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Terapia Immunomodulante e Target
Therapies nel Trattamento del
Melanoma Metastatico
Pier Francesco Ferrucci
Direttore, Unità di Oncologia Medica del Melanoma
Istituto Europeo di Oncologia - Milano
Pisa, 13/11/2015
Agenda
1.
IMMUNOTERAPIA:
Anti-CTLA4
Anti-PD1
Combinazioni anti-CTLA4 e anti-PD1
2. TERAPIA TARGET:
Anti-BRAF
Anti-MEK
Combinazioni anti-BRAF e antiMEK
The T-Cell Antitumor Response
2
1
Tumor antigens
presented to T cells
3
Tumor antigens
released by
tumor cells
4
Effector T cells
recognize
tumor antigens
5
T cells kill
tumor cells
T cells are
activated; they
proliferate and
differentiate into
effector and
memory cells
Tumors Use Complex, Overlapping
Mechanisms to Evade and Suppress the
Immune System
1
APC
Inhibition of tumor antigen
presentation
(eg, down regulation of MHC I)
Tumor
Cell
Inhibition of attack by
immune cells
2
Secretion of
immunosuppressive factors
(eg, TGF-B)
(eg, disruption of T-cell checkpoint
pathways)
3
Activated Tcell
T-reg
4
Recruitment of
immunosuppressive cell
types
(eg, Tregs)
Regulation of T-Cell Activation:
Balancing Activating and Inhibitory Signals
• Immune checkpoints limit, or
“check,” an ongoing immune
response
• Prevents damage to the body’s
healthy tissues
–
–
Negative co-stimulation, also called
“co-inhibition,” helps shut down
immune responses
PD-1, CTLA-4, and LAG-3 are examples
of co-inhibitory “checkpoint”
molecules
• Amplitude and quality of a Tcell response is regulated by a
balance of activating and
inhibitory signals
CTLA-4 = cytotoxic T-lymphocyte antigen-4;
LAG-3 = lymphocyte activation gene-3;
PD-1 = programmed death-1;
PD-L1 = programmed death-ligand 1.
APC/
Tumor
T cell
B7-2 (CD86)
CD28 Activation
B7-1 (CD80)
CTLA-4 Inhibition
PD-L1
PD-1 Inhibition
PD-L2
B7-1 (CD80) Inhibition
LAG-3 Inhibition
MHC
CD40
CD137L
OX40L
TCR
CD40L
Activation
CD137 Activation
OX40 Activation
Rationale for Blockade
of Immune Checkpoint Molecules
CTLA-4 and PD1
CTLA-4 and PD-1/L1 Checkpoint
Blockade
Priming phase
(lymph node)
Effector phase
(peripheral tissue)
T-cell migration
Dendritic cell
MHC
TCR
TCR
CD28
Dendritic cell
T cell
B7
Cancer
cell
T cell
T cell
T cell
MHC
PD-1
PD-L1
CTLA-4
Ribas A. N Engl J Med. 2012;366:2517-2519.
Cancer
cell
Ipilimumab: Mechanism of Action
T cell
activation
T cell
inhibition
T cell
potentiation
CTLA-4
T cell
CD28
TCR
MHC
APC
T cell
T cell
CD28
TCR
B7
MHC
APC
CTLA-4
CTLA-4
B7
TCR
IPILIMUMAB
MHC
B7
blocks
CTLA-4
APC
Adapted from Weber. J Cancer Immunol Immunother 2009;58:823.
