M. Del Vecchio
Responsabile Gruppo Melanoma Dipartimento di Oncologia Medica
Fondazione IRCCS Istituto Nazionale dei Tumori Milano
Aggiornamenti in oncologia tra ricerca e clinica
Melanoma maligno
Metastatic melanoma. Limited survival outcomes associated
with historical treatment options
• Historical data indicate median overall survival for patients with metastatic melanoma of 6 to 9 months
• In a meta-analysis of 42 phase 2 trials in 2,100 patients with metastatic melanoma treated in North America (Korn, JCO 2008):
0 12 24 36 100
80 60 40 20 0
Median overall survival was 6.2 months (range:
5.5–6.9 months)
1-year survival rate was 25.5%
(range: 23.6–27.4%)
Months
Signalling Pathways
Sullivan RJ et al. Clin Cancer Res 2013;19:5283-5291
Genomic Classification of Cutaneous Melanoma
Treatment Options for BRAF V600- Mutant Metastatic Melanoma
BRAF/MEK Inhibitors
• Dabrafenib + trametinib
• Vemurafenib + cobimetinib
• Immunotherapy
• Ipilimumab
• Nivolumab
• Nivolumab + ipilimumab
• Pembrolizumab
Combinatorial approaches to overcome BRAFi/MEKi resistance
Manzano JL et al. Ann Transl Med 2016
RAFI Resistance Mechanisms
Lito P et al. Nat Med 2013;19:1401-1409
For Internal Use Only. Not for Distribution outside Novartis.
Rationale for Combination of Dabrafenib and Trametinib in BRAF-mutant Tumours
AE=adverse event; BRAFi=BRAF inhibitor; HR=hazard ratio; MAPK=mitogen-activated protein kinase; MEK=MAPK kinase; MEKi=MEK inhibitor; ORR=objective response rate; OS=overall survival; pERK=phosphorylated extracellular signal-regulated kinase; PFS=progression-free survival; RR=response rate.
1. Grob JJ, et al. Poster presented at SMR 2014;
2. Hauschild A, et al. Poster presented at ASCO 2013;
3. Schadendorf D, et al. Poster presented at SMR 2013;
4. Flaherty KT, et al. N Eng J Med 2012;367:107–14;
5. King AJ, et al. PLoS ONE 2013;8(7):e67583.
pERK
Proliferation Survival Invasion Metastasis
RAS
Mutant BRAF
MEK
Preclinical BRAFi + MEKi5
− Delays BRAFi resistance
− Reduces hyperproliferative skin AEs
MEK inhibitor (trametinib)
− OS: 15.6 months3
− PFS: 4.8 months4
− RR: 22%4
− Rash AE3,4
BRAF inhibitor (dabrafenib)
− OS: 20.1 months1
− PFS: 6.9 months2
− ORR: 59%2
− Hyperproliferative skin AEs1,2
Goals of combination are to:
Suppress MAPK-dependent resistance mechanism
–Improve PFS, RR and OS –Prolong duration of response Reduce the incidence of BRAFi-induced proliferative skin lesions
COMBI-d: Progression-free Survival
Presented By Georgina Long at 2015 ASCO Annual Meeting
COMBI-v PFS
PRESENTED AT ESMO 2016.
SLIDES ARE THE PROPERTY OF THE AUTHOR. PERMISSION REQUIRED FOR REUSE.
COMBI-v: Duration of Response
12
● 36 of 68 patients (53%) with a CR on dabrafenib + trametinib are still in CR
● 21 of 41 patients (51%) with a CR on vemurafenib are still in CR
Patients
Survival, months
0 10 20 30 40
Dabrafenib + Trametinib
0 10 20 30 40
Survival, months
Patients
Vemurafenib
Median DOR (95% CI), months Dabrafenib + Trametinib Vemurafenib
All responders (CR + PR) 13.8 (11.3-17.7) 7.9 (7.4-9.3)
Complete responders 39.6 (26.5-NR) 29.9 (16.7-NR)
Partial responders 10.8 (9.2-12.0) 7.3 (5.8-7.5)
Complete response Partial response
Complete response Partial response
PRESENTED AT ESMO 2016.
SLIDES ARE THE PROPERTY OF THE AUTHOR. PERMISSION REQUIRED FOR REUSE.
