Download New Insights on Merkel Cell Carcinoma

New Insights on Merkel Cell Carcinoma
Emory Melanoma / Skin Cancer Symposium
Saturday, Feb 27, 2016; Emory Conference Center
35 min talk + 10 min questions
Paul Nghiem, MD, PhD
Professor & Head, UW Dermatology/Medicine & Pathology
George F. Odland Endowed Chair in Dermatology
Clinic:
Seattle Cancer Care Alliance
Fred Hutchinson Cancer
Research Center
Research:
Univ of WA
Lake Union Campus
UV DNA Damage/Cell cycle
Merkel cell carcinoma
Overview
• Pathogenesis & the Merkel polyomavirus
– Risk factors
– Viral oncogenesis
Overview
• Pathogenesis & the Merkel polyomavirus
– Risk factors
– Viral oncogenesis
• Tumor / viral immunity
– Humoral and cellular immunity
Overview
• Pathogenesis & the Merkel polyomavirus
– Risk factors
– Viral oncogenesis
• Tumor / viral immunity
– Humoral and cellular immunity
• Therapy
– Current & future immune-based therapies
Why is MCC important?
• More lethal than melanoma
– ~40% mortality (~15% for melanoma)
Why is MCC important?
• More lethal than melanoma
– ~40% mortality (~15% for melanoma)
• Reported incidence increasing
– Quadrupled since 1986
– Currently ~2,000 new cases/yr in USA
Why is MCC important?
• More lethal than melanoma
– ~40% mortality (~15% for melanoma)
• Reported incidence increasing
– Quadrupled since 1986
– Currently ~2,000 new cases/yr in USA
• Optimal therapy is unique among skin CAs
– Proper tx is relatively benign, effective
What is a Merkel Cell?
Friedrich Merkel, 1875
Mechanoreceptors in basal
layer of epidermis?
What is a Merkel Cell?
Friedrich Merkel, 1875
Mechanoreceptors in basal
layer of epidermis?
copyright: Paul Nghiem & Paul Quade, www.EchoMedicalMedia.com
What is a Merkel Cell?
Friedrich Merkel, 1875
Mechanoreceptors in basal
layer of epidermis?
• Essential for light touch
Maricich, et al, Science, 2009
• Derived from epidermis (not neural crest)
Van Keymeulen, et al, J Cell Biol, 2009
Morrison, et al, Dev Biol, 2009
copyright: Paul Nghiem & Paul Quade, www.EchoMedicalMedia.com
Merkel cell CA: clinical appearance
(easy to miss)
Clinician’s Impression at the Time of
Bx in 106 MCC pts
 BENIGN
56%
• Cyst/Acneiform lesion
• Lipoma
• Dermatofibroma
 MALIGNANT
•
•
•
•
32%
6%
5%
36%
Non-melanoma skin CA
Lymphoma
Metastatic Carcinoma
MCC
 Indeterminate
• "Nodule"
19%
6%
2%
1%
8%
Heath, JAAD, 2008
"Perinuclear dot pattern"
of cytokeratin-20
MCC Reported Incidence is Rising
1500 new
cases/yr
in USA
in 2005
(NCDB data)
Lemos & Nghiem
JID 2007
Many cases
‘missed’
CK20
antibody
1600 new
cases/yr
in USA
in 2006
(SEER data)
Albores-Saavedra
J Cut. Path 2009
Increase in Risk Factors
• Prolonged sun exposure
– 98% Caucasian; Latitude associated; sunexposed skin
• Immune suppression (HIV, SOTR, CLL)
• Age > 50
Paulson & Nghiem,
unpublished
Clinical appearance
(easy to miss)
Clinical Presentation
Generic description: "Firm papule / nodule, often
red or purple"
We wanted more concrete data…
A: Asymptomatic
E: Expanding rapidly
I: Immune Compromised
O: Older than 50
U: UV-exposed, fair skin
89% of MCCs: ≥ 3 features
(sensitive, NOT specific!)
A: Asymptomatic
E: Expanding rapidly
I: Immune Compromised
O: Older than 50
U: UV-exposed, fair skin
89% of MCCs: ≥ 3 features
(sensitive, NOT specific!)
