Download Melanoma as a model for a dual revolution in Precision Medicine

Melanoma as a model for a dual
revolution in Precision Medicine
Alexander EGGERMONT. MD, PhD
Gustave Roussy Cancer Campus Grand Paris
BREAKTHROUGH ACTIVITY IN
STAGE IV MELANOMA
160

100
IPI-Pretreated
BREAKTHROUGH
IPI-Naive
Percent Change From Baseline in
Longest Diameter of Target Lesion
80
60
40
20
0
‒20
‒40
‒60
-80
‒80
‒100
Individual Patien BREAKTHROUGH ts Treated With MK-3475
BREAKTHROUGH
THE MELANOMA PARADIGM
MUTATION DRIVEN DRUG DEVELOPMENT
INNOVATIVE IMMUNOMODULATION
Molecular Alterations in Melanoma
KIT
Amplified or mutated in 20% -40%
acral and mucosal melanoma
15% mutation
FGFR
GRB2
N-Ras
GTP
B-Raf
C-Raf
MEK
SOS
Ras
GDP
PI3K
Akt
Amplified in 10% -15%
TOR
50% -65%
V600E
mutation
ERK
MITF
ELK
PTEN
p16
25% -50% loss
CDK2/4
Amplified
in 30%
Cyclin D
Frequent loss
Amplified
in 30%
Adapted from Sosman, Curr. Oncol. Rep. 11, 405 (2009)
Vemurafenib and Dabrafenib
show similar efficacy
Vemurafenib
DTIC
(n=337)
Chapman et al.,
NEJM 2011
Dabrafenib
(n=187)
Hauschild et al.,
Lancet 2012
OS 9.7-13.6 mts
Gain: 3.9 mts
HR 0.70
V600E (91%): 13.3-10.0 HR = 0.75
V600K:(9%)
14.5– 7.6 HR = 0.43
PFS 1.6- 6.9 mts
Gain 5.3 mts*
HR 0.38
6
SUCCESS AND FAILURE
Molecular Alterations in Melanoma
BRAF + MEK Inhibitors
KIT
Amplified or mutated in 20% -40%
acral and mucosal melanoma
15% mutation
FGFR
GRB2
N-Ras
GTP
B-Raf
C-Raf
MEK
SOS
Ras
GDP
PI3K
Akt
Amplified in 10% -15%
TOR
50% -65%
V600E
mutation
ERK
MITF
ELK
PTEN
p16
25% -50% loss
CDK2/4
Amplified
in 30%
Cyclin D
Frequent loss
Amplified
in 30%
Adapted from Sosman, Curr. Oncol. Rep. 11, 405 (2009)
A SOBERING END RESULT
Median Follow-up: D + T = 11 months and Vem = 10 months
≈ 8 weeks
•
•
Why translates 4 months
additional PFS only into 2
months OS benefit?
What kind of pricing will
this OS benefit justify?
• Early events driven by bad prognosis
patients?
• Single BRAFi patients subsequently
treated in D+T NNP?
• D+T faster PD, thus less 2nd line therapy?
Drug Development Challenges
• Tumor by evolution is “moving target”
• Heterogeneity and Innate resistance
• Acquired resistance/Additional mutations
• We still suffer from Mono-Dimensional
thinking about pathways
We need to address:
• Nodes of Convergence of Pathways
• Cross Talk Complexity between pathways
eIF4F Node of Convergence
Ras/Raf – PI3K- Caspase cascade
KIT
Amplified or mutated in 20% -40%
acral and mucosal melanoma
15% mutation
FGFR
GRB2
N-Ras
GTP
B-Raf
C-Raf
MEK
SOS
Ras
GDP
PI3K
Akt
Amplified in 10% -15%
ERK
50% -65%
V600E
mutation
Caspase cascade
MITF
TOR
PTEN
Nexus:ELKeIF4F
p16
25% -50% loss
CDK2/4
Amplified
in 30%
Cyclin D
Frequent loss
Amplified
in 30%
Adapted from Sosman, Curr. Oncol. Rep. 11, 405 (2009)
12
Drug Development Challenges
We need to adddress:
• Nodes of Convergence of Pathways
• Cross Talk Complexity between
pathways
Differential response of BRAF inhibition in
BRAF mutant melanoma vs colon cancer
90%
81%
80%
70%
60%
50%
40%
30%
20%
5.20%
10%
0%
Melanoma
Colon cancer
N Engl J Med. 2010 363:809-19
Kopetz et al., ASCO 2010
CROSS TALK and RESISTANCE
Human colon cancer growth in mice
No drug
EGFR inhibitor
BRAF inhibitor
BRAF+EGFR
inhibitor
Prahallad et al, Nature 2012
PUTS AN END TO TWO PARADIGMS
!
