Europe-Balkan-Course-2018--Management-of-melanoma-with-immunotherapy-and-targeted-treatment-Martin-Algarra.pdf

Neoadjuvant immunotherapy in stage III Melanoma -NADINA Traial

1. Management of Melanoma with
Immunotherapy and Targeted therapies
Salvador Martín Algarra MD, PhD
Medical Oncology
Clínica Universidad de Navarra
Pamplona –Madrid
Spain
5th ESO-ESMO Eastern Europe and Balkan
Region Masterclass in Medical Oncology
June 20, 2018 -Belgrade, Serbia

2. Disclosures
Advisory boards for Amgen, BMS, Incyte, MSD, Pierre Fabre, Roche.

3. MELANOMA
•Cutaneous melanoma (CM) incidence rates continue to increase, and
the reasons are unknown.(Liu-Smith F, JAAD 2017)
•Despite improvements in prevention, diagnosis, and treatment, vast
differences inmelanomaburden still exist between populations: highest
rates reported in Australia (37 per 100,000) and the lowest in South-
Central Asia (0.2 per 100,000).
•The greatest burden frommelanomafalls on Australia[New Zealand],
North American, European, elderly, and male populations. (Karimkhani
C, BrJD 2017)

4. MELANOMA
•Europe lags behind Australia and the United States in terms of incidence rates, but
within Europe incidence rates vary widely.
•Switzerland has the highest rates (19.2 cases per 100,000) and Greece the lowest (2.2
cases per 100,000).
•There is also evidence of clear North–South and East–West incidence gradients across
the continent.
•The reason for such variation is unclear and may be associated with differences in
affluence and recreational sun exposure. However, it is also likely to be (at least in
part) related to discrepancies in cancer registrationbetween different countries, in
particular in Eastern Europe.
Ali Z, Yousaf N, Larkin J. Melanoma epidemiology, biology and prognosis EJC Supplements 11(2):81-91, September 2013

5. MELANOMA
Cutaneous melanoma is a readily curable neoplasm,
with 85% of diagnosed patients enjoying long-term
survival following simple surgical excision.

6. >90%
50-90%
10-60%
<10%

7. Single Agent Chemotherapy
•Dacarbazine (DTIC)
•FDA approved in 1975
•Response rates 8-12% in phase III trials
•Standard arm in clinical trials
•Temozolomide (Temodal)
•Active metabolite of dacarbazine
•Oral
•Similar efficacy to dacarbazine (ref. 1)
•Penetrates central nervous system
•Other chemotherapeutic agents
•Fotemustine
•Carboplatin
•Paclitaxel
•All response rates <15% (e.g. ref. 2)
1.Patel et al. Ann Oncol 2008: 19 Abstract LBA8
2.Hauschild et al. JCO 27, 2328 (2009)

8. Combination Chemotherapy #Patients ORR

DTIC+CISPLATINO >150 32%
DTIC+CDDP+BCNU 39 10 - 25%
DTIC+CDDP+BCNU
+ TAMOXIFENO
384 38 - 63%
DTIC + IF alfa2 100 30 - 39%

10. Melanoma has become one of the
most fast-paced and exciting fields in
cancer research over the past years.

11. A better understanding of risk factorsand
molecular and immunological alterations key for
have leads to the identifications of new targeted
and immunomodulatorytherapies.
With these new agents, the field has set a
remarkable standard for achievement in cancer
research.

12. Major changes for stage III in AJCC 8
th
edition
GershenwaldJE et al. CA Cancer J Clin, 2017
•New N subcategories
•3 → 4 stage III subgroups
•New TNM combinations

13. Major changes for stage IV in AJCC 8
th
edition

14. •Growing number of positive clinical trials.
•Approval of new agents and combinations.
•Useful knowledge to design trials and
translational studies in other neoplasms.

15. There have been significant advances in the
treatment of melanoma over the last six years:
•Immunotherapy
•Targeted therapy
•Oncolytic virus therapy

17. T cell
Dendritic
cell
MHC
B7
Antigen
CTLA4
TCR
CTLA4 Receptors Are Up -Regulated Following T-Cell Activation
CD28

18. T cell
MHC
B7
TCR
CD28
Antigen
CTLA4
Dendritic
cell
CTLA4 Negatively ModulatesT -Cell Activation
CTLA4 binds B7 with greater affinity than does CD28
and sends a negative signal to the T cell.