If red, rapidly growing,
non-tender nodule on
sun-exposed skin of
pt over 60:
? biopsy
MCC Presenting Site
In 138 patients
Heath, JAAD, 2008
MCC Presenting Site
In 138 patients
 Skin: Primary MCC (n=
123)
 Nodal Presentation (n=15)
(no primary)
thought experiment...
Assuming there is palpable
nodal disease...
better to have a primary or not?
Heath, JAAD, 2008
How does one stage an MCC patient?
2010 AJCC
Staging System
Replaced 5
conflicting staging
systems...
How does one stage an MCC patient?
2010 AJCC
Staging System
Replaced 5
conflicting staging
systems...
Bianca Lemos, MD
AJCC MCC Staging System (2009)
– Stage I:
• Ia:
• Ib:
– Stage II:
• IIa:
• IIb:
• IIc:
– Stage III:
• IIIa:
• IIIb:
– Stage IV:
Local, ≤ 2cm
Nodes negative by path exam
Nodes not clinically detectable
Local, > 2cm
Nodes negative by path exam
Nodes not clinically detectable
Primary tumor invading bone/muscle/fascia/cartilage
Regional Nodal Disease
Nodes pos by path exam and not clinically detectable
Nodes clinically detectable; in-transit metastasis
Distant Metastatic Disease
How predictive was the
7th Edition system?
Analysis with an
independent
(subsequent) cohort
Can we make it better?
published 2009
Local disease (n=213; MCC-specific survival)
IA (n=112)
MCC-specific survival (%)
100
IB (n=48)
75
IIA (n=32)
50
IIB (n=21)
25
0
0
1
2
3
4
5
6
7
8
Time from diagnosis (years)
9
10
11
Nodal and distant disease (n=215; MCC-specific survival)
MCC-specific survival (%)
100
75
IIIA (n=78)
50
IIIB (n=111)
25
IV (n=26)
0
0
1
2
3
4
5
6
Time from diagnosis (years)
7
8
Nodal and distant disease (n=215; MCC-specific survival)
MCC-specific survival (%)
100
75
IIIA (n=78)
50
IIIB (n=111)
known or unknown primary?
25
IV (n=26)
0
0
1
2
3
4
5
6
Time from diagnosis (years)
7
8
IIIB Patients by Primary Lesion Status (n=111; MCC-specific survival)
MCC-specific survival (%)
100
IIIB Unknown Primary Lesion
(n=62)
75
50
IIIB Known Primary Lesion
(n=49)
25
0
Univariate analysis by competing risks regression:
HR 0.31; p<0.01; 95% CI 0.16 – 0.60
Multivariate analysis by competing risks regression:
(controlling for age at dx, sex, and immune suppression)
HR 0.43; p=0.04; 95% CI 0.20 – 0.94
0
1
2
3
4
5
6
Time from diagnosis (years)
7
8
“Unknown primary” lesion 
better survival across independent cohorts
80
Unknown primary
(76%)
Unknown primary
(65%)
70
% Survival
60
Unknown primary
(57%)
50
40
Known primary
(36%)
30
Known primary
(28%)
Known primary
(33%)
20
10
0
2 year overall survival
(Tarantola et al; n=50)
5 year MCC-specific survival
(Seattle; n=104)
5 year MCC-specific survival
(Busam et al; n=115)
Among Stage IIIB Patients the Presence or Absence
of a Primary Matters
Known primaries
Poorly functioning immune
cells cannot eliminate the
primary tumor
Poorly
functioning
immune cells
Primary tumor
Positive
Positive
lymph node
lymph node
Among Stage IIIB Patients the Presence or Absence
of a Primary Matters
Known primaries
Poorly
functioning
immune cells
Poorly functioning immune
cells cannot eliminate the
primary tumor
Primary tumor
Positive
Positive
lymph node
lymph node
Unknown primaries
Functional killer T cells
secrete effector cytokines
or molecules to destroyed
the primary tumors.
These patients do
much better!!
Highly
functioning
immune cells
Primary
Tumor
gone
Positive
lymph node
% with Unknown Primary
The immune system likely mediates
regression of primary tumors
100%
80%
66%
60%
40%
p < 0.0001
(Fisher’s exact)
20%
0%!!