COMBI-v and COMBI-d: Overall Survival Curves
13
D + T in COMBI-v D + T in COMBI-d1 2-year OS 53% (95% CI, 48-58) 52% (95% CI, 45-59) 3-year OS 45% (95% CI, 39-50) 44% (95% CI, 37-51)
Vem in COMBI-v D + Pbo in COMBI-d1 2-year OS 39% (95% CI, 34-45) 43% (95% CI, 36-50) 3-year OS 31% (95% CI, 26-36) 32% (95% CI, 25-38)
OS Probability
Months From Randomization
0 6 12 18 24 30 36 42
1.00
0.75
0.50
0.25
0.00
Patients at risk, n COMBI-d: D + Pbo COMBI-d: D + T COMBI-v: D + T COMBI-v: Vem
21 2 21
1 35
2 35
2
17 5 18
7 31
1 28
9
13 8 14
3 24
5 20
3
10 4 11
1 20
1 15
4
84 96 17 1 11
9
69 86 15 0 10
3
57 76 12 7 81
7 13 33 22
Pbo, placebo. 1. Flaherty KT, et al. J Clin Oncol. 2016;34 (suppl) [abstract 9502].
CoBRIM: OS benefit remained stable during long-term follow-up of extended treatment
14
C, cobimetinib; OS, overall survival; P, placebo; V, vemurafenib. Data cutoff: 20 June 2016
Time, Months
OS, %
C + V P + V
Median OS, months (95% CI) 22.5 (20.3, 28.8) 17.4 (15.0, 19.8) HR (95% CI); P-value 0.76 (0.60–0.96); P = 0.0188
Five Baseline Factors Influenced OS
aECOG = 0 ECOG ≥ 1
N = 93 1Y = 71%
2Y = 43%
3Y = NE
N = 56 1Y = 42%
2Y = 19%
3Y = 16%
LDH Normal N = 617 LDH ≥ ULN
Disease Sites ≥ 3 Disease Sites < 3
N = 161 1Y = 76%
2Y = 55%
3Y = 38%
N = 237 1Y = 90%
2Y = 75%
3Y = 70%
LDH >1-≤ 2 × ULN
LDH ≥ 2 × ULN N = 70 1Y = 40%
2Y = 7%
3Y = 7%
N = 149 1Y = 60%
2Y = 33%
3Y = 9%
N = 219 1Y = 54%
2Y = 25%
3Y = 7%
N = 398 1Y = 85%
2Y = 67%
3Y = 57%
aRegression tree analysis.
NE, not estimable. PRESENTED BY GV LONG AT SMR 2015
COMBI-d: Normal LDH a and < 3 Disease Sites b
Presented by: Keith T. Flaherty, MD
aBaseline LDH ≤ ULN; bAny organ at baseline with ≥ 1 metastasis could be counted as a single disease site; +, censored.
96 93 77 65 56 45 36 2 0
76 72 62 52 46 41 35 4 0
D+Pbo D+T Number at risk
Dabrafenib + Trametinib (n = 76)
Dabrafenib + Placebo (n = 96)
3-y OS, 62%
3-y OS, 45%
1.0
0.8
0.6
0.4
0.2
0.0
0
Months From Randomization
OS Probability
2-y OS, 68 % 2-y OS, 61%
6 12 18 24 30 36 42 48
96 64 41 25 16 5 3 0
76 56 39 34 28 25 19 0
D+Pbo D+T Number at risk
0
Months From Randomization
6 12 18 24 30 36 42
1.0
0.8
0.6
0.4
0.2
0.0
3-y PFS, 15%
3-y PFS, 38%
Dabrafenib + Trametinib (n = 76)
Dabrafenib + Placebo (n = 96)
PFS Probability
OS
PFS
PRESENTED AT ESMO 2016.
SLIDES ARE THE PROPERTY OF THE AUTHOR. PERMISSION REQUIRED FOR REUSE.