19. FDA Approval in Advanced Melanoma
IPILIMUMAB 1
st
line
03/2011

21. Molecular Genotype and Location of Primary Site
Curtin NEJM 2005;352:2135
BRAF
or
NRAS
PTEN
KIT
CCND1
KIT
CCND1
KIT
CDK4
Acral Mucosal
SolarIntermittent Solar

22. 0.0%
50.0%
noCSD CSD acralmucosal
KIT
RAS
BRAF Curtin J et al. J Clin Oncol 2006
“The Melanomas”

23. Curtin JA et al.

24. RAS–RAF Pathway
RTK = receptor tyrosine kinase; GTP = guanosine triphosphate; ERK =
extracellular signal-related kinase; MEK = MAP (mitogen-activated
protein).
2. Garnett MJ, et al. Cancer Cell 2004;6:313–9.
4. Wan PTC, et al. Cell 2004;116:855–67.
BRAF
Activated RAS
MEK
ERK
P
Oncogenic BRAF
signaling
4
Normal RAS–RAF
pathway signaling
2
Growth
factors
RTK
Mutated
BRAF
Excessive cell
proliferation and
survival
MEK
ERK
P
PP
RAS–GTP
Normal cell
proliferation and
survival
•Constitutive
activation is
independent of
extracellular factors
•Not responsive to
normal regulatory
signals
•Normal activation
of RAS by
extracellular factors

26. •Given the preponderance of BRAF
mutationsin melanoma, there has been
continued interest in the development of
inhibitors of BRAF for nearly a decade.
BRAF as target in Oncology

27. BRAF Mutations & Kinase Activity
•Ninety percent of BRAFmutations in melanoma
result in substitution at position V600
.

28. FDA Approval in Advanced Melanoma BRAF-V600+
VEMURAFENIB 1
st
line
10/2011

29. EMA Drugs Approval in Advanced Melanoma
Date of issue of marketing authorization for the European Union
•Ipilimumab* 13/07/2011 -20/09/2013*
•Vemurafenib 17/02/2012
•Dabrafenib 28/06/2013
•Trametinib 30/06/2014
•Nivolumab 19/06/2015
•Pembrolizumab 17/07/2015
•DabrafenibwithTrametinib 23/07/2015
•Vemurafenibwith Cobimetinib20/11/2015
•TalimogeneLaherparevec 16/12/2015
•Nivolumabwith Ipilimumab 01/04/2016

30. EMA Drugs Approval in Advanced Melanoma
Date of issue of marketing authorization for the European Union
•Ipilimumab* 13/07/2011 -20/09/2013*
•Vemurafenib 17/02/2012
•Dabrafenib 28/06/2013
•Trametinib 30/06/2014
•Nivolumab 19/06/2015
•Pembrolizumab 17/07/2015
•DabrafenibwithTrametinib 23/07/2015
•Vemurafenibwith Cobimetinib20/11/2015
•TalimogeneLaherparevec 16/12/2015
•Nivolumabwith Ipilimumab 01/04/2016

31. Anti-CTLA4 Antibody Releases a Block for T -Cell Activation
T cell
MHC
TCR
CD28
Antigen
CTLA4
Dendritic
cell
B7
Antibody to CTLA4 prevents interaction with B7 and
blocks the negative signal.

32. Robert C, et al. N Engl J Med 2011;364:2517–2526
CA184-024
Phase 3 trial of ipilimumab plus DTIC vs DTIC in 1
st
line patients

33. Similar results with Ipilimumab
in first and second line
•No long term differences in survival
•Chemotherapy toxicity may limit Ipilimumab administration
•Chemotherapy may deplete CD4 lymphocytes
•Combination with Fotemustine with similar results

34. Pooled overall survival data from 1861 Ipilimumab-treated
patients in 12 clinical trials
•3-year estimated survival rate of 22% observed in patients treated with ipilimumab
•A plateau in the survival curve begins at approximately 3 years, with some patients followed for up to 10 years
•Consistency of long-term survival data for ipilimumab in metastatic melanoma, regardless of doses, regimens and treatment line
Patients at Risk
Ipilimumab 1861 839 370 254 192 170 120 26 15 5 0
Proportion of patients alive (%)
0
10
20
30
40
50
60
70
80
90
100
Months
0 12 24 36 48 60 72 84 96 108 120
Median OS, months (95% CI): 11.4 (10.7–12.1)
3-year OS rate, % (95% CI): 22 (20–24)
Ipilimumab
CENSORED
Schadendorf D, et al. Presented at ECC 2013: oral presentation 24LBA Schadendorf D, et al. J Clin Oncol. 2015;33:1889-1894.