0%
Immune Suppressed
IIIb cases:
(n = 11 )
Not Immune
Suppressed
(n = 92)
% with Unknown Primary
The immune system likely mediates
regression of primary tumors
100%
80%
66%
60%
40%
p < 0.0001
(Fisher’s exact)
20%
0%!!
0%
Immune Suppressed
IIIb cases:
(n = 11 )
Not Immune
Suppressed
(n = 92)
Bottom line on initial therapy...
Surgery & radiation:
>95% of patients ‘free of
detectable disease’...
but
MCC recurs in nearly half
Bottom line on initial therapy...
Surgery & radiation:
>95% of patients ‘free of
detectable disease’...
but
MCC recurs in nearly half
Metastatic MCC  chemotherapy (‘small cell regimen’)
- shrinks MCC in most cases
- over half progress by 3 mos...
Chemotherapy & metastatic MCC
PFS after 1st line chemo
Iyer, et al, in preparation
53% of patients ‘respond’...
Half progress by 93 days after starting chemo
(Quite toxic therapy...unsatisfactory results...need options!)
Given links to immune suppression, UV...
how does MCC arise?
A new human virus that causes cancer (in 2008)
Moore/Chang
(KSHV)
Present in 8/10
MCCs
Schematic of
MCPyV genome
Validated in
dozens of studies
Virus (MCPyV) is
extremely
common!
Virus on us all yet only
1 in 3000 will get MCC…how?
Adapted from Bhatia/Afanasiev, et al, Curr Oncol Rep, 2011
Virus on us all yet only
1 in 3000 will get MCC…how?
What are mutation patterns in virus-pos vs virus-neg tumors?
Adapted from Bhatia/Afanasiev, et al, Curr Oncol Rep, 2011
3 studies
in late
2015...
genetic
mutations
in viruspos &
virus-neg
MCC...
3 studies
in late
2015...
genetic
mutations
in viruspos &
virus-neg
MCC...
3 studies
in late
2015...
genetic
mutations
in viruspos &
virus-neg
MCC...
“MCC-High”
“MCC-Low”
49 MCCs...
Goh, et al. 2015.
Oncotarget
“MCC-High”
“MCC-Low”
49 MCCs...
Goh, et al. 2015.
Oncotarget
“MCC-High”
“MCC-Low”
49 MCCs...
Goh, et al. 2015.
Oncotarget
Viral status
greatly affects
mutation
frequency
Goh, et al. 2015.
Oncotarget
Viral status
greatly affects
mutation
frequency
100-fold
difference
between
MCC-Lo &
MCC-Hi
Goh, et al. 2015.
Oncotarget
Virus-negative MCCs  ‘neoantigens’
Goh, et al. 2015. Oncotarget
PDL1-pos (‘immune visible’) tumors
have more mutations
Wong, et al. 2015.
Cancer Res.
PDL1-pos (‘immune visible’) tumors
have more mutations
Virus-neg tumors
may be
immunogenic...
We will return to
this!
Wong, et al. 2015.
Cancer Res.
Humoral immunity: a powerful biomarker
Kelly Paulson, MD, PhD Denise Galloway, PhD Jody Carter, PhD
Mark Wener, MD Will Simonson,MD, PhD
Antibodies to T-Ag (not capsid) fall after tx
Antibodies to T-Ag (not capsid) fall after tx
Capsid antibodies:
>60% of us have them!
T-Ag antibodies:
<1% of 530 population controls
~50% of newly diagnosed MCCs
Antibodies to T-Ag (not capsid) fall after tx
Capsid antibodies:
>60% of us have them!
T-Ag antibodies:
<1% of 530 population controls
~50% of newly diagnosed MCCs
Antibodies to T antigen reflect disease burden
“This could be clinically useful...”