COMBI-v: Normal LDH and < 3 Organ Sites With Metastasis
17
Patients at risk, n
D + T Vem
OS Probability
Months From Randomization Vemurafenib (n = 161)
Median OS, 26.4 (95% CI, 21.5-46.8) HR, 0.47 (95% CI, 0.33-0.67)
3-y OS, 70%
3-y OS, 46%
2-y OS, 52%
2-y OS, 79%
Dabrafenib + trametinib (n = 141) Median OS, NR (95% CI, NR-NR)
14 1 16
1 13
5 14
6 12
5 12
5 11
5 91
10 4 75
96 68
83 58
21 16 1.00
0.75
0.50
0.25
0.00
0 6 12 18 24 30 36 42
Patients at risk, n
D + T Vem
Months From Randomization
3-y PFS, 39%
3-y PFS, 16%
2-y PFS, 46%
2-y PFS, 27%
Vemurafenib (n = 161) Median PFS, 10.7 (95% CI, 9.0-11.1)
HR, 0.52 (95% CI, 0.39-0.70)
PFS Probability
Dabrafenib + trametinib (n = 141) Median PFS, 23.0 (95% CI, 18.1-29.7)
14 1 16
1 12
3 93
98 50
76 40
59 22
49 12
43 8
19 2 1.00
0.75
0.50
0.25
0.00
0 6 12 18 24 30 36 42
OS PFS
COMBI-d: Treatment-Related Adverse Events (≥20% of Patients)
Presented By Georgina Long at 2015 ASCO Annual Meeting
Discontinuations
20
V + P (n = 246) 30 Sept 2015
P + V (n = 245) 20 June 2016
C + V (n = 247) 30 Sep 2015
C + V (n = 248) 20 June 2016
Discontinued both V and C/P 216 (88) 225 (92) 193 (78) 209 (84)
Disease Progression 180 (73) 185 (76) 127 (51) 135 (54)
Adverse Events 21 (8.5) 21 (8.6) 36 (14.6) 38 (15.3)
Deaths 2 (0.8) 3 (1.2) 3 (1.2) 4 (1.6)
Other
a13 (5.3) 16 (6.5) 27 (10.9) 32 (12.9)
Conclusion TT
• BRAFI/MEKI: Standard of Care in BRAF mut metastatic melanoma patients
• Open Issues:
Strategies for overcoming the resistance
Intermittent dosing of double MAPKi (S1320 Trial)
Treatment Beyond Progression
BeyPro2 Trial
Treatment Beyond Progression: BeyPro2
BRAFI + MEKI PD
«local» PD
«systemic» PD Second line treatment Second line treatment Combo + local treatment
• Study Design: multicenter phase II randomized study
• Sites: 16
• Number of Patients: 120
• Primary endpoint : OS, Secondary PFS, ORR, Toxicity
• BRAF/MEK Inhibitors
• Dabrafenib + trametinib
• Vemurafenib + cobimetinib
• Immunotherapy
• Ipilimumab
• Nivolumab
• Nivolumab + ipilimumab
• Pembrolizumab
Treatment Options for BRAF V600–
Mutant Metastatic Melanoma
Topics
• Background and Rationale
• Immunotherapy with immune checkpoint inhibitors (anti-CTLA4 and anti-PD1)
• New combinations (e.g. anti-PD1 + anti-IDO)
• Combination of immune checkpoint inhibitors and vaccinations
• Combination of targeted therapy and immune checkpoint inhibitors
• Search for Biomarkers
Slide 6
27 Survival Rate Ipilimumab +
gp100 (n=403)
Ipilimumab + placebo (n=137)
gp100 + placebo (n=136)
1 year 44% 46% 25%
2 year 22% 24% 14%
median OS (mts) (95%
CI)
10.0 8.5-11.5
10.1 8.0-13.8
6.4 5.5-8.7
Kaplan-Meier: analysis of survival
lpilimumab + gp100 (A) lpilimumab + placebo (B) gp100 + placebo (C)
Proportion alive
Years
Comparison HR p- value
Arms A vs. C 0.68 0.0004
Arms B vs. C 0.66 0.0026
1 2 3 4
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
1 2 3 4
No. At Risk
Ipi plus gp100 403 297 223 163 115 81 54 42 33 24 17 7 6 4 0
Ipi 137 106 79 56 38 30 24 18 13 13 8 5 2 1 0
gp100 136 93 58 32 23 17 16 7 5 5 3 1 0 0 0
MDX010-20
median f/u (mts) 27.8
21 17.2
Hodi FS, et al. N Engl J Med 2010;363:711–723 1 year
2 years
Rapid and Durable Changes in Target Lesions
Presented by: Jedd D. Wolchok, MD, PhD
1 mg/kg nivolumab + 3 mg/kg ipilimumab
First occurrence of new lesion
• A 52-year-old patient presented with extensive nodal and visceral disease
• Baseline LDH was elevated (2.3 x ULN); symptoms included nausea and vomiting
• Within 4 wk, LDH normalized and symptoms resolved
• At 12 wk, there was marked reduction in all areas of disease as shown
Weeks since treatment initiation
Change in target lesions from baseline (%)
Pre- treatment
12 weeks
