator-assessed.10
PD-L1 Expression MCPyV Status
Ch
an
ge
Fro
m B
as
eli
ne
in
Ta
rge
t L
es
ion
s (
%)
100
75
50
25
0
−25
−50
−75
−100
≥1%<1%Unknown
PositiveNegativeUnknown
25
0
−25
−50
−75
−100
Median change: −19.2%
(range: −100% to 73%)
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CheckMate 358
Pathologic Response
11
0
10
20
30
40
50
60
70
80
Site review (n=26) Central review (n=17)
pCR
MPR
Other
Re
sp
on
se (
%)
NA
pCR = pathologic complete response;
MPR = major pathologic response (≤10% of residual viable tumor); NA = not assessed.
65%
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CheckMate 358
Overall Survival
12
Postop interval,
months
OS rate, %
(95% CI)
6 100 (100, 100)
12 100 (100, 100)
18 100 (100, 100)
24 75.0 (31.5, 93.1)
27 26 25 20 19 16 012812131416
0 2 4 6 8 10 260
20
40
60
80
100
Ove
rall
Su
rviv
al (%
)
24222018161412
Months
No. at
risk
Median (95% CI):
NR (20.2, NR)
Data from 247 MCC patients,
AJCC stage III, U. Washington
MCC Repository
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Treatment of MCC stage I-III
immune check point inhibitors trial adjuvant/neoadjuvant therapyDrug/trial Target n stage Median follow
up
outcome
Ipilimumab adjuvant
NCT02196961 ADMEC (DECOG)
Ph II , open, controlled vs
observation
CTLA-4 40 I-IV 22 mo Negative
(futilioty
analysis : no
difference in
PFS
Nivolumab adjuvant
NCT02196961 ADMEC-0
(DECOG)
Ph II , open, controlled vs
observation
PD1 ac
cru
ing
I-IV pending pending
Avelumab adjuvant
NCT03271372
Ph III blinded, controlled vs placebo
PD-L1 ac
cru
ing
III pending pending
Nivolumab neo-adjuvant
NCT02488759 phase II open single
arm
PD-1 29 II-IV 15 mo ORR40%
Pathologic
response 65%
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Treatment of advanced MCC
• Until 2017 no standard of care :
– chemotherapy 1st line :ORR ≈around 57% median PFS 3 months
– Chemotherapy 2e line : ORR ≈ 23% with limited durability
(duration of response ≈4 mos; median PFS, 61 days; 6-mo
durable response rate, 6.7%)
1Lebbe C, et al. Eur J Cancer 2015;51(16):2396-2403; 2. NCCN
guidelines. MCC. 2016.v1;.3 Iyer JG, et al. J Clin Oncol
2014;32(Suppl):Abstract 9091 and unpublished dataDo not duplicate or d
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Treatment of advanced MCC
ImmunotherapyTrial N line ORR (CR) Median PFS Median OS Follow-up
Pembrolizumab 50 1st 56% (24%) 16.8 [95% CI 4.6,.]
mo
NR 14.9 mo
Avelumab 29 1st 62%(10%) NR NR 5.1 mo+
Nivolumab 25 1 and
>2nd
64% (32%) NR NR 11 mo
Avelumab 88 >2nd 33%
(11.4%)
2.7 [95% CI 1.4,6.9]
mo
12.6 [95%
CI 7.5,17.1]
mo
29.2 mo
All single arm phase II trials
Kaufman Lancet Oncol 2016; 17: 1374–85, AACR 2017, ASCO 2018Topalian AACR 2017 Angelo ASCO
2017, Nghiem ASCO 2018
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1 10 1000
10
20
30
40
50
60
Somatic Mutations/Mb
Ob
jecti
ve R
esp
on
se R
ate
(a
nti
-PD
-1 o
r an
ti-P
D-L
1)
Anal
Breast
Cervical
Colon - MMRd
Colon - MMRp
SCC Skin
Endom.H&N
HCC
Melanoma
Mesothel.
Noncolon MMRd
Uveal Mel
NSCLC - Nonsq.NSCLC - Squam.
