Do not duplicate or distribute without permission from ...€¦ · Julie E. Stein,1 Ibrahima Soumaoro, 11Ricardo F. Zwirtes,11 Tian Chen, ... •Resume NIVO if PD within 1 year •PFS

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)


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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immune check point inhibitors trial adjuvant/neoadjuvant therapy

Drug/trial Target n stage Median follow

up

outcome

Ipilimumab adjuvant



observation


(futility analysis

: no difference

in PFS

Nivolumab adjuvant

NCT02196961 ADMEC-0 (DECOG)


observation

PD1 ac

cru

ing

I-IV pending pending

Avelumab adjuvant

NCT03271372


PD-L1 ac

cru

ing

III pending pending



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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immune check point inhibitors trial adjuvant/neoadjuvant therapyDrug/trial Target n stage Median follow

up

outcome

Ipilimumab adjuvant



observation


(futilioty

analysis : no

difference in

PFS

Nivolumab adjuvant

NCT02196961 ADMEC-0

(DECOG)


observation

PD1 ac

cru

ing

I-IV pending pending

Avelumab adjuvant

NCT03271372


PD-L1 ac

cru

ing

III pending pending



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%



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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)


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%



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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


historical data (N= 62)

Iyer, et al (Cancer

Medicine, 2016)

X

Pembrolizumab 1st line

(N= 50)


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%



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Overall survival with avelumab 2 line

2


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


* 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


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 ?

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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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Documents

Do not duplicate or distribute without permission from ...€¦ · Julie E. Stein,1 Ibrahima Soumaoro, 11Ricardo F. Zwirtes,11 Tian Chen, ... •Resume NIVO if PD within 1 year •PFS