Study Design MDX010-20:
Randomized, Double-blind, Phase III
Pre-treated
Metastatic
Melanoma
(N=676)
R
A
N
D
O
M
I
Z
E
Ipilimumab 3 mg/kg + gp100
(N=403)
Ipilimumab 3 mg/kg + placebo
(N=137)
gp100 + placebo
(N=136)


Primary endpoint: overall survival
Secondary objectives: BORR, duration of response, PFS
Hodi S et al. NEJM 2010;363(8):711-23
Proportion of patients alive (%)
Durability of Survival Benefit with
Ipilimumab in Heavily Pretreated Patients:
100
lpilimumab alone
80
lpilimumab + gp100
gp100 alone
60
40
20
0
0
1
2
3
4
Years
mOS,
months
95% CI
HR
P value
1-year
OS (%)
2-year
OS (%)a
3-year
OS (%)b
Ipilimumab +
gp100
10.0
8.5–11.5
0.68
<0.001
44
19
15
Ipilimumab
10.1
8.0–13.8
0.66
0.003
46
25
25
gp100
6.4
5.5–8.7
25
14
10
aPatients
bPatients
randomised ≥2 years prior to study survival cut-off date (N = 474)
randomised ≥3 years prior to study survival cut-off date (N = 259)
Hodi FS, et al. N Engl J Med 2010;363:711–23
McDermott D, et al. Ann Oncol 2013;24:2694–8
Specific Patterns of Response
• Ipilimumab monotherapy resulted in four distinct response
patterns, 2 captured with conventional RECIST/WHO criteria
and 2 by new irRC:
1. shrinkage in baseline lesions, without new lesions;
2. durable stable disease (in some patients followed by a slow, steady
decline in total tumor burden);
3. response after an increase in total tumor burden;
4. response in the presence of new lesions.
All these patterns were associated with favorable
survival.
Specific Patterns of Toxicities
SKIN: Immune-related dermatitis
Back: confluent red rash
Back: close up of papular lesions
Right upper arm:
vacuolar changes
Anti-CD8 staining:
extensive epidermal exocytosis
Jaber SH, et al. Arch Dermatol 2006;142:166–172
GASTROINTESTINAL:
Immune-related Enterocolitis
ENDOCRINE:
Immune-related Endocrinopathies
6/30/04
baseline (4.5 mm)
12/3/04
headache and fatigue after 5 doses
(10.8 mm)
Ipilimumab-related pituitary swelling and dysfunction
Resolution of symptoms with hormone replacement therapy,
with slow return of some endocrine function
Blansfield JA, et al. J Immunother 2005;28:593–598
LIVER: Immune-related Hepatitis
• Monitor liver function tests (LFTs): increases in
AST and ALT or total bilirubin should be
evaluated to exclude other causes of hepatic
injury and monitored until resolution
• Withold ipilimumab dosing in patients with
moderate aspartate AST or ALT elevations of > 5
to ≤ 8 times ULN, or moderate total bilirubin
elevation of > 3 to ≤ 5.1
• Permanently discontinue ipilimumab for any of
the following:
– Severe AST or ALT elevations of > 8 times ULN;
– Total bilirubin elevations of > 5 times ULN;
– Symptoms of hepatotoxicity.
• Systemic high-dose corticosteroids may be
required
PD1 Pathway As a Key
Checkpoint in Cancer
Effects of PD1 Signalling on T-cell Function
• Normal function: attenuate immune responses to avoid
immune system attack of ‘self’
• Direct effects on activated CD4+/CD8+ T cells
– PD1: PD-L1/L2 = ↓proliferation
– PD1: PD-L1 = ↓IL-2
– PD1: PD-L1 = ↑CD8+ T-cell anergy
• Indirect effects via Treg cells
– PD1: PD-L1 = ↑naïve CD4+ cell conversion → Treg
– PD1: PD-L1 = ↑Treg function (inhibition of CD8+ T-cell
responses)
Blank C, et al. Cancer Immunol Immunother. 2007;56:739–45.
Carter LL, et al. Eur J Immunol 2002;32:634–43.
Chikuma S, et al. J Immunol 2009;182:6682–89.