• Targeted Agents will be effective accross
different tumor types with that target
– importance of organ of origin
– Answer is NO
• For combination therapies one must
demonstrate the antitumor effects for each
individual agent
– Answer is NO
16
Drug Development Challenges
OUR
MONO-DIMENSIONAL THINKING
ABOUT PATHWAYS
THE MELANOMA PARADIGM
MUTATION DRIVEN DRUG DEVELOPMENT
INNOVATIVE IMMUNOMODULATION
REVOLUTION IN IMMUNOTHERAPY
BREAKING TOLERANCE
Immune-Checkpoint-Blockers
INHIBIT THE INHIBITOR
vs
ACTIVATE THE ACTIVATOR
Balancing T cell activation:
playing with T cell receptors
Activating
receptors
Inhibitory
receptors
•
PD-1 and CTLA4 play distinct
roles in regulating T cell
immunity.
•
CTLA4 modulates early phases
of T cell priming (naïve and
memory T cells)
•
PD-1 is expressed on antigenexperienced T cells (TILs and
Tregs)
•
PD-1/PDL-1 interaction
downregulates overt
inflammation in lesions
•
PDL-1 expressed on Tumor Cells
and Plasmoid DCs
CTLA-4
CD28
PD-1
OX40
TIM-3
CD137
Agonistic
antibodies
LAG-3
T-cell stimulation
Blocking
antibodies
Specific response to tumour, regardless of its
characteristics, including mutation status
Adapted from Mellman, et al. Nature 2011;480(7378):480–489; Pardoll DM. Nat Rev Cancer 2012;12:252–264.
21
Immunotherapy strategies
Cytokines
IFN
IL2
IL7
IL21
GmCSF
Adoptive Tcell therapy
Activated
TCR engineered
CARs
Vaccination
DC
DNA
RNA
Immuocyte
depletion
Treg
MDSC
MoAb-conjugates
Anti CTLA-4 Monoclonal Antibodies
Perpetuate T Cell Activation
Reawaken silenced Immune Responses
IL-2
.. .
T-cell
.. ... ....
...
IL-2
. ..
TCR
Antigen
MHC
CD28
~
TCR
B7
CD28
Antigen
MHC
~
CTLA-4
.. . ...
. ......
B7
TCR
CD28
APC
Antigen
MHC
~
B7
CTLA-4
Anti-CTLA-4
mAb
ANTI-CTLA4
Ipilimumab Data
Potential for long-term survival with IT
anti-CTLA-4 (ipilimumab)
Ipilimumab was the first therapy to improve overall survival in
unresectable or metastatic melanoma in a randomised phase 3 trial1
Proportion of patients alive (%)
•
100
80
Median OS,
months
95% CI
HR
P value
Ipilimumab + gp100
10.0
8.5–11.5
0.68
<0.001
Ipilimumab
10.1
8.0–13.8
0.66
0.003
6.4
5.5–8.7
gp100
60
40
20
0
0
1
2
3
4
Years
• In clinical trials, most adverse events associated with ipilimumab were immune related and
managed using ipilimumab-specific treatment guidelines2
• Most frequently reported adverse events associated with ipilimumab monotherapy (all grades)
in a clinical study were: diarrhoea (27%), rash (26%) and pruritus (26%) 2
1. Adapted from Hodi FS, et al. N Engl J Med 2010;363:711–723; 2. Data on File, Bristol-Myers-Squibb Company, Princeton, NJ.