Paulson, Carter, et al, CA Research, 2010
Detecting
MCC
recurrences
using
serology
PPV = 66%
NPV = 97%
Paulson, et al,
submitted
MCC Specific Survival by Oncoprotein Ab Titer
100
MCC specific Survival (%)
Oncoprotein Ab Positive (n = 114)
75
Oncoprotein Ab Negative (n = 105)
50
25
0
Competing-risks Regression
Controlling for: Age, Stage, and Sex
p = 0.037
Paulson, et al,
submitted
Hazard Ratio = 0.46
95% CI = 0.224 – 0.955
0
1
2
3
Time after Diagnosis (Days)
4
5
59
MCC Specific Survival by Oncoprotein Ab Titer
100
MCC specific Survival (%)
Oncoprotein Ab Positive (n = 114)
75
Oncoprotein Ab Negative (n = 105)
50
25
0
Sero-neg patients:
follow with scans
Competing-risks Regression
Controlling for: Age, Stage, and Sex
p = 0.037
Paulson, et al,
submitted
Hazard Ratio = 0.46
95% CI = 0.224 – 0.955
0
1
2
3
Time after Diagnosis (Days)
4
5
60
Assay ‘live’ (available) as of January 2014...
Run by UW Lab Medicine (50 ul serum)
Cost $200 (very modest vs CT scan)
Helps both virus-pos and virus-neg patients...
Antibodies are useful for tracking MCC...
What are T cells good for?
Antibodies are useful for tracking MCC...
What are T cells good for?
Survival!!
If CD8+ T cells are moderate or high within tumor,
survival is 100% (n=146 patients + n=150 patients)
How do CD8 T
cells recognize
their target?
killer CD8 T cell
MCC cell
expressing MCPyV protein
Finding MCPyV-specific T cells
David Koelle
MCPyV-Antigen source
MCPyV
proteome
map
Jayasri Iyer
x
x
x
x
Finding MCPyV-specific T cells
David Koelle
MCPyV-Antigen source
Persistently expressed in MCCs
MCPyV
proteome
map
x
x
x
x
95 peptides: covering 389 AA
Jayasri Iyer
Finding MCPyV-specific T cells
David Koelle
T cell source
Blood
MCPyV-Antigen source
“TIL”
Persistently expressed in MCCs
MCPyV
proteome
map
x
x
x
x
95 peptides: covering 389 AA
Jayasri Iyer
Finding MCPyV-specific T cells
David Koelle
T cell source
Blood
MCPyV-Antigen source
“TIL”
Persistently expressed in MCCs
MCPyV
proteome
map
x
x
x
x
95 peptides: covering 389 AA
Antigen presenting cells
Assay:
T cells produce IFN-γ if recognize peptide
Jayasri Iyer
First 26 MCPyV epitopes identified from
blood and MCC tumors
MCPyV
MCPyV
proteome
map
x
x
x
x
Persistently expressed in MCCs
95 peptides: covering 389 AA
epitopes
discovered
‘Tools’ for MVPyV-specific T cell study
Iyer, et al, Clin Ca Res, 2011
Iyer/Afanasiev et al, CCR, 2011; Afanasiev et al, submitted
% subjects with tet+ T cells
‘Tools’ for MVPyV-specific T cell study
Iyer, et al, Clin Ca Res, 2011
Iyer/Afanasiev et al, CCR, 2011; Afanasiev et al, submitted
0%
Control subjects MCC patients
(n=10)
(n=9)
Why do virus-positive tumors grow if
patients have virus-specific T cells??
Virus infected cell
CD8
T cell
Jim Dowdalls/Photo Researchers, Inc
Are virus-specific T cells dysfunctional?