Anti-PD1 Mechanism of Action
Recognition of tumour by T cell through MHC/antigen
interaction mediates IFNγ release and PD-L1/2
upregulation on tumour
Priming and activation of T cells through MHC/antigen
and CD28/B7 interactions with antigen-presenting cells
IFNγ
IFNγR
T-cell
receptor
T cell
receptor
MHC
MHC
PI3K
NFκB
Other
Tumour cell
PD-L1
Shp-2
PD-L2
PD-1
PD-1
CD28
B7
T cell
PD-1
PD-L1
Shp-2
PD-1
PD1 Receptor Blocking Ab
PD-L2
Dendritic
cell
Activity of Anti-PD-1/PD-L1 in Patients With
Advanced Melanoma
Agent
Pts,
n
ORR
(at Optimal
Dose), %
Grades 3/4
Tx-Related
AEs, %
6-Mo
PFS, %
12-Mo
PFS, %
Median
PFS,
Mos
1-Yr
OS, %
2-Yr
OS, %
Nivolumab
(anti-PD-1)[1-3]
104
31
(41)
22
41
36
3.7
62
43
Pembrolizumab
(anti-PD-1)[4,5]
135
38
(52)
13
NA
NA
>7
81
58
BMS559
(anti-PD-L1)[6]
55
17
5
NA
NA
NA
NA
NA
MPDL3280A
(anti-PD-L1)[7]
44
29*
36
43
NA
NA
NA
NA
*Includes 4 patients with UM without a response.
1. Topalian SL, et al. J Clin Oncol. 2014;32:1020-1030. 2. Sznol M, et al. ASCO 2013. Abstract 9006.
3. Topalian SL, et al. N Engl J Med. 2012;366:2443-2454. 4. Ribas A, et al. ASCO 2013. Abstract 9009.
5. Hamid O, et al. N Engl J Med. 2013;369:134-144. 6. Brahmer JR, et al. N Eng J Med. 2012. 366:2455-2465. 7.
Hamid O, et al. ASCO 2013. Abstract 9010.
CTL Infiltrates in Regressing Metastatic
Melanoma Lesion After MK-3475 Treatment
Baseline: February 29, 2012
August 20, 2012
CD8+ IHC
CD8+ IHC
Ribas A, et al. ASCO 2013. Abstract 9009.
AEs in > 5% of Patients
Adverse Event (N = 135)
All Grades, n (%)
Grades 3/4, n (%)
Any
107 (79.3)
17 (12.6)
Fatigue
41 (30.4)
2 (1.5)
Rash
28 (20.7)
3 (2.2)
Pruritus
28 (20.7)
1 (0.7)
Diarrhea
27 (20.0)
1 (0.7)
Myalgia
16 (11.9)
0
Headache
14 (10.4)
0
Increased AST
13 (9.6)
2 (1.5)
Asthenia
13 (9.6)
0
Nausea
13 (9.6)
0
Vitiligo
12 (8.9)
0
Hypothyroidism
11 (8.1)
1 (0.7)
Increased ALT
11 (8.1)
0
Cough
11 (8.1)
0
Pyrexia
10 (7.4)
0
Chills
9 (6.7)
0
Abdominal pain
7 (5.2)
1 (0.7)
Anti-PD1 in Advanced Melanoma:
Expert Perspective
• Excellent toxicity profile (Grade 3/4 irAEs: 13% Pembro,
22% Nivo)
• Response rates in Ipi-naive pts 41% (Nivo), 52% (Pembro)
- Lower response rates in patients who progressed after Ipi,
BRAF inhibitor, or LDH >ULN
• Response duration (even when stopped):
– 81% at 1y (Pembro), 64% beyond 24 wks (Nivo)
– Median DoR of 22.9 mos (Nivo)
• Survival outcomes:
– Extimated median OS is >24 mo (Pembro)
– 2-yr OS: 48%; 3-yr OS: 41% (Nivo)
Rationale for concurrent Blockade
of Immune Checkpoint Molecules
CTLA-4 and PD1
Blocking CTLA-4 and PD1
Perifery
Tumour microenvironment
Activation
(cytokines, lysis, proliferation,
migration to tumour)
MHC
Dendritic
cell
B7
TCR
TCR
+++
CD28
B7 CTLA-4
+++ T cell
---
MHC
+++
T cell
PD1
PD-L1
Tumour cell
--anti-PD1
anti-CTLA-4
PD1
PD-L2
--anti-PD1
CTLA-4 blockade (ipilimumab)
PD1 blockade (nivolumab)
Ribas A. N Engl J Med 2012;366(26):2517–9.