Ovarian
Pancreatic
Prostate
RCC
SarcomaSCLC
Urothelial
MCC
Yarchoan et al NEJM 2017
Harms et al Cancer Res 2015
Nghiem, Bhatia et al NEJM 2016
VN-
MCC
VP-
MCC
Correlation between
Tumor Mutational
Burden and ORR
Yarchoan, et al, NEJM 2017
Paulson, et al, unpublished
Harms, et al, CA Res, 2015
Nghiem, et al, present study
Paul Nghiem, MD, PhD
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Response kinetics in patients with advanced MCC receiving pembrolizumab 1st line
Time, months
Median time to response
among responders:
2.8 months (range 1.5 - 9.7)
Ch
an
ge
in
Ta
rge
t L
esio
ns,
%
-50
50
0 6 12 18 24 30 36-100
100
0
+20%
0
-30%
Paul Nghiem, MD, PhD
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Response kinetics in patients with advanced MCC receiving
avelumab 2nd line
Presented by: Howard Kaufman
• Median time to
response:
6 wks (range, 6-18 wks)
• 22/28 (78.6%)
responses started by
first assessment at week
7
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Progression-free survival with pembrolizumab Ist line
Database Cutoff Date : 06Feb2018
1st line chemotherapy
historical data (N= 62)
Iyer, et al (Cancer
Medicine, 2016)
X
Pembrolizumab 1st line
(N= 50)
1st line chemotherapy
historical data (N=67)
Cowey, et al (Future
Oncology, 2017)
Pro
gre
ssio
n-F
ree
-Su
rviv
al (%
)
100
90
80
70
60
50
40
30
20
10
0
0 6 12 18 24 30 36
Months since treatment initiation
50 30 19 15 10 6 0N at risk
Median PFS (months)
Pembrolizumab 16.8 [95% CI 4.6,.]
Chemo (Iyer) 3.1 [0.4-33, range]
Chemo (Cowey) 4.6 [95% CI 3.0-7.0]
3%X
42%
25%X
60%
45%
6%X
52%
22%
4%X
48%
16%
4%X
48%
10%
Paul Nghiem, MD, PhD
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Progression-free survival with avelumab 2nd line
2
0Paul Nghiem, MD, PhD
* This figure is for illustrative purposes only and is not a direct head-to-head comparison; it incorporates multiple different data sets and is not from a randomized clinical trial
1. Cowey CL, et al. Future Oncol. 2017;13(19):1699-1710. 2. Becker J, et al. Oncotarget. 2017;8(45):79731-41. 3. Iyer JG, et al. Cancer Med. 2016;5(9):2294-301.
Time since treatment initiation, mo
PFS
, %
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36
Number at riskAvelumab 88 43 32 30 27 24 21 20 20 20 19 16 13 8 3 3 2 1 0
Avelumab
1-y PFS rate: 29% 2-y PFS rate: 26%
Cowey 2017
Becker 2017
Iyer 2016
Cowey 2017 20 11 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Becker 2017 34 30 6 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Iyer 2016 30 15 6 4 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0
and retrospective chemotherapy data1-3,*
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Overall survival with pembrolizumab 1st line
Database Cutoff Date : 06Feb2018
1st line chemotherapy
historical data (N= 62)
Iyer, et al (Cancer
Medicine, 2016)
X
Pembrolizumab 1st line
(N= 50)
1st line chemotherapy
historical data (N=67)
Cowey, et al (Future
Oncology, 2017)
Ove
rall
Su
rviv
al (%
)
100
90
80
70
60
50
40
30
20
10
0
0 6 12 18 24 30 36
Months since treatment initiation
43 31 21 16 11 0 0N at risk
Median OS (months)
Pembrolizumab NR [95% CI 26.0,.]