Topics
• Background and Rationale
• Immunotherapy with immune checkpoint inhibitors (anti-CTLA4 and anti-PD1)
• New combinations (e.g. anti-PD1 + anti-IDO)
• Combination of immune checkpoint inhibitors and vaccinations
• Combination of targeted therapy and immune checkpoint inhibitors
• Search for Biomarkers
Primary Analysis of Pooled OS Data:<br />1861 Patients
OS: Randomized Patients
31
Alive (%)
Time (Months)
0 10 20 30 40 50 60 70 80 90 100
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
IPI 10 mg/kg IPI 3 mg/kg
OS
IPI 10 mg/kg n = 365
IPI 3 mg/kg n = 362
Events (%) 262 (72) 279 (77)
Median (95% CI),
mo 15.7 (11.6, 17.8) 11.5 (9.9, 13.3)
HR (95% CI) 0.84 (0.70, 0.99)
Log-rank P value 0.04
Minimum OS follow-up: ~43 mo Number of patients at risk
IPI 10 mg/kg 365 306 253 217 196 181 161 151 137 126 120 118 111 105 94 16 0
IPI 3 mg/kg 362 310 253 205 168 146 131 118 107 95 87 83 80 76 71 8 0
54%
48% 38%
31%
31%
23%
Safety Summary: Treated Patients
IPI 10 mg/kg n = 364
IPI 3 mg/kg n = 362
AEs during initial treatment phase Any grade Grades 3-5 Any grade Grades 3-5
AEs, % 95 59 93 52
Treatment-related AEs, % 79 34 63 19
Serious AEs, % 64 53 51 43
AEs leading to discontinuation, % 31 26 19 16
Immune-related AEs, % 74 30 54 14
32
• During the entire study period, study-drug toxicity led to death in
• 4 patients (1%) in the 10 mg/kg arm
• Diarrhea leading to general deterioration, fulminant colitis, multi-organ failure, bowel perforation
• 2 patients (<1%) in the 3 mg/kg arm
• Multifocal colon perforation, myocardial infarction from complications of diarrhea
and colitis
Response to NIVO Monotherapy
33
*3 mg/kg IV Q2W dose selected for phase III studies of NIVO monotherapy
Dose, mg/kg
ORR,
%, (n/N)
Median Duration of Response, months (range)
All doses 32 (34/107) 23 (4–32)
0.1 35 (6/17) 10 (6–27+)
0.3 28 (5/18) 32 (4–32)
1 34 (12/35) 24 (8–31+)
3* 41 (7/17) 22 (9–27+)
10 20 (4/20) 26 (17–27+)
Database lock Oct 2015 Database lock Sep 2014
Time to Response and Durability of Response
34
• Follow-up (range): 32–82 months
• 44% (15/34) of responding patients showed a response at first tumor assessment (8 weeks)
• Responses ongoing in 13/34 (38%) responders
Database lock Oct 2015
Patients
0 8 16 24 32 40 48
Time (Month)
On treatment Off treatment First response Ongoing response
Overall Survival at 5 Years of Follow-up
35
Probability of Survival
Months 0.0
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84
Database lock Oct 2015
107 86 64 51 49 43 41 36 29 17 15 12 3 1 0
Number of Patients at Risk All Patients
All Patients (events: 69/107), median and 95% CI: 17.3 (12.5–37.8) NIVO 3 mg/kg (events: 11/17), median and 95% CI: 20.3 (7.2–NR)
17 15 11 9 8 7 7 6 6 6 6 6 1 0
NIVO 3 mg/kg
36
OS Rate, % (95% CI)*
Landmark timepoint All Patients
(N = 107)
NIVO 3 mg/kg (n = 17)
12-month 63 (53–71) 65 (38–82)
24-month 48 (38–57) 47 (23–68)
36-month 42 (32–51) 41 (19–63)
48-month 35 (26–44) 35 (15–57)
60-month 34 (25–43) 35 (15–57)
Median OS, months (95% CI) 17.3 (12.5–37.8) 20.3 (7.2-NR)
Database lock Oct 2015
Summary of Overall Survival
*Based on Kaplan-Meier estimates NR, not reached
Long term outcomes from Pembrolizumab<br />Keynote 001: 3 year survival
Presented By Marc Ernstoff at 2016 ASCO Annual Meeting
ASCO 2016
CA209-067: Study Design
aVerified PD-L1 assay with 5% expression level was used for the stratification of patients; validated PD-L1 assay was used for efficacy analyses
bPatients could have been treated beyond progression under protocol-defined circumstances Unresectable or
Metatastic Melanoma
• Previously untreated
• 945 patients
Treat until progressionb
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
IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo Randomize
1:1:1
Stratify by:
• Tumor PD-L1 expressiona
• BRAF mutation status
• AJCC M stage
N = 314
N = 316
N = 315
Randomized, double-blind,
phase III study to compare NIVO+IPI
or NIVO alone to IPI alone
ASCO 2016
Progression-Free Survival (Intent-to-Treat Population)
49%
42%
18%
46%
39%
14%
Percentage of PFS
PFS per Investigator (months) 0
10 20 30 40 50 60 70 80 90 100
0 3 6 9 12 15 18 21 24 27
314 316 315
174 148 78
133 114 46
103 94 25
8 8 3 219
177 137
156 127 58
126 104 40
48 46 15
0 0 0 Number of patients at risk:
Nivolumab + Ipilimumab Nivolumab Ipilimumab
NIVO+IPI NIVO IPI
aStratified log-rank P<0.00001 vs. IPI
bExploratory endpoint
Progression-free Survival (%)
NIVO + IPI (N = 314) NIVO (N = 316) IPI (N = 315) Median PFS, months (95% CI) 11.5 (8.9, 16.7) 6.9 (4.3, 9.5) 2.9 (2.8, 3.4)
HR (99.5% CI) vs. IPI 0.42 (0.31, 0.57)a 0.55 (0.43, 0.76)a --
HR (95% CI) vs. NIVO 0.76 (0.60, 0.92)b -- --
Database lock Nov 2015
ASCO 2016
Response to Treatment
aBy RECIST v1.1 NR = not reached Database lock Nov 2015
NIVO + IPI (N = 314)
NIVO (N = 316)
IPI (N = 315) ORR, % (95% CI)a 57.6 (52.0, 63.2) 43.7 (38.1, 49.3) 19.0 (14.9, 23.8)
Two-sided P value vs IPI <0.001 <0.001 --
Best overall response, %
Complete response 12.1 9.8 2.2
Partial response 45.5 33.9 16.8
Stable disease 13.1 10.4 21.9
Progressive disease 22.6 38.0 48.9
Unknown 6.7 7.9 10.2
Median duration of response, months (95% CI) NR (20.5, NR) 22.3 (20.7, NR) 14.4 (8.3, NR)
Ongoing response among responders, % 72.5 72.4 51.7
ASCO 2016
Progression-free Survival by Tumor PD-L1 Expression
Database lock Nov 2015
NIVO + IPI (N = 210)
NIVO (N = 208)
IPI (N = 202) Median PFS, months
(95% CI)
11.1 (8.0, 22.2)
5.3 (2.8, 7.1)
2.8 (2.8, 3.1) HR (95% CI) vs NIVO 0.74
(0.58, 0.96)a ─ ─
NIVO + IPI (N = 68)
NIVO (N = 80)
IPI (N = 75) Median PFS, months
(95% CI)
NR (9.7, NR)
22.0 (8.9, NR)
3.9 (2.8, 4.2) HR (95% CI) vs.
NIVO
0.87
(0.54, 1.41)a ─ ─
Percentage of PFS
PFS (months) 0
10 20 30 40 50 60 70 80 90 100
0 3 6 9 12 15 18 21 24 27
210 208 202
113 89 45
86 69 26
69 55 12
5 7 0 142
108 82
101 75 34
81 62 22
31 29 7
0 0 0 Number of
patients at risk:
NIVO + IPI NIVO IPI
NIVO + IPI NIVO IPI
Tumor PD-L1 Expression Level <5%
*Exploratory endpoint
Percentage of PFS
PFS (months) 0
10 20 30 40 50 60 70 80 90 100
0 3 6 9 12 15 18 21 24 27
aExploratory endpoint
68 80 75
44 51 21
33 39 14
22 36 8
3 1 2 53
57 40
39 45 17
31 37 12
13 16 6
0 0 0 Number of
patients at risk:
NIVO + IPI NIVO IPI
NIVO + IPI NIVO IPI
Tumor PD-L1 Expression Level ≥5%
• For the original PD-L1 PFS analysis, the descriptive hazard ratio comparing NIVO+IPI vs NIVO was 0.96, with a similar median PFS in both groups (14 months)
Types of tumor microenvironment and cancer immunotherapeutic modules
Teng MWL et al. Cancer Res 2015; 75:2139
ASCO 2016
Safety Summary
• Updated safety information with 9 additional months of follow-up were consistent with the initial report
• 68.8% of patients who discontinued NIVO+IPI due to treatment-related AEs achieved a response
aOne reported in the NIVO group (neutropenia) and one in the IPI group (colon perforation) Database lock Nov 2015
NIVO+IPI (N = 313)
NIVO (N = 313)
IPI (N = 311)
Patients reporting event, % Any grade Grade 3-4 Any grade Grade 3-4 Any grade Grade 3-4 Treatment-related adverse
event (AE) 95.8 56.5 84.0 19.8 85.9 27.0
Treatment-related AE leading
to discontinuation 38.7 30.7 10.5 7.3 15.4 13.5
Treatment-related deatha 0 0.3 0.3
Topics
• Background and Rationale
• Immunotherapy with immune checkpoint inhibitors (anti-CTLA4 and anti-PD1)
• New combinations (e.g. anti-PD1 + anti-IDO)