CA209-067: Study Design
Study design:
Randomized, double-blind, phase III study
to compare NIVO alone or NIVO + IPI to IPI alone
NIVO 3 mg/kg Q2W +
IPI-matched placebo
Unresectable or
Metatastic Melanoma
• Previously untreated
• Tissue available for
PD-L1 testing
Stratify by:
Randomize
1:1:1
NIVO 1 mg/kg +
IPI 3 mg/kg Q3W for
4 doses then NIVO
3 mg/kg Q2W + NIVOmatched placebo
• PD-L1 status*
• BRAF status
• AJCC M stage
IPI 3 mg/kg Q3W for
4 doses +
NIVO-matched placebo
*Verfied PD-L1 assay using 5% cutoff, was used for the stratification of patients;
validated PD-L1 assay was used for the results of the study.
**Patients could have been treated beyond progression under protocol-defined circumstances.
28
Treat until
progression**
or
unacceptable
toxicity
Co-primary Endpoint: PFS (Intent-to-Treat)
1.0
NIVO
(N=316)
NIVO + IPI
(N=314)
IPI
(N=315)
6.9
(4.3–9.5)
11.5
(8.9–16.7)
2.9
(2.8–3.4)
HR (95% CI)
vs. IPI
0.57
(0.43–0.76)*
0.42
(0.31–0.57)*
--
HR (95% CI)
vs. NIVO
--
0.74
(0.60–0.92)**
--
Median PFS, months
(95% CI)
0.9
Proportion alive and progression-free
0.8
0.7
0.6
*Stratified log-rank P<0.00001 vs. IPI
0.5
**Exploratory endpoint
0.4
0.3
NIVO
0.2
NIVO + IPI
IPI
0.1
0.0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Months
Number at Risk
NIVO
316
292
271
170
160
147
136
132
124
124
106
86
50
38
14
9
6
2
1
1
1
0
NIVO + IPI
314
293
275
208
191
173
164
163
151
151
137
116
65
54
18
11
7
2
1
0
0
0
IPI
315
285
265
118
95
77
68
63
54
54
47
42
24
17
7
4
3
0
0
0
0
0
29
Response to Treatment
NIVO
(N=316)
NIVO + IPI
(N=314)
IPI
(N=315)
<0.00001
<0.00001
19.0 (14.9–
23.8)
--
Complete response
8.9
11.5
2.2
Partial response
34.8
46.2
16.8
Stable disease
10.8
13.1
21.9
Progressive disease
37.7
22.6
48.9
Unknown
7.9
6.7
10.2
NR (11.7, NR)
NR (13.1, NR)
NR (6.9, NR)
ORR, % (95% CI)
Two-sided P value vs IPI
43.7 (38.1–49.3) 57.6 (52.0–63.2)
Best overall response — %
Duration of response (months)
Median (95% CI)
NR, not reached.
30
PFS by PD-L1 Status (5% Cutoff)
PD-L1-positive (≥5%)*
PD-L1-negative (<5%)*
1.0
0.8
Proportion alive and progression-free
Proportion alive and progression-free
1.0
0.6
0.4
0.2
0.0
0
Number at Risk
NIVO
80
mPFS
HR
NIVO
14.0
0.40
NIVO + IPI
14.0
0.40
IPI
3.9
--
5
0.8
0.6
0.4
0.2
mPFS
HR
NIVO
5.3
0.60
NIVO + IPI
11.2
0.42
IPI
2.8
--
0.0
10
0
15
Months
5
NIVO
NIVO + IPI
IPI
10
15
20
1
Months
Number at Risk
54
38
4
0
NIVO
208
98
63
5
NIVO + IPI
68
47
34
1
0
NIVO + IPI
210
123
88
9
IPI
75
24
16
2
0
IPI
202
59
26
1
• Similar results were obtained using a 1% cutoff.