25
Potential for long-term survival with IT:
ipilimumab example
• Primary analysis of pooled overall survival data for patients
(N=1861) with melanoma across trials of ipilimumab 3mg/kg
1.0
0.9
Median overall survival: 11.4 months (95% CI: 10.7–12.1)
Proportion alive
0.8
0.7
0.6
3-year overall survival: 22% (95% CI: 20–24)
0.5
0.4
0.3
0.2
0.1
Ipilimumab
CENSORED
0.0
0
Patients at risk
Ipilimumab 1861
12
24
36
48
839
370
254
192
1. Adapted from Schadendorf D, et al. Oral presentation at ESMO 2013: abstract 24LBA.
60
72
Months
170
120
84
96
108
120
26
15
5
0
26
Ipilimumab + DTIC in Melanoma in 1st line.
IMPACT MEDIAN SURVIVAL only 2.1 MONTHS
Remarks:
DTIC may have rather limited
the ipilimumab effect than
enhance it
DITC is does NOT LEAD TO
IMMUNOGENIC CELL DEATH
and thus may be a poor
combination therapy
candidate
Robert C et al. N Engl J Med 2011.
DRUGS OF THE YEAR 2013
ANTI-PD1/PD1-L
CTLA-4
and
PD-1/PDL1
Mostly PERIPHERAL
Tumor Microenvironment
Mostly CENTRAL in LNN
Activation
(cytokines, lysis, proliferation,
migration to tumor)
MHC
Dendritic
cell
B7
B7
TCR
TCR
+++
CD28
CTLA-4
+++
---
T cell
MHC
+++
Tumor cell
T cell
PD-1
PD-L1
--anti-PD-1
anti-CTLA-4
PD-1
PD-L2
--anti-PD-1
CTLA-4 Blockade (ipilimumab tremelimumab)
PD-1 Blockade (nivolumab, lambrolizumab)
ANTI-PD1
Nivolumab
Pambrolizumab = MK-3475
Data
Clinical activity of nivolumab was assessed in a phase 1 trial in
patients with advanced solid tumours
LUNG: NSCLC
Died/treated: 88/129
Median OS: 9.6 months
80
60
42%
40
14%
20
0
0
3
6
9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Months since treatment initiation
100
80
70%
Renal Cell Carcinoma
Died/treated: 15/34
Median OS: >22 months
60
50%
40
20
0
0
3
6
9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
100
Overall survival (%)
Overall survival (%)
100
Overall survival (%)
•
Survival with anti-PD-1 NIVOLUMAB
LUNG, RENAL, MELANOMA
80
62%
60
MELANOMA
Died/treated: 60/107
Median OS: 16.8 months
43%
40
20
0
0
3
6
9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Months since treatment initiation
• 17% of patients had grade 3-4 adverse
events; most were manageable using
standard protocols
• Most frequently reported adverse
events (all-grades): rash (15%),
diarrhoea (13%), pruritus (11%)
Months since treatment initiation
Adapted from Topalian SL, et al. Oral presentation at ASCO 2013: J Clin Oncol 2013;31(15 suppl): abstract 3002; Hodi FS, et al. Poster presentation at ESMO
2013:abstract 880.
