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Roma 22 Settembre 2012
La terapia medica del melanoma
metastatico
Paola Queirolo
Dept. Medical Oncology A
National Institute for Cancer Research -Genova
Metastatic Melanoma: medical
treatments
 Chemotherapy
Single agent or poly-Chemotherapy
monochemotherapy best option of care
 Immunotherapy : alpha IFNs, IL-2
Vaccinations
 Bio-chemotherapy
 Targeted therapies
Overall Survival for Metastatic Melanoma
Proportion alive
Survival data from 42 Phase II
trials with over 2‘100 stage IV
patients1:
12 month OS: 25.5 %, median
OS: 6.2 months
(stage IV melanoma including
patients with brain
metastases)
Time (months)
Adapted from Korn 2008
Due to the lack of efficacious therapy, the preferred treatment
for metastatic melanoma remains the inclusion in a clinical trial
1Korn
EL et al. J Clin Oncol 2008;26(4):527-34.
R, Hauschild A, Jost L. Cutaneous malignant melanoma: ESMO clinical recommendations for diagnosis, treatment and
follow-up. Ann Oncol 2008;19 Suppl 2:ii86-8.
2Dummer
Metastatic Melanoma :
Single Agent Options
Overall responses with monotherapy
25
20
15
10
5
0
RR
DTIC
FTM
20
24
BCNU CCNU CDDP
18
13
15
TAX
Alc.V
IFNa2
IL-2
14,5
13
17
17
Khayat, Educational Book, ASCO 2000
CT/BioCT AND RR
Phase II trials
Authors
Regimen
N.
Pts
RR
Survival
(month)
Legha
Cancer J Sci
Am ‘97
CVD+IL-2+IFN
115
60%
12
Comella
Eur J Cancer
‘97
FTM+DTIC+IFN
43
40%
5.7
Legha
JCO ‘98
CVD+IL-2+IFN
53
64%
11.8
CV+TMZ+IL-2+IFN
48
47%
7.5
Atkins
Clin Cancer
Res ‘02
CT/BioCT AND RR
Authors
Regimens
N.
Pts
RR
Survival
(month)
Rosenberg
JCO ‘99
CDDP+DTIC+Tam
CD+IL-2+IFN+Tam
52
50
27%
44%
15
10
Eton
JCO ‘02
CVD
CVD+IL-2+IFN
92
91
25%
48%
9
s 11
Avril
JCO ‘04
DTIC
Fotemustine
112
117
6.8%
5.6
15.2% s 7.3
Kaufmann
JCO ‘05
Tmz
Tmz+IFN
134
137
13%
24%
Bedikian
JCO ‘06
DTIC
DTIC+Oblimersen
385
386
7.5%
7.8
13.5% s 9
8
s 9
Metastatic Melanoma:
Phase III Biochemo vs Chemo
Author
Keilholz
(JCO ‘05)
Atkins
(JCO ‘08)
Regimen
CVDI-Il-2
vs.
CVDI
CVD-bio
vs.
CVD
No. of
pts
RR
OS
23
9
21
9
17
9
12
9
363
416
NEW DRUGS. FDA and EMA approval in
2011
• Targeted immunotherapy: anti-CTLA-4 mAbs
• Molecular targeted therapies: anti B raf V600
mut
Melanoma is an immunogenic cancer
• Spontaneous remissions
• TILs associated with regression
• Ab and CTL responses to melanoma Antigens
IMMUNOTHERAPY OF MELANOMA
 BRMs: rIFN alfa, rIL-2, GM-CSF, IL-12,IL-18, IL-21
 Adoptive immunotherapy: TIL,NK,DC
 Vaccines: autologous, allogeneic, peptides, anti idiotypes Abs,
gene modified ca cells, dendritic pulsed
 DNA based therapy: allovectin 7
 Targeted therapies acting on immunological cells : antCTLA4
Safety: Immune Breakthrough Events
IBEs: Immune-mediated adverse events based on
the action of Anti CTLA-4 mAbs
• Correlation with clinical response
• Usually linked to drug-exposure and reversible
• Manageable with established therapies (e.g.
