Pier Francesco Ferrucci
Direttore, Unità di Oncologia Medica del Melanoma Istituto Europeo di Oncologia - Milano
Terapia Immunomodulante e Target Therapies nel Trattamento del
Melanoma Metastatico
Pisa, 13/11/2015
1. IMMUNOTERAPIA:
Anti-CTLA4 Anti-PD1
Combinazioni anti-CTLA4 e anti-PD1
2. TERAPIA TARGET:
Anti-BRAF Anti-MEK
Combinazioni anti-BRAF e antiMEK
Agenda
Tumor antigens released by
tumor cells
Tumor antigens presented to T cells
T cells are
activated; they proliferate and differentiate into effector and
memory cells
Effector T cells recognize
tumor antigens
T cells kill tumor cells
The T-Cell Antitumor Response
1
4 2
3
5
Tumors Use Complex, Overlapping
Mechanisms to Evade and Suppress the Immune System
(eg, Tregs) (eg, TGF-B) (eg, down regulation of MHC I)
(eg, disruption of T-cell checkpoint pathways)
Inhibition of tumor antigen presentation
1
Secretion of
immunosuppressive factors 2
Inhibition of attack by immune cells
3 Recruitment of
immunosuppressive cell types
4
APC
Tumor Cell
T-reg Activated T-
cell
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 T- cell 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
PD-1
B7-1 (CD80) PD-L1
PD-L2
CD40 CD40L
CD137 OX40 CD137L
OX40L
LAG-3 MHC
CD28 Activation B7-2 (CD86)
B7-1 (CD80) CTLA-4 Inhibition
TCR
Inhibition
Inhibition
Activation
Activation Activation Inhibition
Rationale for Blockade
of Immune Checkpoint Molecules
CTLA-4 and PD1
CTLA-4 and PD-1/L1 Checkpoint Blockade
Ribas A. N Engl J Med. 2012;366:2517-2519.
Priming phase (lymph node)
Effector phase (peripheral tissue)
T-cell migration
Dendritic cell T cell
MHC TCR
B7
CD28
CTLA-4
T cell Cancer
cell TCR MHC
PD-1
PD-L1 T cell
Cancer cell Dendritic cell
T cell
Ipilimumab: Mechanism of Action
T cell inhibition T cell
activation
T cell potentiation
T cell
TCR CTLA-4
APC
MHC B7
T cell
TCR
CTLA-4
APC
MHC B7
T cell
TCR
CTLA-4
APC
MHC B7
IPILIMUMAB
blocks CTLA-4
CD28 CD28
Adapted from Weber. J Cancer Immunol Immunother 2009;58:823.
Primary endpoint: overall survival
Secondary objectives: BORR, duration of response, PFS
Hodi S et al. NEJM 2010;363(8):711-23
R A N D O M I Z E
Pre-treated Metastatic Melanoma
(N=676)
(N=137)
(N=136) (N=403)
gp100 + placebo
Ipilimumab 3 mg/kg + placebo Ipilimumab 3 mg/kg + gp100
Study Design MDX010-20:
Randomized, Double-blind, Phase III
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
Durability of Survival Benefit with
Ipilimumab in Heavily Pretreated Patients:
Proportion of patients alive (%)
Years
lpilimumab alone lpilimumab + gp100 gp100 alone
0 20 40 60 80 100
0 1 2 3 4
aPatients randomised ≥2 years prior to study survival cut-off date (N = 474)
bPatients 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
Right upper arm:
vacuolar changes
Back: confluent red rash Back: close up of papular lesions
Anti-CD8 staining:
extensive epidermal exocytosis
Jaber SH, et al. Arch Dermatol 2006;142:166–172
GASTROINTESTINAL:
Immune-related Enterocolitis
6/30/04 baseline (4.5 mm)
12/3/04
headache and fatigue after 5 doses (10.8 mm)
ENDOCRINE:
Immune-related Endocrinopathies
Blansfield JA, et al. J Immunother 2005;28:593–598
Resolution of symptoms with hormone replacement therapy, with slow return of some endocrine function
Ipilimumab-related pituitary swelling and dysfunction
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.
MHC
PD-L1
PD-1 PD-1
PD-1 PD-1
PD1 Receptor Blocking Ab
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
T-cell receptor T cell
receptor
PD-L1 PD-L2
PD-L2 MHC
CD28 B7
T cell
NFκB Other
PI3K
Dendritic cell Tumour cell
IFNγ IFNγR
Shp-2
Shp-2
Anti-PD1 Mechanism of Action
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
Ribas A, et al. ASCO 2013. Abstract 9009.
CD8+ IHC CD8+ IHC
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
CTLA-4 blockade (ipilimumab)
T cell Tumour cell
TCR MHC
PD-L1 PD1
- - -
T cell Dendritic
cell
MHC TCR
CD28 B7 CTLA-4
- - -
Activation
(cytokines, lysis, proliferation, migration to tumour)
B7 + + + + + +
anti-CTLA-4 anti-PD1
Tumour microenvironment
+ + +
PD-L2 PD1
anti-PD1
- - -
Perifery
PD1 blockade (nivolumab)
Ribas A. N Engl J Med 2012;366(26):2517–9.