31
Efficacy and Safety of the Anti-PD-1
Monoclonal Antibody PEMBROLIZUMAB
(MK-3475) in 411 Patients With Melanoma
Antoni Ribas,1 F. Stephen Hodi,2 Richard Kefford,3,4 Omid Hamid,5
Adil Daud,6 Jedd D. Wolchok,7 Wen-Jen Hwu,8 Tara C. Gangadhar,9
Amita Patnaik,10 Anthony M. Joshua,11 Peter Hersey,4
Jeffrey Weber,12 Roxana Dronca,13 Hassane Zarour,14
Kevin Gergich,15 Xiaoyun (Nicole) Li,15 Robert Iannone,15
S. Peter Kang,15 Scot Ebbinghaus,15 Caroline Robert16
1 University of
California, Los Angeles, CA; 2Dana-Farber Cancer Institute, Boston, MA; 3Crown Princess Mary Cancer Centre,
Westmead Hospital and Melanoma Institute Australia, Sydney, Australia; 4University of Sydney, Sydney, Australia; 5The Angeles
Clinic and Research Institute, Los Angeles, CA; 6University of California,
7
San Francisco, CA; Memorial Sloan-Kettering Cancer Center, New York, NY; 8MD Anderson Cancer Center, Houston, TX;
9 Abramson Cancer Center at the University of Pennsylvania, Philadelphia, PA; 10 South Texas Accelerated Research Therapeutics,
San Antonio, TX; 11Princess Margaret Hospital, Toronto, Ontario;
12 H. Lee Moffitt Cancer Center, Tampa, FL; 13 Mayo Clinic, Rochester, MN; 14 University of Pittsburgh, Pittsburgh, PA; 15 Merck &
Co., Inc., Whitehouse Station, NJ; 16Institut Gustave-Roussy, Villejuif, France
Pembrolizumab in advanced Melanoma
100
Change From Baseline in Sum of
Longest Diameter of Target Lesion, %
80
60
40
72%
20
0
-20
-40
-60
-80
IPI-T
IPI-N
-100
Individual Patients Treated With Pembrolizumab
patients w ith measurable disease at baseline by RECIST v1.1 by central review and ≥1 postbaseline assessment (n = 317).
Percentage changes >100% w ere truncated at 100%.
Analysis cut-off date: October 18, 2013.
aIn
Presented by: Antoni Ribas
Time to and Durability of Response: Swimmer Plot
Pembrolizumab in advanced melanoma
• 88% of responses ongoinga
• Median response duration not
reached (range, 6+ to 76+
weeks)
aOngoing
response defined as alive, progression free, and without new anticancer therapy.
Analysis cut-off date: October 18, 2013.
Presented by: Antoni Ribas
Presented by:
Pembrolizumab: ORR
Based on Tumor PD-L1 Expression
ORR by PD-L1 Positivity
By Dose/Schedule
ORR by PD-L1 Positivity
Across Doses/Schedules n=113
Unselected
49
50
Rate, %
PD-L1–
P = 0.0007a
60
40
PD-L1+
Proportion PDL1+
40
10 mg/kg
Q3W
n = 47
2 mg/kg
Q3W
n = 31
86%
77%
55%
Overall response rate to Pembro:
30
20
13
10
0
Overall Response Rate
a1-sided
10 mg/kg
Q2W
n = 35
P values calculated by logistic regression, adjusting for dose/schedule.
PD-L1 positivity defined as staining in ≥1% of tumor cells.
Analysis cut-off date: 18 October 2013.
1. Daud A et al. Presented at: 2014 Annual AACR Meeting; April 5-9, 2014; San Diego, CA.
Unselected
51%
32%
39%
PD-L1+
57%
39%
59%
PD-L1–
20%
9%
14%
• Differences in PD-L1 positivity may
partly explain ORR differences between
dosing cohorts
Presented by: Richard Kefford
Change From Baseline in Sum of
Longest Diameter of Target Lesion, %
Pembrolizumab
Waterfall Plot
100
80
PD-L1+
PD-L1–
60
40
20
0
-20
-40
-60
-80
-100
Individual Patients
aEvaluable
patients were those patients in the training set w ith evaluable tumor PD-L1 expression w ho had measurable disease at baseline per central review and
≥1 postbaseline tumor assessment.
Percentage changes >100% truncated at 100%.
PD-L1 positivity defined as staining in ≥1% of tumor cells.