35. EMA Drugs Approval in Advanced Melanoma
Date of issue of marketing authorization for the European Union
•Ipilimumab* 13/07/2011 -20/09/2013*
•Vemurafenib 17/02/2012
•Dabrafenib 28/06/2013
•Trametinib 30/06/2014
•Nivolumab 19/06/2015
•Pembrolizumab 17/07/2015
•DabrafenibwithTrametinib 23/07/2015
•Vemurafenibwith Cobimetinib20/11/2015
•TalimogeneLaherparevec 16/12/2015
•Nivolumabwith Ipilimumab 01/04/2016

36. PLX4032 is a Selective Inhibitor of the
OncogenicBRAF Kinase
ERK = extracellular signal-related kinase; MEK = MAP (mitogen-activated
protein) kinase kinase.
11. Bollag G, et al. Nature 2010;467:596–9.
12. Tsai J, et al. Proc Natl Acad Sci USA2008;105:3041–6.
13. Yang H, et al. Cancer Res2010;70:5518–27.
14. Søndergaard JN, et al. J Transl Med 2010;8:39.
PLX4032 :
•Developed by a structure-guided
discovery approach coupled with
optimization chemistry
11,12
•Binds to and selectively inhibits
oncogenic BRAF
V60011
•Has a novel mode of action.
PLX4032
Oncogenic BRAF
signalingarrested
with PLX4032
blocks
constitutively
active pathway
13
Mutated
BRAF
Arrested cell
proliferation
13
and
promoted cell death
14
MEK
PLX4032 (RG7204)
11
12
ERK

41. Progression-free survival
100
90
80
70
60
50
40
30
0
Probability of
progression
-
free survival (%)
20
10
Time (months)
0 1 4 6 8 10 12 142 3 5 7 9 11 13
132129 85 62 41 25 11 111593 73 45 33 18 6
No. at
risk
Median PFS 6.7 months (95% CI: 5.5, 7.8 months)
PFS at 6 months 54% (95% CI: 45, 63%)
BRIM 2: An Open-label, Multicenter Phase II Study of Vemurafenib (PLX4032, RG7204) in Previously Treated Patients with BRAF
V600E
Mutation-positive Metastatic Melanoma Abstract #8509

42. Changes in the sum of diameters from baseline
by disease stage
Individual patients treated with vemurafenib
60
40
20
0
-20
-40
-60
-80
-100
M1a
M1b
M1c
Disease stage
Percent change from baseline
in diameter of target lesion
*******
* 7 Confirmed CRs

43. Overall survival
100
90
80
70
60
50
40
30
0
Probability of
overall survival (%)
20
10
Time (months)
01 4 6 8 10 12 152 3 5 7 9 11 13
132131 118 97 83 71 34128122 109 90 78 55 19
No. at
risk
14
7 0
Median OS not reached
OS at 6 months 77% (95% CI: 70, 85)
12 months 58% (95% CI: 49, 67)

45. 100
90
80
70
60
50
40
30
20
10
0
Overall survival (%)
No. of patients in follow up
Dacarbazine
Vemurafenib
0 1 2 3 4 5 6 7 8 9101112
Vemurafenib (N=336)
Est 6 mo survival 84%
Months
336
336
283
320
192
266
137
210
98
162
64
111
39
80
20
35
1
6
1
1
Dacarbazine (N=336)
Est 6 mo survival 64%
9
14
Hazard ratio 0.37
(95% CI; 0.26 -0.55)
Log-rank P<0.0001
Overall survival (Dec 30, 2010 cutoff)

46. 0.20.40.61.02 4 106
Hazard ratio and 95% confidence interval
20
All patients 549
Age: <65 yrs
≥65 yrs
421
128
Sex: Female
Male
240
309
ECOG status: 0
1
365
184
Disease stage: IIIc
M1a
M1b
M1c
24
55
102
368
LDH : Normal
Elevated
318
231
BRIM3: PFS by baseline characteristic
Factor
Number
of patients
Favors
vemurafenib
Favors
dacarbazine

47. All patients 672
Age: <65 yrs
≥65 yrs
512
160
Sex: Female
Male
293
379
ECOG status: 0
1
457
215
Disease stage: IIIc
M1a
M1b
M1c
33
74
126
439
LDH : Normal
Elevated
390
282
Factor
Number
of patients
0.20.40.61.02 4 106
Hazard ratio and 95% confidence interval
Favors
vemurafenib
Favors
dacarbazine
20
BRIM3: OS by baseline characteristic

48. Selected adverse events (% of patients)
Vemurafenib, n= 336 Dacarbazine, n= 282
Adverse events All Grade 3Grade≥ 4 All Grade 3Grade ≥4
Arthralgia 49 3 - 3 <1 -
Rash 36 8 - 1 - -
Fatigue 33 2 - 31 2 -
Photosensitivity 30 3 - 4 - -
LFTs 18 7 <1 5 1 -
Cutaneous SCC 12 12 - <1 <1 -
Keratoacanthoma 8 6 - - - -
Skin papilloma 18 <1 - - - -
Nausea 30 1 - 41 2 -
Neutropenia <1 - <1 11 5 3
Discontinuations due to AE: 6% Vemurafenib; 4% Dacarbazine