T cell surface receptor phenotype
reveals functional profile
Activated cells, characterized by expression of:
Acute antigen
exposure
Adapted from Afanasiev, Nghiem, MCC book chapter
CD28
Co-stimulatory receptor (ligand: B7); required for T cell activation
CD69
Earliest inducible cell surface glycoprotein during T cell activation;
plays a role in T cell proliferation
CD137 (41BB)
Member of TNF-receptor family; induced by T cell activation;
important in T cell proliferation, cytokine secretion and cytotoxicity
CD38
Cyclic ADP ribose hydrolase; marker of T cell activation; functions in
cell adhesion, signal transduction and calcium signaling
HLA-DR
MHC class-II surface receptor that is upregulated with T cell activation
T cell surface receptor phenotype
reveals functional profile
Activated cells, characterized by expression of:
Acute antigen
exposure
Adapted from Afanasiev, Nghiem, MCC book chapter
CD28
Co-stimulatory receptor (ligand: B7); required for T cell activation
CD69
Earliest inducible cell surface glycoprotein during T cell activation;
plays a role in T cell proliferation
CD137 (41BB)
Member of TNF-receptor family; induced by T cell activation;
important in T cell proliferation, cytokine secretion and cytotoxicity
CD38
Cyclic ADP ribose hydrolase; marker of T cell activation; functions in
cell adhesion, signal transduction and calcium signaling
HLA-DR
MHC class-II surface receptor that is upregulated with T cell activation
T cell surface receptor phenotype
reveals functional profile
Activated cells, characterized by expression of:
Acute antigen
exposure
CD28
Co-stimulatory receptor (ligand: B7); required for T cell activation
CD69
Earliest inducible cell surface glycoprotein during T cell activation;
plays a role in T cell proliferation
CD137 (41BB)
Member of TNF-receptor family; induced by T cell activation;
important in T cell proliferation, cytokine secretion and cytotoxicity
CD38
Cyclic ADP ribose hydrolase; marker of T cell activation; functions in
cell adhesion, signal transduction and calcium signaling
HLA-DR
MHC class-II surface receptor that is upregulated with T cell activation
T
cell
Exhausted T cells, characterized by prolonged expression of:
PD-1
Programmed death-1; inhibitory T cell receptor (ligands: PDL1 (B7-H1), PD-L2 (B7-DC)); reduces T cell proliferation and
effector functions
CTLA-4
(CD152)
Cytotoxic T-Lymphocyte Antigen 4; inhibitory receptor (ligand:
B7); effectively competes for ligands with CD28 (which has
lower avidity than CTLA-4), preventing T cell activation
Tim-3
T cell Immunoglobulin Mucin-3; inhibitory T cell receptor
(ligand: galactin-9); leads to decrease in effector T cell
function
Chronic antigen
exposure
Adapted from Afanasiev, Nghiem, MCC book chapter
T cell surface receptor phenotype
reveals functional profile
Activated cells, characterized by expression of:
Acute antigen
exposure
T
cell
CD28
Co-stimulatory receptor (ligand: B7); required for T cell activation
CD69
Earliest inducible cell surface glycoprotein during T cell activation;
plays a role in T cell proliferation
CD137 (41BB)
Member of TNF-receptor family; induced by T cell activation;
important in T cell proliferation, cytokine secretion and cytotoxicity
CD38
Cyclic ADP ribose hydrolase; marker of T cell activation; functions in
cell adhesion, signal transduction and calcium signaling
HLA-DR
MHC class-II surface receptor that is upregulated with T cell activation
Recently activated T cells, characterized by expression of:
Combination of activation and inhibition markers via appropriate
immunoregulatory feedback mechanisms
Exhausted T cells, characterized by prolonged expression of:
PD-1
Programmed death-1; inhibitory T cell receptor (ligands: PDL1 (B7-H1), PD-L2 (B7-DC)); reduces T cell proliferation and
effector functions
CTLA-4
(CD152)
Cytotoxic T-Lymphocyte Antigen 4; inhibitory receptor (ligand:
B7); effectively competes for ligands with CD28 (which has
lower avidity than CTLA-4), preventing T cell activation
Tim-3
T cell Immunoglobulin Mucin-3; inhibitory T cell receptor
(ligand: galactin-9); leads to decrease in effector T cell
function
Chronic antigen
exposure
Adapted from Afanasiev, Nghiem, MCC book chapter
T cell surface receptor phenotype
reveals functional profile
Activated cells, characterized by expression of:
Acute antigen
exposure
T
cell
CD28
Co-stimulatory receptor (ligand: B7); required for T cell activation
CD69
Earliest inducible cell surface glycoprotein during T cell activation;
plays a role in T cell proliferation
CD137 (41BB)
Member of TNF-receptor family; induced by T cell activation;
important in T cell proliferation, cytokine secretion and cytotoxicity
CD38
Cyclic ADP ribose hydrolase; marker of T cell activation; functions in
cell adhesion, signal transduction and calcium signaling
HLA-DR
MHC class-II surface receptor that is upregulated with T cell activation
Recently activated T cells, characterized by expression of:
Combination of activation and inhibition markers via appropriate
immunoregulatory feedback mechanisms
Exhausted T cells, characterized by prolonged expression of:
PD-1
Programmed death-1; inhibitory T cell receptor (ligands: PDL1 (B7-H1), PD-L2 (B7-DC)); reduces T cell proliferation and
effector functions
CTLA-4
(CD152)
Cytotoxic T-Lymphocyte Antigen 4; inhibitory receptor (ligand:
B7); effectively competes for ligands with CD28 (which has
lower avidity than CTLA-4), preventing T cell activation
Tim-3
T cell Immunoglobulin Mucin-3; inhibitory T cell receptor
(ligand: galactin-9); leads to decrease in effector T cell
function
Chronic antigen
exposure
Adapted from Afanasiev, Nghiem, MCC book chapter
Are the ‘brakes’ ON in MCC-specific T cells?