• Combination of immune checkpoint inhibitors and vaccinations
• Combination of targeted therapy and immune checkpoint inhibitors
• Search for Biomarkers
SMR 2014
T-Cell Checkpoint Regulation: other immune checkpoints
• T-cell responses are regulated though a complex balance of inhibitory (“checkpoint”) and activating signals
• Tumors can dysregulate checkpoint and activating pathways, and consequently the immune response
• Targeting checkpoint and activating pathways is an evolving approach to cancer therapy, designed to promote an immune response
Adapted from Mellman I, et al. Nature. 2011:480;481–489; Pardoll DM. Nat Rev Cancer. 2012;12:252–264.
PD-1 CTLA-4 Inhibitory receptors Activating receptors
TIM-3
LAG-3
Antagonistic (blocking) antibodies Agonistic antibodies
T-cell stimulation CD28
OX40
CD137
ONCHQ13NP09700
Co-inhibitory Receptor Pathways
Anderson AC et al. Immunity 2016; 44:989
Hierarchy of Co-inhibitory Receptors
Anderson AC et al. Immunity 2016; 44:989
Specification of Checkpoint-Receptor Pathways
Anderson AC et al. Immunity 2016; 44:989
Clinical Trials
• Safety Study of Anti-LAG-3 With and Without Anti-PD-1 in the Treatment of Solid Tumors
ClinicalTrials.gov Identifier: NCT01968109
Sponsor: Bristol-Myers Squibb
A Phase 1 Dose Escalation and Cohort Expansion Study of the Safety, Tolerability, and Efficacy of Anti-LAG-3
Monoclonal Antibody (BMS-986016) Administered Alone
and in Combination With Anti-PD-1 Monoclonal Antibody
(Nivolumab, BMS-936558) in Advanced Solid Tumors
Clinical Trials
• Safety and Efficacy of LAG525 Single Agent and in combination with PDR001 in Patients with Advanced Malignancies
ClinicalTrials.gov Identifier: NCT02460224
Sponsor: Novartis Pharm.
A Phase I/II, Open Label, Multicenter Study of the Safety
and Efficacy of LAG525 Single Agent and in Combination
With PDR001 Administered to Patients With Advanced
Malignancies
IDO
A phase III Randomized, Double Blind, Placebo-Controlled
Study of Pembrolizumab (MK-3475) in Combination with
Epacadostat or Placebo in subjects with unresectable or
metastatic melanoma Keynote-252
Clinical Trials
• Pembrolizumab plus Bevacizumab for Treatment of Brain Metastases in Metastatic Melanoma or Non-Small Cell Lung Cancer
ClinicalTrials.gov Identifier: NCT02681549 Sponsor: Yale University
Phase II Trial
53 pts: 33 with NSCLC
Future Perspectives
• Combination of immunotherapy and targeted therapy
• Search for Biomarkers helping to determine Frontline Treatment for unresectable metastatic BRAF-mutant melanoma
• New Combinations
• Combination of immune checkpoint inhibitors and vaccinations
• Combination of immune checkpoint inhibitors and RT
TVEC: summary of genetic modifications
Modification Result
Use of new HSV-1 strain (JS1) Improved tumor cell killing ability compared with other strains
Deletion of ICP34.5 Prevents HSV infection of non-tumor cells, providing tumor-selective replication
Deletion of ICP47 Enables antigen presentation
Earlier insertion of US11 Increases replication and oncolysis of tumor cells
Insertion of human GM-CSF gene
Enhances anti-tumor immune response by
recruiting and stimulating dendritic cells to tumor
site
T-VEC + PEMBROLIZUMAB
• MASTERKEY-265 trial
• Phase 1b T-VEC (HCV-1 oncolytic immunotherapy)+ pembrolizumab in stage IIIB-IV melanoma
• Pembrolizumab starting at day36
• Injectable lesions, no prior therapy
• 21 pts enrolled
• 19% BRAF mut
• Safety: 33% G3-4 Adverse Events
• Fatigue, pyrexia, chills
• Confirmed RR=48%
• CR=14%
• Time to response= 17 weeks
• Increased of CD8+ during T-VEC, reduced after pembrolizumab start
Long et al, Abst # 9568
T-VEC+ Pembrolizumab associated with clinical benefit, trials ongoing!