49. Conclusions
•Vemurafenib associated with 63% decrease in hazard of
death (p<.0001)
•74% decrease in hazard of tumor progression (p<.0001)
•Benefit seen in all subgroups, including M1c and LDH
•Manageable safety profile with few drug related
discontinuations
•First single drug for melanoma to improve response rate,
PFS, and OS compared to standard chemotherapy
•Vemurafenib is a promising new therapy for patients with
metastatic BRAF
V600E
-mutated melanoma and a foundation
upon which to build combination therapies

51. EMA Drugs Approval in Advanced Melanoma
Date of issue of marketing authorization for the European Union
•Ipilimumab* 13/07/2011 -20/09/2013*
•Vemurafenib 17/02/2012
•Dabrafenib 28/06/2013
•Trametinib 30/06/2014
•Nivolumab 19/06/2015
•Pembrolizumab 17/07/2015
•DabrafenibwithTrametinib 23/07/2015
•Vemurafenibwith Cobimetinib20/11/2015
•TalimogeneLaherparevec 16/12/2015
•Nivolumabwith Ipilimumab 01/04/2016

53. 0 1 2 3 4 5 6 7 8 9
187 182 167 112 98 39 28 7 4 0
63 53 32 16 12 5 4 2 0 0
Dabrafenib:
median PFS 6.7 mos
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
DTIC:
median PFS 2.9 mos
Hazard ratio 0.35 (95% CI 0.20, 0.61)
PFS: Independent reviewer-assessed
(cut-off: 19 December 2011)
Proportion Alive Without Progression
Time from Randomization (Months)
Number at risk

54. Preliminary Activity in V600K BRAF mutant melanoma
•Evidence of activity in V600K
•Overall Response Rate 44% (4/9)
40
-60
-40
-20
0
20
% Change Lesion CT Scan
40
-60
-40
-20
0
20
V600K
Stable Disease
Best Unconfirmed Response
Partial Response ProgressiveDisease
150 mg BID (Parts 1 and 2)
54
 
M1b (patients without symbol are M1c)

55. Partial Response in Brain
61 yoV600E Multiple Metastases
Baseline Week 4 Week 10
55

56. Part 2 -Extracranialresponse correlates with
brain lesion reduction (n=10)
40
30
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
Maximum %
Change from Baseline
Patients
40
30
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
% Decrease from baseline Brain
Extracranial
56

58. VemurafenibExpanded access program
Larkin et al,JCO 2013(suppl,abstr 9046)

60. Sekwon Jang , Michael B Atkins
Which drug, and when, for patients with BRAF-mutant melanoma?
The Lancet Oncology, Volume 14, Issue 2, 2013, e60 -e69
The MAPK signalling pathway and targeted drugs
Cobimetinib
B

61. EMA Drugs Approval in Advanced Melanoma
Date of issue of marketing authorization for the European Union
•Ipilimumab* 13/07/2011 -20/09/2013*
•Vemurafenib 17/02/2012
•Dabrafenib 28/06/2013
•Trametinib 30/06/2014
•Nivolumab 19/06/2015
•Pembrolizumab 17/07/2015
•DabrafenibwithTrametinib 23/07/2015
•Vemurafenibwith Cobimetinib20/11/2015
•TalimogeneLaherparevec 16/12/2015
•Nivolumabwith Ipilimumab 01/04/2016

62. T cell activation and inhibition relies upon co-stimulatory (+) or inhibitory signals (−) to prevent widespread autoimmunity
Alexander M. Menzies, Georgina V. Long. Recent advances in melanoma systemic therapy. BRAF inhibitors, CTLA4 antibodies and beyondModified from
European Journal of Cancer, Volume 49, Issue 15, 2013, 3229–3241
pembrolizumab
T cell regulation
CTLA-4is involved in the early
phase of T cell activation.
PD-1is expressed on T cells in
the periphery, and interacts with
PD-L1expressed on tissues.

63. •44% OR
•10mg/Kg >50% RR
•RR not modified by prior Ipilimumab
Hamid et al 2013 NEJM
2013

64. Topalian 2012 NEJM
NivolumabPhase I Study: Response in Melanoma

65. Survival End Points
NIVOLUMAB vsDTIC
Robert C et al. N Engl J Med 2015;372:320-330

66. Robert C et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1503093
Kaplan–Meier Estimates of Progression-free and
Overall Survival.
PEMBROLIZUMAB vsIPILIMUMAB