Analysis cut-off date: 18 October 2013.
1. Daud A et al. Presented at: 2014 Annual AACR Meeting; April 5-9, 2014; San Diego, CA.
Presented by: Richard Kefford
PFS and OS
Based on Tumor PD-L1 Expression
Progression-Free Survival
Overall Survival
100
100
PD-L1+
80
80
PD-L1–
60
PD-L1+
OS, %
PFS, %
60
40
40
P = 0.0051
PD-L1–
20
P = 0.3165
20
0
0
0
20
40
60
80
Time, weeks
0
20
40
60
80
Time, weeks
PD-L1 positivity defined as staining in ≥1% of tumor cells.
Analysis cut-off date: 18 October 2013.
1. Daud A et al. Presented at: 2014 Annual AACR Meeting; April 5-9, 2014; San Diego, CA.
Presented by: Richard Kefford
38
Nivolumab vs DTIC
in advanced melanoma
39
Nivolumab vs DTIC
Progression Free Survival
40
DURABILITY OF RESPONSES
41
BRAFinh in BRAFmutant compared to
anti-PD1 in Wildtype Advanced Melanoma
OS 9.7-13.6 mts
Gain: 3.9 mts
HR 0.70
PFS 1.6- 6.9 mts
Gain5.3mts*
HR 0.38
42
LUNG CANCER
Antitumor Activity of Pembrolizumab
and Correlation With Programmed Death
Ligand 1 (PD-L1) Expression in a Pooled
Analysis of Patients With Advanced NSCLC
Edward B. Garon,1 Leena Gandhi,2 Naiyer Rizvi,3 Rina Hui,4 Ani S. Balmanoukian,5
Amita Patnaik,6 Joseph Paul Eder,7 George Blumenschein, Jr.,8 Charu Aggarwal,9
Jean-Charles Soria,10 Myung-Ju Ahn,11 Matthew Gubens,12 Suresh S. Ramalingam,13
Elizabeth Johnson14 Hendrik-Tobias Arkenau,15 Gregory M. Lubiniecki,16 Jin Zhang,16
Ruth Z. Rutledge,16 Kenneth Emancipator,16 Natasha Leighl17
1 David
Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA;
Cancer Institute, Boston, MA; 3 Memorial Sloan Kettering Cancer Center, New York, NY;
4 Westmead Hospital, University of Sydney, Sydney, Australia; 5 The Angeles Clinic and Research Institute, Los Angeles, CA;
6 START Center for Cancer Care, San Antonio, TX; 7 Yale University, New Haven, CT; 8 The University of Texas MD Anderson Cancer Center, Houston, TX;
9 Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA; 10 Gustave Roussy Cancer Campus, Villejuif, France;
11 Sungkyunkwan University, Samsung Medical Center, South Korea; 12 University of California, San Francisco, San Francisco, CA;
13 Winship Cancer Institute of Emory University, Atlanta, GA; 14 Mayo Clinic, Jacksonville, FL; 15 Sarah Cannon Research Institute UK, London, UK;
16 Merck & Co., Inc., Whitehouse Station, NJ; 17 Princess Margaret Cancer Centre, Toronto, ON
2 Dana-Farber
Pembrolizumab in NCSLC
100
Change From Baseline in Sum of
Largest Diameter of Target Lesion, %
80
60
40
Treatment naive
58%
20
0
-20
-40
-60
-80
-100
aEvaluable patients
were those with measurable disease at baseline per central review who had ≥1 post baseline tumor assessment.
Analysis cut-off date: March 3, 2014.
Previously treated
Pembrolizumab: Time to and
Durability of Response IN NSCLC
• Treatment naive: 100% of responses
ongoing
• Previously treated: 77% of responses
ongoing
Treatment naive
Previously treated
Partial response
Progressive disease
Ongoing treatment
0
10
20
30
Time, weeks
aIncludes
confirmed and unconfirmed responses.