(compared to other viral responses)
PD-1
Tim-3
Examined ‘exhausted’ PD1+/Tim-3+ cells
Are the ‘brakes’ ON in MCC-specific T cells?
(compared to other viral responses)
Tim-3
Examined ‘exhausted’ PD1+/Tim-3+ cells
PD1+Tim3+ (%positive cells)
PD-1
(Data from 4-7 MCC patients)
Afanasiev et al, Clin Ca Research 2013
Are the ‘brakes’ ON in MCC-specific T cells?
(compared to other viral responses)
Tim-3
Examined ‘exhausted’ PD1+/Tim-3+ cells
PD1+Tim3+ (%positive cells)
PD-1
(Data from 4-7 MCC patients)
Afanasiev et al, Clin Ca Research 2013
Are the ‘brakes’ ON in MCC-specific T cells?
(compared to other viral responses)
Tim-3
Examined ‘exhausted’ PD1+/Tim-3+ cells
PD1+Tim3+ (%positive cells)
PD-1
(Data from 4-7 MCC patients)
Afanasiev et al, Clin Ca Research 2013
PD-1 & PDL-1 trials
are beginning...
MCC Clinical Trials Overview
Clinical Trial
Indication
Target
Patient
characteristic
Status
IL-12
(Oncosec)
Local
Injection of IL12 gene
Injectable lesion
Complete
GLA
(Immune Design)
Local
Toll-like
receptor
agonist
Injectable lesion
Complete
PD-1
(Merck)
Metastatic
1st line
PD-1 on T cell
No prior systemic
therapy
Recruiting
PD-L1
(EMD Serono)
Metastatic
2nd line
PD-L1 on
Tumor
Progressed after
receiving chemo
Recruiting
T cell +
PD-L1
(EMD + Pfizer)
Metastatic
Infuse Virus
specific T cells
Virus + MCC
?
4-1BB
(Pfizer)
Metastatic
CD-137 on T
cell
+/- chemo or
immune therapy
closed
PDL1 (2nd line) MCC trial:
55 yo woman; primary lesion on chest x 1 year (had metastases at dx)
Failed chemotherapy (Carbo + etoposide)
Large liver mets: 2 x 11 cm
MCPyV-negative
After 4 weeks (2 doses) of PDL1
Activity of PD-1 blockade with pembrolizumab as
first systemic therapy in patients with advanced
Merkel cell carcinoma
European Cancer Congress / ESMO Vienna, Austria
Sunday, September 27th, 2015
Paul Nghiem1,2, Shailender Bhatia1,2, Adil Daud3, Philip Friedlander4, Harriet
Kluger5, Holbrook Kohrt6, Ragini Kudchadkar7, Evan Lipson8, Lisa Lundgren2,
Kim Margolin6, Sunil Reddy6, Erica Shantha1, William Sharfman8, Elad
Sharon9, John Thompson1,2, Suzanne Topalian8, Mac Cheever1,2
1) University of Washington 2) Fred Hutchinson Cancer Research Center 3) Univ of California
San Francisco 4) Mt Sinai Medical Center 5) Yale University
6) Stanford University 7) Emory University 8) Johns Hopkins University
9) NCI-Cancer Therapy Evaluation Program
Metastatic MCC  platin + etoposide
Initial responses common (53%)  poor durability:
>50% of patients progress by 3 months
>90% of patients progress by 10 months
Iyer, et al, J Clin Oncol 32:5s, 2014 (suppl; abstr 9091)
Median survival = 9.6 months
n = 179
Miller, et al, Curr Treat Options Onc, 2013
85
Trial design: pembrolizumab in MCC
• Strong rationale for anti-PD1 in MCC
– tumor-specific T cells are PD1+, Tim3+
– PDL1 frequent in MCC tumors
• Multi-center (7 sites), single arm, open label,
Phase II trial of first systemic therapy
• Primary endpoint: response rate (RECIST 1.1)
86
Interim results
9/18/15
• 24 patients had received at least one dose of
pembrolizumab
• 14 patients had at least one post-treatment scan
Response in MCC target lesions
% Change in target lesions
at 1st scan
(At first scan, RECIST 1.1 as of 9/18/15 data export)
Progression based
on new lesions
n = 14
* *
Progressive disease:
target lesion f/u data
initially not available =
Partial Response: 1st
scan data initially not
available, at 2nd scan
was -70% =
*Complete responses (RECIST 1.1) occurred in lymph nodes that regressed to < 10 mm.