Future Perspectives
• Combination of immunotherapy and targeted therapy
• Search for Biomarkers helping to determine Frontline Treatment for unresectable metastatic BRAF-mutant melanoma
• New Combinations
• Combination of immune checkpoint inhibitors and vaccinations
• Combination of immune checkpoint inhibitors and RT
Abscopal Effect
Herrera FG, et al. CA Cancer J Clin 2016
Abscopal Effect
Herrera FG, et al. CA Cancer J Clin 2016
Abscopal Effect of local RT
• Trial of SBRT With Concurrent Ipilimumab in Metastatic Melanoma (Phase I)
NCT02406183 21 pts
Sponsor: Radiotherapie, University Hospital, Ghent
• Phase II Trial of Pembrolizumab and Radiotherapy in Melanoma (PERM)
NCT02562625 234 pts
Sponsor: Royal Marsden NHS Foundation Trust
• Study RADVAX: A Stratified Phase I Trial of
Pembrolizumab With Hypofractionated Radiotherapy in Patients With Advanced and Metastatic Cancers (Phase I)
NCT02303990 70 pts
Topics
• Background and Rationale
• Immunotherapy with immune checkpoint inhibitors (anti-CTLA4 and anti-PD1)
• New combinations (e.g. anti-PD1 + anti-IDO)
• Combination of immune checkpoint inhibitors and vaccinations
• Combination of targeted therapy and immune checkpoint inhibitors
• Search for Biomarkers
Effects of BRAFIs
on Melanoma and Immune cells
Hu-Lieskovan S, et al. J Clin Oncol 32:2248, 2014
Antitumor Activity (RECIST v1.1, Investigator Review)
Manageable toxicity, phase II ongoing!
IDO
Response to anti-PD1 therapy in metastatic melanoma: genomic and transcriptomic features
Hugo W et al. Cell 2016; 165:35
EA6134: Ipi/Nivo to D/T vs D/T to Ipi/Nivo<br />PIs: Michael Atkins (ECOG), Bartosz Chmielowski (SWOG)
Presented By Antoni Ribas at 2016 ASCO Annual Meeting
• Prospective
randomized phase II study to evaluate the best sequential approach with combo
immunotherapy (ipilimumab/nivoluma b) followed by
combo target
therapy (dabrafenib/
trametinib) and vice- versa
• Patients affected by metastatic
melanoma BRAF V600 mutated
• Sample size 230 pts
(SECOMBIT) Study
PD Combo I until PD
This study is designed as a phase II randomized trial with no formal comparative test.
Endpoints:
Primary – OS
Secondary – PFS, Total PFS (TPFS): the time to the second progression, % patients alive at 2-3 years, BORR;
Duration of Response, Toxicity, Biomarkers study
PD Combo T until PD
Combo I until
PD Combo T until PD
ARM A Combo T
LGX 450 mg MEK 162 45 mg
ARM B Combo I
Ipilimumab 3 mg/Kg Nivolumab 1mg /Kg
ARM C Sandwich
LGX 450 mg MEK 162 45 mg for 8
weeks
Topics
• Background and Rationale
• Immunotherapy with immune checkpoint inhibitors (anti-CTLA4 and anti-PD1)
• New combinations
• Combination of immune checkpoint inhibitors and vaccinations
• Combination of targeted therapy and immune checkpoint inhibitors
• Search for Biomarkers
Immune parameters in peripheral blood as predictive factors of response to anti-CTLA-4
Subset/immune parameter Type of association with clinical outcome Author/year
Lymphocyte count >1000/mm3 Improved OS when observed at the start of second course Deylon / 2013 Baseline Neutrophil to
Lymphocyte Ratio (NLR) NLR<5 associated with improved OS Ferrucci /2015 Baseline ANC and dNLR ANC>7500 and dNLR>3 associated with increased risk of
death Ferrucci 2016
Monocyte counts, eosinophil
counts Baseline low absolute monocyte count and high absolute
eosinophil count associated with better survival Martens / 2016 1. Eomes+CD8+ and