Analysis cutoff date: March 3, 2014.
40
50
Pembrolizumab in NSCLC
Response Rate by Level of PD-L1
50
ORR, %
40
37
30
22
20
17
10
10
0
Total (N=129)
aEvaluable patients
Strong Positive (n=41)
Weak Positive (n=46)
Negative (n=42)
were those patients in the training set with evaluable tumor PD-L1 expression who had measurable disease at baseline per imaging assessment criteria.
Analysis cut-off date: March 3, 2014.
Kaplan-Meier Estimates of Survival
by degree of PD-L1 expression
OS
Strong
Weak
Negative
100
90
80
70
60
50
40
30
20
10
0
n at risk
Strong
Weak
Negative
0
8
16
44
53
49
28
43
30
18
17
15
24
32
Time, weeks
17
12
7
9
6
1
Overall Survival, %
Progression-Free Survival, %
PFS
40
48
6
0
0
3
0
0
100
90
80
70
60
50
40
30
20
10
0
Strong
Weak
Negative
0 1 2 3 4
5 6 7 8 9 10 11 12 13 14
Time, months
44 43 38 38 34 32 30 27 21 18 9
53 51 48 40 34 31 26 22 18 11 8
49 42 38 34 29 26 21 14 8 6 4
8 5
7 5
2 0
5
5
0
4
4
0
• PFS was longer in patients with PD-L1 strong-positive versus PD-L1 weak-positive/
negative tumors (HR, 0.52; 95% CI, 0.33-0.80)
• OS was longer in patients with PD-L1 strong-positive versus PD-L1 weak-positive/
negative tumors (HR, 0.59; 95% CI, 0.35-0.99)
aEvaluable patients
were those patients in the training set with evaluable tumor PD-L1 expression.
Strong PD-L1 positivity defined as staining in ≥50% of tumor cells, and weak PD-L1 positivity as staining in 1-49% of tumor cells. Negative staining is no PD-L1 staining in
tumor cells.
Data cut-off: March 3, 2014.
Nivolumab SURVIVAL benefit over chemo in NSCLC
CheckMate -017, A Phase 3 Study of Opdivo (Nivolumab)
Compared to Docetaxel in Patients with Second-Line
Squamous Cell Non-small Cell Lung Cancer, STOPPED EARLY
Nivolumab demonstrates superior overall
survival in this Phase 3 trial
Sunday, January 11, 2015 9:06 pm EST
BMS (NYSE:BMY) today announced that an open-label, randomized Phase 3 study
evaluating Nivolumab versus docetaxel in previously treated patients with
advanced, squamous cell non-small cell lung cancer (NSCLC) was stopped early
because an assessment conducted by the independent Data Monitoring Committee
(DMC) concluded that the study met its endpoint, demonstrating superior overall
survival in patients receiving Opdivo compared to the control arm. The company will
share these data – which for the first time indicate a survival advantage with an antiPD1 immune checkpoint inhibitor in lung cancer – with health authorities.
48
Nivolumab in Refractory Renal Cell Cancer
49
PEMBROLIZUMAB in GASTRIC CANCER : 39 pts, median FU: 8.8 months. 2/3
of pts had > two prior therapies, 30% achieved PR 50% of pts some degree of
tumor shrinkage median duration of response: 24 weeks (range 8+ to 33+ wks
ANTI-PD1 in Refractory
Hodgkin’s Lymphoma
39 pts
all pts failed > 2 trtmts
2/3pts failed > 4 trtmts
50% RR (10% CR)
60% No Progression
Durability
51
KEYNOTE-013 TRIAL
Pembrolizumab in Classic Hodgkin Lymphoma
News | December 08, 2014 | ASH 2014, Hematologic Malignancies, Leukemia & Lymphoma
According to Moskowitz (MSKCC) , it is believed that
classic Hodgkin’s lymphoma may represent a uniquely
vulnerable target for PD-1 blockade. Specifically,
amplification of 9p24.1 is frequent in the disease and
results in the overexpression of PD-L1 and PD-L2.