67. EMA Drugs Approval in Advanced Melanoma
Date of issue of marketing authorization for the European Union
•Ipilimumab* 13/07/2011 -20/09/2013*
•Vemurafenib 17/02/2012
•Dabrafenib 28/06/2013
•Trametinib 30/06/2014
•Nivolumab 19/06/2015
•Pembrolizumab 17/07/2015
•DabrafenibwithTrametinib 23/07/2015
•Vemurafenibwith Cobimetinib20/11/2015
•TalimogeneLaherparevec 16/12/2015
•Nivolumabwith Ipilimumab 01/04/2016

68. COMBI-d: PFS and OS
a
a
Intent-to-treat population;
b
Dabrafenib + placebo includes 26 patients who crossed over to combination arm; +, censored.
Overall Survival
212 175 138 104 84 69 57 7 0
211 187 143 111 96 86 76 13 0
Dabrafenib + Trametinib (n = 211)
Dabrafenib + Placebo (n = 212)
b
3-y OS, 44%
3-y OS, 32%
1.0
0.8
0.6
0.4
0.2
0.0
0 6 12 3018
Months From Randomization
OS Probability
D+Pbo
D+T
Number at risk
2-y OS, 52%
2-y OS, 43%
24 36 42
48
Progression-Free Survival
212 110 67 41 29 11 7 1 0
211 137 84 69 54 45 31 0
1.0
0.8
0.6
0.4
0.2
0.0
0
Months From Randomization
PFS Probability
D+Pbo
D+T
Number at risk
6 12 3018 24 36 42 48
3-y PFS, 22%
3-y PFS, 12%
2-y PFS, 30%
2-y PFS, 16%
Dabrafenib + Trametinib (n = 211)
Dabrafenib + Placebo (n = 212)
58% of D+T patients alive at 3 years still on D+T
Keith T. Flaherty et al. ASCO 2016
1610044496

69. Larkin J et al. Combinedvemurafeniband cobimetinib in BRAF-mutated
melanoma. N Engl J Med. 2014 Nov 13;371(20):1867 -76

70. Curti BD. N Engl J Med 2014;371:1929 -1930.
Comparison of Major Clinical End Points for BRAF
Monotherapy with Combined BRAF and MEK Inhibition.

71. EMA Drugs Approval in Advanced Melanoma
Date of issue of marketing authorization for the European Union
•Ipilimumab* 13/07/2011 -20/09/2013*
•Vemurafenib 17/02/2012
•Dabrafenib 28/06/2013
•Trametinib 30/06/2014
•Nivolumab 19/06/2015
•Pembrolizumab 17/07/2015
•Dabrafenibwith Trametinib 23/07/2015
•VemurafenibwithCobimetinib20/11/2015
•TalimogeneLaherparevec 16/12/2015
•Nivolumabwith Ipilimumab 01/04/2016

72. EMA Drugs Approval in Advanced Melanoma
Date of issue of marketing authorization for the European Union
•Ipilimumab* 13/07/2011 -20/09/2013*
•Vemurafenib 17/02/2012
•Dabrafenib 28/06/2013
•Trametinib 30/06/2014
•Nivolumab 19/06/2015
•Pembrolizumab 17/07/2015
•Dabrafenibwith Trametinib 23/07/2015
•VemurafenibwithCobimetinib20/11/2015
•TalimogeneLaherparevec 16/12/2015
•Nivolumabwith Ipilimumab 01/04/2016

73. Postow MA et al. N Engl J Med 2015;372:2006-2017.

75. Updated Progression-Free Survival
50%
43%
18%
43%
37%
12%
Percentage of PFS
Months
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 363024 332721
0IPI
NIVO+IPI (N=314) NIVO(N=316) IPI (N=315)
MedianPFS, mo (95% CI)
11.7
(8.9–21.9)
6.9
(4.3–9.5)
2.9
(2.8–3.2)
HR (95% CI)vs. IPI
0.42
(0.34–0.51)
0.54
(0.45–0.66)
--
HR (95% CI)vs. NIVO
0.76
(0.62–0.94)
-- --
Progression
-
free Survival (%)
5162730333543465877136315
Patients at risk:
0NIVO 16628897103107112120132151178316
0NIVO+ IPI 1671104110118125132137156176218314
NIVO+IPI
NIVO
IPI
8Database lock: Sept 13, 2016, minimum f/u of 28 months

76. Overall Survival
Months
Patients at risk:
73%
74%
67%
64%
59%
45%
Percentage of PFS
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 393024 332721
Overall Survival (%)
36
0IPI 34104129136149164182205228254285315 4
0NIVO 55157175181191201213230244265292316 3
0NIVO+IPI 49170192198200209221226247265292314 7
*P<0.0001
NIVO+IPI (N=314)NIVO(N=316) IPI (N=315)
MedianOS, mo (95% CI) NR
NR
(29.1–NR)
20.0
(17.1–24.6)
HR (98% CI)vs. IPI
0.55
(0.42–0.72)*
0.63
(0.48–0.81)*
--
HR (95% CI)vs. NIVO
0.88
(0.69–1.12)
-- --
NIVO+IPI
NIVO
IPI
76
Database lock: Sept 13, 2016, minimum f/u of 28 months