2. Ki67+Eomes+CD8+ 1. increase at 6 months associated with relapse.
2. Low baseline level associated with relapse Wang / 2012 ICOS+CD4+and ICOS+CD8+ increase at wk7 associated with improved survival Di Giacomo / 2013
PD-1+CD4+ Low pre-treatment level associated with better OS Kwek / 2015 CD14+CD11b+HLA-DR-MDSCs Higher baseline or post-infusion levels
in non responders Gebhardt / 2015
Lin-CD14+HLA-DR-MDSCs Lower frequency in responders Meyer /2014
FOXP3+Treg at wk 12 Decrease associated with improved survival Simeone / 2014 Lin-CD14+HLA-DR-/low MDSC
and CD4+FoxP3+ Tregs Low baseline MDSCs and high Treg frequencies associated
with better survival Martens / 2016
sCD25 High baseline level associated with resistance to therapy Hannani / 2015 IL-17, TGF-β1, IL-10 Baseline IL-17 levels associated with subsequent colitis.
Combined IL-10 and TGF-β1 associated with PFS Tarhini / 2015
1
2
3
4
Case Report: T cell activation and maturation at tumor site associated with objective response to Ipi in metastatic melanoma
M. Del Vecchio, R. Mortarini, G. Tragni, L. Di Guardo, I. Bersani, G. Di Tolla, F. Agustoni, V.
Colonna, J.S. Weber, A. Anichini. J Clin Oncol, 2011;29(32):e783-8. Epub 2011 Oct 11
Regressing lesion Progressing lesion Pre-therapy lesion
Infiltration of activated T cells in the lesion responding to anti-CTLA4
Post-therapy, progressing lesion: FOXP3+lymphocytes Post-therapy, regressing lesion: FOXP3+lymphocytes
Reduced frequency of regulatory T cells
in the lesion responding to Ipilimumab
Is immune escape involved in the progressing lesion?
Regressing lesion Progressing lesion
MART-1
gp100
Why is the progressing lesion not responding ?
HLA-DOB HLA-G HLA-DQA2 HLA-DPB2 HLA-DPB1 HLA-A29.1 HLA-DRB5 HLA-C HLA-F HLA-A HLA-E HLA-DMB HLA-DMA B2MHLA-DRA HLA-DRB3 HLA-B B2MHLA-DRB1 HLA-DRB4 HLA-F HLA-DPA1 HLA-DRA HLA-DRB6 HLA-DPB2 HLA-DQB1
POST1 POST1 POST1 POST2 POST2 POST2
PRE PRE PRE ADR. TISSUE ADR. TISSUE ADR. TISSUE TUMOR only TUMOR only TUMOR only
- 1.5
1 - 1.0
1 - 0.5
0 0.0
0 0.5
0 1.0
1 1.5 1
Why is the progressing lesion not responding ?
Pre-therapy lesion PRE
Post-therapy lesion 1 (regressing lesion)
POST1a
Post-therapy lesion 2 (progressing lesion)
POST2a Adrenal
Tissue Post-2
“Tumor only”
Post-therapy lesion 2- non responding lesion Post-therapy lesion 1- responding lesion HLA Class I
HLA Class I
Post-therapy lesion 1- responding lesion
Post-therapy lesion 2- non responding lesion
HLA Class II expression
Why only some tumors have infiltrating T cells
CD3 CD4
CD8 PD-L1 β−catenin
Lack of T cell infiltrate in β-catenin-areas of a metastatic lesion
Acknowledgements
Human Tumors Immunobiology Unit Andrea Anichini Roberta Mortarini Elena Tassi Valentina Perotti Ilaria Penna Giulia Grazia Ilaria Bersani Alessandra Molla Claudia Vegetti Gabriella Nicolini Paola Baldassari
Medical Oncology Lorenza Di Guardo Carolina Cimminiello Lorenzo Pilla*
Filippo De Braud
Melanoma and Sarcoma Unit Andrea Maurichi
Mario Santinami
Dept. of Pathology Gabrina Tragni*
Barbara Valeri
Functional Genomic Core Facility Loris de Cecco Edo Marchesi Silvana Canevari
Grant support CD4+T cell
CD8+T cell
Melanoma Class IMHC
Class IIMHC
(At least) three different immune profiles associated with lack of response to anti-CTLA4 therapy
Immune profile 1: No T cell infiltration;
Immune profile 2: No T cell infiltration and loss of HLA (I/II) molecules;
Immune profile 3: Presence of infiltrating T cells but loss of HLA molecules;