ORR
CR
PR
SD
86%
21%
45 %
21%
DURABILITY: Seventeen of the 19 responses were ongoing
52
No more blockbusters?
•
Anti-PD1 and anti-PDL1 will be bigger blockbusters than avastin
with a much more meaningful impact in multiple tumor types:
•
IMMUNOTHERAPY: TRANSVERSAL IMPACT
– Melanoma : approved 2014, will take first place for all, adjuvant
to be launched March 2015
– Renal : on its way up the ladder
– Lung: will take first place, adjuvant started (PD1 and PDL1)
– Head and Neck (ASCO 2014) up the ladder
– Bladder (ASCO and ESMO 2014) will take first place
– Stomach (ASCO GI 2014) up the ladder
– Hodgkin (ASH 2014) very important future
– TNBC?
53
Special Report (Fierce Biotech) :
The top 15 late-stage blockbusters in the pipeline
1 Nivolumab, Bristol-Myers Squibb
2 Pembrolizumab (MK-3475, Merck)
5 RG7446 (anti-PDL1), Roche
15 MEDI4736 (anti-PDL1) , AstraZeneca
Projected sales in 2020 >15 Billion
Estimated value at this moment > 60 Billion
54
IMMUNO – COMBOS
INHIBITOR COMBOS
Anti-CTLA4 + Anti-PD1
CTLA-4
and
PD-1/PDL1
Mostly PERIPHERAL
Tumor Microenvironment
Mostly CENTRAL in LNN
Activation
(cytokines, lysis, proliferation,
migration to tumor)
MHC
Dendritic
cell
B7
B7
TCR
TCR
+++
CD28
CTLA-4
+++
---
T cell
MHC
+++
Tumor cell
T cell
PD-1
PD-L1
--anti-PD-1
anti-CTLA-4
PD-1
PD-L2
--anti-PD-1
CTLA-4 Blockade (ipilimumab tremelimumab)
PD-1 Blockade (nivolumab, pembrolizumab)
Presented by: Jedd D. Wolchok, MD, PhD
Change in target lesions from baseline (%)
Best Responses in All Evaluable Patients in
CONCURRENT Nivolumab + Ipilimumab
-80
Presented by: Jedd D. Wolchok, MD, PhD
Patients
OVERALL SURVIVAL MELANOMA
Ipilimumab +Nivolumab by Dose Cohort
100
2 Yr OS 88%
1 Yr OS 94%
90
80
Survival (%)
70
2 Yr OS 79%
1 Yr OS 85%
Survival at 1 yr from 25% to > 90%
60
50
Survival at 2 yr from 12 % 2toYr OS
> 80%
50%
1 Yr OS 57%
40
Survival at 5 yr from 5% to > 50% ?
30
Censored
Nivo 0.3 mg/kg + IPI 3 mg/kg (n=14)
Nivo 1 mg/kg + IPI 3 mg/kg (n=17)
Nivo 3 mg/kg + IPI 1 mg/kg (n=16)
Nivo 3 mg/kg + IPI 3 mg/kg (n=6)
Concurrent Cohorts 1-3 (n=53)
20
10
0
0
Pts at Risk
Nivo 0.3_IPI 3
Nivo 1 _IPI 3
Nivo 3_IPI 1
Nivo 3_IPI 3
Concurrent
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
7
4
0
0
11
5
3
0
0
8
2
3
0
0
5
2
3
0
0
5
2
2
0
0
4
1
0
0
0
1
1
0
0
0
1
0
0
0
0
0
Months
14
17
16
6
53
13
17
16
6
52
11
16
15
6
48
10
15
15
6
46
8
15
15
6
44
7
14
13
6
40
7
14
4
6
31
7
13
2
6
28
7
9
0
3
19
(Sznoll, ASCO 2014)
IMMUNO-COMBO’S
The door is now open for agonists !