77. Subgroup
Patients UnstratifiedHazard Ratio UnstratifiedHazard Ratio(95% CI)
NIVO+IPI NIVO PFS OS PFS OS
Overall 314 316 0.77 0.89
<65 years 185 198 0.74 0.81
≥65 years 129 118 0.82 0.99
BRAFMutant 102 98 0.60 0.71
BRAFWild-type 212 218 0.86 0.97
ECOG PS = 0 230 237 0.79 0.91
ECOG PS = 1 83 78 0.72 0.82
M0/M1a/M1b 129 132 0.67 0.84
M1c 185 184 0.83 0.90
LDH ≤ ULN 199 197 0.72 0.89
LDH > ULN 114 112 0.79 0.86
LDH > 2 x ULN 37 37 0.70 0.71
PD-L1 ≥5% 68 80 0.87 1.05
PD-L1<5% 210 208 0.73 0.84
PFS and OS Subgroup Analyses (All Randomized Patients)
Descriptive comparison between NIVO+IPI and NIVO
77
NIVO+IPI NIVO
20 1
NIVO+IPI NIVO
20 1

78. OS in Melanoma
78
55%
30-35%
1,2
46% 56% 70%47% 73%
2-year OS
74%
74%
83%
Pembro10 mg
a
/kgQ2W
9
Dab + Tram
10
Vem+ Cobi (PhI)
11
1-year OS
3-year OS
Nivolumab 41% (ph I)
8 Dab + Tam (Ph III)
13
44%
1990 2010 2012 20132011 2014 2015
4-year OS
Dab + Tram
10
Nivolumab 35% (ph I) 8
51%
Pembro (Ph III)
5-year OS
Nivolumab 35% (ph I) 8
40%Pembro (Ph I)
Nivolumab 57,7% (ph III)
Vem + Cobi (Ph I)
11
Vem + Cobi (Ph I)
11
64%
Vem + Cobi (Ph I)1137%
2016
1.SmPC COTELLIC Cobimetinib EMA. 2. SmPC MEKINIST Trametinib EMA. 3. SmPC OPDIVO Nivolumab EMA. 4. SmPC TAFINLAR
Dabrafenib EMA. 5. SmPC YERVOY Ipilimumab EMA. 6. SmPC ZELBORAF Vemurafenib EMA.
Ipilimumab17% (ph I) 8
Nivolumab + Ipilimumab (ph II)
Nivolumab + Ipilimumab (ph III)
71%
73%
58%Nivolumab + Ipilimumab (ph II)
Nivolumab + Ipilimumab (ph III)64%
Nivolumab + Ipilimumab (real life)78%

79. EMA Drugs Approval in Advanced Melanoma
Date of issue of marketing authorization for the European Union
•Ipilimumab* 13/07/2011 -20/09/2013*
•Vemurafenib 17/02/2012
•Dabrafenib 28/06/2013
•Trametinib 30/06/2014
•Nivolumab 19/06/2015
•Pembrolizumab 17/07/2015
•Dabrafenibwith Trametinib 23/07/2015
•VemurafenibwithCobimetinib20/11/2015
•TalimogeneLaherparevec 16/12/2015
•Nivolumabwith Ipilimumab 01/04/2016

80. •is a herpes simplex virus type-1–derived oncolytic
immunotherapy designed to selectively replicate in
tumors, produce GM-CSF, and enhance local and
systemic antitumor immune responses
1
1. Amgen. Imlygic
®
Summary of Product Characteristics. Section 4.1.
Talimogene laherparepvec

81. •Talimogene laherparepvec is the first approved
oncolytic virus therapy (US, EU, and Australia)
•Indicated (as monotherapy) for the treatment of adults
with unresectable melanoma that is regionally or
distantly metastatic (Stage IIIB, IIICand IV M1a) with
no bone, brain, lung or other visceral disease
1
1. Amgen. Imlygic
®
Summary of Product Characteristics. Section 4.1.
Oncolytic Virus Therapy

82. Proposed mechanism of action for talimogene laherparepvec
Johnson DB, Puzanov I, Kelley C. Talimogene laherparepvec (T-VEC) for the treatment of advanced melanoma. Immunotherapy. 2015 Jul; 7(6): 611–619.

83. The 26% response rate, with durability in both injected and
uninjected lesions including visceral sites, together with the survival
rates, are evidence of systemic effectiveness

84. Baseline and at 3 months CT images of:
•The injection site in the left shoulder,
•retroperitoneal lymph node, and
•lungs.
PET images at baseline and at 8 months
Matched sites of lesions before
(baseline) and after (follow-up) therapy.