Chemo (Iyer) 9.5
Chemo (Cowey) 10.2 [95% CI 7.4-15.2]
70%X70.1%
86%
45%X 44%
72%
30%X28.7%
69%
20%X24.5%
69%
18%X
64%
10%X
64%
Paul Nghiem, MD, PhD
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Overall survival with avelumab 2 line
2
2Paul Nghiem, MD, PhD
and retrospective chemotherapy data1,2,*
Time since treatment initiation, mo
OS,
%
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36
Number at riskAvelumab 88 82 68 60 52 46 42 38 35 33 32 31 29 19 13 8 6 3 0
Avelumab
1-y OS rate: 50%
2-y OS rate: 36%
Cowey 2017
Becker 2017
Cowey 2017 20 17 12 5 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0Becker 2017 34 34 26 9 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0
OS, overall survival
* This figure is for illustrative purposes only and is not a direct head-to-head comparison; it incorporates multiple different data sets and is not from a randomized clinical trial
1. Cowey CL, et al. Future Oncol. 2017;13(19):1699-1710. 2. Becker J, et al. Oncotarget. 2017;8(45):79731-41.Do not duplicate or d
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Incidence of TRAEs (N=88) Avelumab 2 line
2
3Paul Nghiem, MD, PhD
* IRRs occurring ≤2 d after infusion and signs/symptoms occurring ≤1 d
after infusion that had resolved ≤2 d after onset were included in this
expanded definition of IRR, which was based on a prespecified list of
MedDRA Preferred Terms† Includes rash, rash maculopapular, and rash pruritic
AE (any grade in ≥10% or any grade ≥3) Any grade, n (%) Grade ≥3, n (%)
Any TRAE 67 (76.1) 10 (11.4)
Fatigue 22 (25.0) 0
IRR* 19 (21.6) 0
Rash† 14 (15.9) 0
Diarrhea 11 (12.5) 0
Nausea 11 (12.5) 0
Hypothyroidism 6 (6.8) 1 (1.1)
Blood CPK increased 5 (5.7) 3 (3.4)
ALT increased 4 (4.5) 1 (1.1)
Lymphopenia 3 (3.4) 2 (2.3)
GGT increased 2 (2.3) 1 (1.1)
Autoimmune disorder 1 (1.1) 1 (1.1)
Blood cholesterol increased 1 (1.1) 1 (1.1)
Ileus 1 (1.1) 1 (1.1)
Neutrophil count decreased 1 (1.1) 1 (1.1)
Transaminases increased 1 (1.1) 1 (1.1)
ALT, alanine aminotransferase; CPK, creatine phosphokinase; GGT, gamma-glutamyltransferase;
IRR, infusion-related reaction; TRAE, treatment-related adverse event
• 2-y study data were consistent with the established avelumab safety profile
– No new types of events were reported with prolonged treatment (range, 0.5–36.4 mo)
• No treatment-related deaths have been observed
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Incidence of irAEs (N=88) Avelumab 2 line
2
4Paul Nghiem, MD, PhD
AST, aspartate aminotransferase; irAE, immune-related adverse event
* Identified by a prespecified list of MedDRA Preferred Terms and followed by comprehensive medical review
AE Any grade, n (%) Grade ≥3, n (%)
Any irAE* 17 (19.3) 4 (4.5)
Hypothyroidism 5 (5.7) 1 (1.1)
Rash 5 (5.7) 0
Diarrhea 2 (2.3) 0
Erythema 2 (2.3) 0
ALT increased 1 (1.1) 1 (1.1)
AST increased 1 (1.1) 0
Autoimmune disorder 1 (1.1) 1 (1.1)
Hyperthyroidism 1 (1.1) 0
Pruritus 1 (1.1) 0
Rash maculopapular 1 (1.1) 0
Transaminases increased 1 (1.1) 1 (1.1)
Tubulointerstitial nephritis 1 (1.1) 0
• irAEs were similar to the established avelumab safety profile
• No new irAEs were reported with prolonged treatment
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In conclusion
• Anti PD1/PDL1 are major advances in the treatment of
advanced MCC
• Rapid and durable responses
• Excellent safety profile
Avelumab EMEA approval 2017
in advanced MCC
Reimbursement ?
1st line? 2 lineDo not duplicate or d
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Limitations of Current Data on anti-PD-1/PD-L1 Treatment in MCC
Presented By Selma Ugurel at 2018 ASCO Annual Meeting
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