Activating
receptors
Inhibitory
receptors
CTLA-4
CD28
•
PD-1 and CTLA4
•
Inhibitor Blocker
Combo’s
•
Inhibitor Blockers +
Agonists
•
Inhibitor Blockers +
Cytokines
•
inhibitor Blockers +
vaccines
PD-1
OX40
TIM-3
CD137
Agonistic
antibodies
LAG-3
T-cell stimulation
Blocking
antibodies
Specific response to tumour, regardless of its
characteristics, including mutation status
Adapted from Mellman, et al. Nature 2011;480(7378):480–489; Pardoll DM. Nat Rev Cancer 2012;12:252–264.
60
Immunotherapy + Other Modalities
Guidance by Immunogenic Cell Death
Zitvogel & Kroemer
Radiation
Adhesion molecules
(CAM-1) and death
receptors (FAS)
Peptide
pools
Chemotherapy
CD8 T-cell
Upregulation of MHC-1
Uploading of
antigen processing
machinery
Targeted therapies
Vascular normalisation
T-cell initiation
Effector immune
infiltrate Release of tumour
Cytokine release
antigens (cascade)
Translocation of
calreticulin
CD8 T-cells
TAA crosspresentation
Dendritic
cell
MDSC
Treg cells
M2 macrophages
TAA
Upregulates MHC-1
Adhesion molecules/
death receptors
APM
CD8 T-cells
(homeostatic peripheral
expansion)
MDSC
CD8 T-cells
T-cell function
Treg cells
Activation of apoptosis
Blockage of cell cycle
Adapted from Hodge JW. Semin Oncol 2012;39(3):323–339; Drake CG Ann Oncol 2012;23 Suppl 8:viii41-6; Ménard C, et al. Cancer Immunol Immunother
2008;57:1579-87; Hannani D, et al. Cancer J 2011;17:351-358; Ribas A at al. Curr Opin Immunol 2013:25:291-296.
61
OVERALL SURVIVAL MELANOMA
Ipilimumab +Nivolumab by Dose Cohort
100
2 Yr OS 88%
1 Yr OS 94%
90
80
Survival (%)
70
2 Yr OS 79%
1 Yr OS 85%
Survival at 1 yr from 25% to 90%
60
50
Survival at 2 yr from 12 % 2toYr OS
80%
50%
1 Yr OS 57%
40
Survival at 5 yr from 5% to > 50% ?
30
Censored
Nivo 0.3 mg/kg + IPI 3 mg/kg (n=14)
Nivo 1 mg/kg + IPI 3 mg/kg (n=17)
Nivo 3 mg/kg + IPI 1 mg/kg (n=16)
Nivo 3 mg/kg + IPI 3 mg/kg (n=6)
Concurrent Cohorts 1-3 (n=53)
20
10
0
0
Pts at Risk
Nivo 0.3_IPI 3
Nivo 1 _IPI 3
Nivo 3_IPI 1
Nivo 3_IPI 3
Concurrent
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
7
4
0
0
11
5
3
0
0
8
2
3
0
0
5
2
3
0
0
5
2
2
0
0
4
1
0
0
0
1
1
0
0
0
1
0
0
0
0
0
Months
14
17
16
6
53
13
17
16
6
52
11
16
15
6
48
10
15
15
6
46
8
15
15
6
44
7
14
13
6
40
7
14
4
6
31
7
13
2
6
28
7
9
0
3
19
(Sznoll, ASCO 2014)
PREDICTIONS
• IMMUNO COMBOS will dominate the scene for years
to come
• Breaking tolerance is first prerequisite
• Breaking tolerance will get Nobel Price
• Will be backbone for any treatment of metastatic
melanoma patients and many tumors to come
– Lung, Renal, Bladder, Lymphomas, H&N, etc etc …
• Will cure / “clinically cure” > 50% of advanced
melanoma patients over next 5 years
THANK YOU
64
COME VISIT GUSTAVE ROUSSY
Cancer Campus Grand Paris