Activity of MK-3475 in patients with advanced MCC
(RECIST 1.1 data as of 9/18/15)
n = 14 includes 2 patients who have PD based only on new
lesions (no f/u data on target lesions currently)
Key:
Progressive disease:
target lesion f/u data
not available =
Progressive Disease =
Stable Disease =
Partial Response =
Complete Response =
*Complete responses (RECIST 1.1) occurred in lymph nodes that regressed to < 10 mm.
Response to anti-PD1
Baseline:
- Bulky tumors in pelvis: bladder compression
- Subcutaneous metastases on R leg
Baseline
Response to anti-PD1
Baseline:
- Bulky tumors in pelvis: bladder compression
- Subcutaneous metastases on R leg
Baseline
3 wks after pembrolizumab
After 1 dose:
- SQ lesion barely palpable at 3 weeks; biopsy showed. . .
What happened in the SQ tumor?
What happened in the SQ tumor?
What happened in the SQ tumor?
Pathologic CR after single dose of pembrolizumab
Partial response on pembrolizumab
Bulky pelvic disease:
Baseline
1st scan (13 wks) after PD1
Bladder symptoms resolved
Continues on trial (week 34)
No side effects
Tumors continue to shrink
Partial response on pembrolizumab
Bulky pelvic disease:
Baseline
1st scan (13 wks) after PD1
Bladder symptoms resolved
Continues on trial (week 34)
No side effects
Tumors continue to shrink
Conclusions: Pembrolizumab in MCC
• Responses (RECIST 1.1) in 10 of 14 patients (71%)
– More durable than chemotherapy (historical)
• Biomarker studies will address:
– Virus-pos vs. virus-neg MCC responses?
– Does PD-1 increase the number and/or function of
preexisting virus-specific T cells in blood/tumor?
(possible in 5 of 15 cases thus far)
• Expansion plans underway...for first line &
relapsed disease
Vision for future MCC management
1. Minimize recurrences
- best initial management (surgery, RT)
- immune-stimulation in ‘adjuvant’ setting...
Vision for future MCC management
1. Minimize recurrences
- best initial management (surgery, RT)
- immune-stimulation in ‘adjuvant’ setting...
2. If recurrence:
- find early by serology or scans
- reduce tumor & reverse immune evasion
- immune-therapy for long-lasting control...
Thanks to funding sources
Michael Piepkorn Endowment
Bezos Immune Therapy Fund
Lab Team
Jayasri Iyer
Research fellows:
Erica Shantha Candice Church
Graduate and medical students/doctors:
Ata Moshiri, Olga Afanasiev, Natalie Miller, Kelly Paulson, Natalie Vandeven
UV & DNA repair
Research scientists:
Dafina Ibrani, Lola Yelistratova, Chris Lewis, Ryan Doumani Masaoki Kawasumi, Kaifeng Hung
Undergraduate research assistants & students:
Jamil Qazi, Hannah Thomas, Austin Anderson, Christine Ma, Kaushik P, Seesha T, Tessa Marx