85. Areas of cutaneous response:
•At baseline,
•at 6 weeks, and
•at 4 months.
By 4 months, lesions either had completely
resolved or only flat, pigmented areas
remained.
Representative biopsies taken at 8 months
demonstrated no melanoma.

86. (A)Survival curves for all patients enrolled and for
those who achieved complete response (CR),
partial response (PR), or surgical CR (sCR).
(B)Survival curves by disease stage.

87. Conclusion:
… on the basis of the high frequency and durability of overall objective responses, the
promising 1-year and overall survival rates of the patients enrolled, and the low toxicity
and straightforward outpatient administration of the agent, the results of this phase II trial
clearly justify that a randomized, controlled, phase III study is performed.

88. Long-term follow-up of T-VEC single-arm Phase 2 study –
Overall Survival
NemunaitisJJ, et al. SMR 2015:abstract (and poster).
Number of patients at risk:50403321141199888887555531 11 10
Kaplan
–
Meier
(%)
Study month
0
20
40
60
80
100
0 10 20 50 70 80 90 100 1154030 110605 15 25 35 45 55 65 105958575
T-VEC (N = 50)
Median (95% Cl), months: 16.2 (10.9–not estimable)
Number of
years K–M survival estimate, % (95% CI)
1 57.4 (42.4–69.8)
2 43.0 (28.4–56.7)
5 43.0 (28.4–56.7)
6 36.8 (20.8–53.0)
7 36.8 (20.8–53.0)
8 36.8 (20.8–53.0)
9.5 36.8 (20.8–53.0)

90. Study design and
endpoints
Randomisationstratification:
1.Disease stage
2.Prior non-adjuvant systemic treatment
3.Site of disease at first recurrence
4.Presence of liver metastases
Patients enrolled between May 2009 and July 2011.
Discontinuation of treatment because of progressive disease was not required before 24 weeks unless
alternate therapy was clinically indicated.
*Responses were determined using modified WHO criteria by a blinded EAC;
†TTF was defined as time from baseline to first clinically relevant disease progression for
which no objective response was subsequently achieved or until death.
EAC, endpoint assessment committee;.
2:1
N = 436
IntralesionalT-VEC
≤ 4 mL ×10
6
pfu/mL
once, then after 3
weeks, ≤ 4 mL ×10
8
pfu/mL Q2W
Subcutaneous
GM-CSF 125 μg/m
2
daily ×14 days of
every 28-day cycle
Injectable,
unresectable
Stage IIIB–IV
melanoma
Primary endpoint
•Durable response rate (DRR), defined
as objective response (PR + CR)
beginning within 12 months of
initiating therapy and lasting
continuously for
≥ 6 months*
Key secondary endpoints
•OS
•Best overall response*
•Tumour burden
•Onset and duration of response
•Time to treatment failure (TTF)
†
Phase 3 OPTiM, OncoVEXGM-CSF Pivotal Trial

91. Antitumour activity seen with T-VEC
Andtbacka RHI, et al. J Clin Oncol 2015;33:2780–8.
*Patients with > 150% increase in tumour dimensions.
Waterfall plot of best response for all patients per investigator assessment.
Response assessments per EAC were not available for all patients.
EAC only reviewed the subset of patients with overall response per investigator or who received treatment for 9 months.
50
0
-50
100
150
-100
****************************
50
0
-50
100
150
-100
Change from baseline (%)
************ Stage IIIB/C (n = 29)
Stage IV M1a (n = 33)
Stage IV M1b (n = 9)
Stage IV M1c (n = 17)
Stage IIIB/C (n = 80)
Stage IV M1a (n = 56)
Stage IV M1b (n = 31)
Stage IV M1c (n = 41)
T-VEC
GM-CSF

92. Durable response seen with T-VEC
Kaufman H, et al. ECC 2013:abstract 3733 (and poster);
Ross MI, et al. ASCO 2014:abstract 9026 (and poster);
Andtbacka RHI, et al. J Clin Oncol 2015;33:2780–8.
*The estimated probability was obtained using the Kaplan–Meier method;
†
Arrows indicate patients for whom duration of response was censored at last tumour assessment
because there was no evidence (per EAC assessment) that their response had ended.
•Majority of responders still in response at end of evaluation
period
•In ITT population, median (range) time to follow-up was:
•20.6 months (0.0–44.3) in the T-VEC arm
•18.5 months (0.0–43.0) in the GM-CSF arm
Estimated probability* of
being in response among
all responders, % (95% CI)
GM-CSF
(n = 8)
T-VEC
(n = 78)
For at least 3 months
46.9
(12–76)
86.7
(77–93)
For at least 6 months
46.9
(12–76)
80.6
(69–88)
For at least 9 months
46.9
(12–76)
68.0
(55–78)
For at least 12 months
46.9
(12–76)
65.0
(51–76)
Duration of longest response among responders (per EAC)
15129 6 3 0 63 91215
PR
CR
Best response
Censored
†
18
Duration of response (months)
T-VEC GM-CSF