CA209-067: Study Design
28
Study design:
Randomized, double-blind, phase III study to compare NIVO alone or NIVO + IPI to IPI alone
Unresectable or Metatastic Melanoma
• Previously untreated
• Tissue available for PD-L1 testing
Treat until progression**
or unacceptable
toxicity NIVO 3 mg/kg Q2W +
IPI-matched placebo
NIVO 1 mg/kg + IPI 3 mg/kg Q3W for
4 doses then NIVO 3 mg/kg Q2W + NIVO-
matched placebo
IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo
Randomize 1:1:1
Stratify by:
• PD-L1 status*
• BRAF status
• AJCC M stage
*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.
Co-primary Endpoint: PFS (Intent-to-Treat)
NIVO (N=316)
NIVO + IPI (N=314)
IPI (N=315)
Median PFS, months (95% CI)
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)** --
*Stratified log-rank P<0.00001 vs. IPI
**Exploratory endpoint
29
Proportion alive and progression-free
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
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
316 314 315
292 293 285
271 275 265
170 208 118
160 191 95
147 173 77
136 164 68
132 163 63
124 151 54
124 151 54
106 137 47
86 116
42 50 65 24
38 54 17
14 18 7
9 11 4
6 7 3
2 2 0
1 1 0
1 0 0
1 0 0
0 0 0 Number at Risk
NIVO NIVO + IPI IPI
NIVO NIVO + IPI IPI
Response to Treatment
NIVO (N=316)
NIVO + IPI (N=314)
IPI (N=315)
ORR, % (95% CI) 43.7 (38.1–49.3) 57.6 (52.0–63.2) 19.0 (14.9–
23.8) Two-sided P value vs IPI <0.00001 <0.00001 --
Best overall response — %
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
Duration of response (months)
Median (95% CI) NR (11.7, NR) NR (13.1, NR) NR (6.9, NR)
NR, not reached.
30
PFS by PD-L1 Status (5% Cutoff)
31
80 68 75
54 47 24
38 34 16
4 1 2
0 0 0 NIVO
NIVO + IPI IPI
Proportion alive and progression-free
1.0
0.8
0.6
0.4
0.2
0.0
0 5 10 15
Months
208 210 202
98 123
59
63 88 26
5 9 1
1
1.0
0.8
0.6
0.4
0.2
0.0
0 5 10 15 20
Months
Number at Risk
NIVO NIVO + IPI IPI Number at Risk
Proportion alive and progression-free
PD-L1-positive (≥5%)* PD-L1-negative (<5%)*
mPFS HR
NIVO 14.0 0.40
NIVO + IPI 14.0 0.40
IPI 3.9 --
NIVO NIVO + IPI IPI mPFS HR
NIVO 5.3 0.60
NIVO + IPI 11.2 0.42
IPI 2.8 --
*Per validated PD-L1 assay.
• Similar results were obtained using a 1% cutoff.
ORR by PD-L1 Status (5% Cutoff)
NIVO NIVO + IPI IPI
PD-L1- positive
ORR, % (95% CI)
57.5 (45.9, 68.5)
72.1 (59.9, 82.3)
21.3 (12.7, 32.3)
PD-L1- negative
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).
• NIVO + IPI resulted in a higher ORR vs. NIVO alone regardless of PD-L1 status
32
Rapid and durable changes in target lesions
+ 1 mese + 2 mesi
+ 12 mesi + 5 mesi
Tempo 0
+ 8 mesi
Safety Summary
Patients Reporting Event, %
NIVO (N=313) NIVO + IPI (N=313) IPI (N=311) Any
Grade Grade 3–4
Any Grade
Grade 3–
4
Any Grade
Grade 3–
4 Treatment-related adverse
event (AE) 82.1 16.3 95.5 55.0 86.2 27.3
Treatment-related AE leading to
discontinuation 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 0.3
*One reported in the NIVO group (neutropenia) and one in the IPI group (cardiac arrest)
35
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
Improve complete response rate
pERK BRAF
MEK
Proliferation Survival Invasion Metastasis
BRAFi : RR 77%
MEKi RR 35%
RAS
Suppress MAP kinase dependent resistance mechanisms and improve duration of response
Decrease incidence of BRAFi-induced proliferative skin lesions
Goals of Combination:
COMBI-v
Co-BRIM
n=495
11.3 months
HR=0.60
COMBI-v Co-BRIM
COMBI-v Co-BRIM
COMBI-v
Co-BRIM
What may the Future Hold?
Evaluation in combination
Chemotherapy Radiotherapy Targeted agents Other I-O therapies
Immune checkpoints
inhibitors
Novel targets Evaluation
earlier in disease
Evaluation across cancer
types
Optimization
Biomarkers Schedule/regimen Outcomes assessment
What may the Future Hold?
Evaluation in combination
Chemotherapy Radiotherapy Targeted agents Other I-O therapies
Immune checkpoints
inhibitors
Novel targets Evaluation
earlier in disease
Evaluation across cancer
types
Optimization
Biomarkers Schedule/regimen Outcomes assessment