*Per validated PD-L1 assay.
31
ORR by PD-L1 Status (5% Cutoff)
•
NIVO + IPI resulted in a higher ORR vs. NIVO alone regardless of PD-L1 status
NIVO
NIVO + IPI
IPI
PD-L1positive
ORR, %
(95% CI)
57.5
(45.9, 68.5)
72.1
(59.9, 82.3)
21.3
(12.7, 32.3)
PD-L1negative
ORR, %
(95% CI)
41.3
(34.6, 48.4)
54.8
(47.8, 61.6)
17.8
(12.8, 23.8)
PD-L1 positivity defined as ≥5% tumor cell surface staining. Pre-treatment tumor specimens were
centrally assessed by PD-L1 immunohistochemistry (using a validated BMS/Dako assay).
32
Rapid and durable changes in target lesions
Tempo 0
+ 1 mese
+ 5 mesi
+ 8 mesi
+ 2 mesi
+ 12 mesi
Safety Summary
NIVO (N=313)
Patients Reporting Event, %
Any
Grade
Treatment-related adverse
event (AE)
Treatment-related AE leading to
discontinuation
NIVO + IPI (N=313)
IPI (N=311)
Grade 3–4
Any
Grade
Grade 3–
4
Any
Grade
Grade 3–
4
82.1
16.3
95.5
55.0
86.2
27.3
7.7
5.1
36.4
29.4
14.8
13.2
Diarrhea
1.9
1.3
8.3
6.7
4.5
4.2
Colitis
0.6
0.6
8.3
6.4
7.7
7.4
Treatment-related death*
0.3
0
*One reported in the NIVO group (neutropenia) and one in the IPI group (cardiac arrest)
35
0.3
Concurrent Therapy With Ipilimumab and
Nivolumab: Expert Perspective
• Up to 70% ORR with 17% CRs and 82% in remission for all
patients receiving concurrent treatment
• Up to 50% rate of grade 3/4 irAEs at optimal doses: LFTs,
lipase, amylase, rash, colitis
• BRAF status, PD-L1 tumor staining not clearly associated with
response (maybe to Nivo)
• Response in sequential patients associated with plasma
ipilimumab levels prior to starting nivolumab
• Concurrent 2-yr OS of 79% = impressive !!!
• Benefit worth the toxicity?
Molecularly Targeted Therapy
New Targets  New Drugs
Rationale for Combination of BRAFi
+ MEKi in BRAF Mutant Tumors
Rationale for Combination of BRAFi +
MEKi in BRAF Mutant Tumors
RAS
BRAF
BRAFi : RR 77%
Goals of Combination:
MEK
MEKi RR 35%
Improve complete response rate
Decrease incidence of BRAFi-induced
proliferative skin lesions
pERK
Proliferation
Survival
Invasion
Metastasis
Suppress MAP kinase dependent
resistance mechanisms and improve
duration of response
COMBI-v
n=495
Co-BRIM
COMBI-v
Co-BRIM
11.3 months
HR=0.60
COMBI-v
Co-BRIM
COMBI-v
Co-BRIM
What may the Future Hold?
Evaluation
earlier
in disease
Optimization
Biomarkers
Schedule/regimen
Outcomes assessment
Immune
checkpoints
inhibitors
Evaluation
across cancer
types
Novel targets
Evaluation in
combination
Chemotherapy
Radiotherapy
Targeted agents
Other I-O therapies
What may the Future Hold?
Evaluation
earlier
in disease
Optimization
Biomarkers
Schedule/regimen
Outcomes assessment
Immune
checkpoints
inhibitors
Evaluation
across cancer
types
Novel targets
Evaluation in
combination
Chemotherapy
Radiotherapy
Targeted agents
Other I-O therapies
Della serie….
Grazie per l’attenzione