94. Conclusion
This randomized phase III study demonstrated that treatment with T-VEC, an oncolytic virus
immunotherapy, improved DRR compared with GM-CSF in patients with unresected stage
IIIB, IIIC, or IV melanoma. T-VEC treatment resulted in long-lasting CRs, suggesting T-VEC
could delay or prevent relapses or preclude progression to later stages of disease.
T-VEC represents a novel potential new treatment option for patients with injectable
metastatic melanoma and limited visceral disease.

95. Clinicaltrial
OPTIMAL TREATMENT FOR METASTATIC MELANOMA

96. Combination / Sequencing with

97. The rationale of using combination checkpoint inhibitor–
based regimens may include the concomitant effects on:
•Re-activation of T cells,
•Increased trafficking of tumor reactive lymphocytes into the tumor
tissue, and
•Enhanced killing of cancer cells.
Immunotherapy Combinations With Checkpoint Inhibitors in
Metastatic Melanoma: Current Approaches and Future Directions.
Atkins M. Semin Oncol. 2015 Dec;42 Suppl 3:S12-9.

98. 98
•BRAF inhibitor alone or BRAF + MEK inhibitors → rapid and clinically significant responses
•Immunotherapy → less frequent objective responses, but clinically significant durability
•Combining targeted therapy with immunotherapy
−Can harness and perpetuate the enhanced anti-tumor response following targeted inhibition
−May lead to durable response and prolonged survival
Combining Targeted Therapy With Immunotherapy
Figure modified from Ribas A et al. Clin Cancer Res 2012 and Hamid O et al. SMR 2015.
Melanoma survival curves depending on the type of therapy
Immunotherapy
Percent alive
Years
1 2 30
Targeted therapy
Percent alive
Years
1 2 30
Combination?
Percent alive
Years
1 2 30
+ =

99. 1
st
line treatment in BRAF+ Advanced Melanoma
Checkpoint & TK Inhibitors
•Dabrafenib + Trametinib
•Vemurafenib + Cobimetinib
•Nivolumab
•Pembrolizumab
•Nivolumab+ Ipilimumab

100. 2
nd
line treatment in BRAF+ Advanced Melanoma
Checkpoint & TK Inhibitors
•Nivolumab
•Pembrolizumab
•Nivolumab+ Ipilimumab
•Dabrafenib + Trametinib
•Vemurafenib + Cobimetinib

101. 1
st
line treatment in BRAFwtAdvanced Melanoma
•Nivolumab
•Pembrolizumab
•Nivolumab+ Ipilimumab

102. •Ipilimumab
•Quimioterapia
•c-KIT+ (<5%)
2
nd
line treatment in BRAFwtin Advanced Melanoma

103. •Talimogene laherparepvec
Unresectable melanoma that is regionally or distantly
metastatic (Stage IIIB, IIIC and IV M1a)
BRAFwtor +

104. •Radiotherapy
•ILP
•EQT
•…
Rescue/Palliative treatment in Advanced Melanoma

105. Are rare toxicities becoming less rare?
The number of patients treated
with ICI grows, and rare irAEs
cases will be more common as the
volume of real-world data
increases.
Clinically severe, prolonged, and
even fatal uncommon irAEs may
occur and early intervention must
be a priority.
High-grade irAEs can occur,
particularly with combination
immunotherapy.
irAEs may occur late, even after
terminating active treatment.
There is a potential for long-term
chroniccomplications.
Skin, gut, endocrine, lung and
musculoskeletal irAEs are relatively
common. Cardiovascular, hematologic,
renal, neurologicand ophthalmologic
irAEs are rare but are well-recognized.
Incidence of irAEs with anti PD1 or
PDL1 monotherapy appears to be
broadly similar across tumor types.
With increasing patient exposure to
immunotherapy, the nature and range
of irAEs is becoming more clearly
defined.
irAEs are generally manageable with
glucocorticoidsalthough clinically
severe, prolonged, and even fatal
events rarely occur.

106. How to integrate in clinical practice the new
therapies for advanced melanoma
ProactiveAttitude
•Be aware of the impressive continuous advances we
are living now in the knowledge of the biology and
therapy melanoma.
•Consult and refer patients to experienced centers,
participating in clinical trials.
•Potentiate translational research.