corticosteroids)
Novel targets for immunotherapy
Potential Treatment Strategies
- Antagonize receptors that suppress the immune response
(e.g. CTLA-4 and PD-1)
- Activate receptors that amplify the immune response
(e.g. CD40 on APC; 4-1 BB and OX40 on T cells)
- Inhibit or deplete immunosuppressive mechanisms
(e.g. Tregs, IL-10, TGF-beta…)
- Combinations of the above
Anti-CTLA-4 mAbs:
SAFETY
• GI toxicity:
Diarrhea: watery to frank blood
Bx: inflammatory colitis
• Skin toxicity:
Rash, pruritus and vitiligo
• Endocrine Toxicity:
Hypophysitis; Thyroiditis
Endocrinopathies
Pituitary Insufficiency in a patient with metastatic melanoma
• Presumed Autoimmune Hypophysitis
- Confusion, fatigue, impotence
- Headache
• Low ACTH/cortisol
• ↓ T4, testosterone and/or prolactin
• Increased pituitary size on MRI
• Asymptomatic with replacement therapy
- Slow return of some endocrine
function
Blansfield JA, Beck KE, Tran K, Yang JC, Hughes MS, Kammula US, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can
induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother 2005;28(6):593-8.
Anti-CTLA-4 mAbs
• Tumor responses are sufficient but not
necessary for prolonged survival
• Rationale for proceed with therapy after early
progression
• Increased volume of lesions may be due to
lymphocytic infiltrate
Bulanhagui et al. ASCO 2006
“Conventional” response
• Response in baseline
lesions
Response in baseline lesions
50
Change from baseline SPD (%)
25
Change from baseline SPD (%)
50
2,810
2,482
2,154
1,826
1,498
1,171
843
515
187
-140
-468
25
0
9 months
-25
-50
-75
-100
-125
-9
-3
3
9
15
21
27
33
39
45
51
0
-25
PR
5.2 months
-50
-75
CR
-100
-125
-9
-3
3
9
15
21
27
33
39
Relative week from first dose date
• Stable disease
45
51
SPD (mm2)
'Stable disease' with slow, steady
decline in total tumor volume
2,894
2,556
2,218
1,881
1,543
1,206
868
530
193
-145
-482
PD
“Non conventional” response
150
125
100
75
50
25
0
-25
-50
-75
-100
-125
19,373
17,242
15,111
12,980
10,849
6 months
8,718
6,587
SPD (mm2)
• Response after initial
increase in total tumour
volume
Change from baseline SPD (%)
Response after initial increase
in total tumor volume
4,456
2,325
194
-1,937
-9
-3
3
9
15
21 27
33
39 45
51
Relative week from first dose date
Change from baseline SPD (%)
1,272
50
1,124
25
975
9.4 months
0
827
678
–25
530
–50
382
233
–75
85
–100
-64
-212
–125
-9
-3
3
9
15
21
27
33
39 45
51
SPD (mm2)
• Response in index lesions
and new lesions after the
appearance of new
Response in index and new lesions
At or after the appearance of new lesions
Example of conventional pattern of response: response
in baseline lesions
Baseline
Week 12
Anti CTLA4 . Esempio di risposta
Screening
Week 72
Durable & ongoing response
without signs of IRAEs
Week 12
Initial increase in
total tumour burden (mWHO PD)
Week 16
Responding
Courtesy of K. Harmankaya
Kaplan-Meier Analysis of Survival
1.0
lpi + Gp100
lpi Alone
Gp100 Alone
0.9
Proportion alive
0.8
0.7
0.6
Comparison
Arms A vs. C
Arms B vs. C
0.5
HR
0.68
0.66
0.4
0.3
0.2
0.1
0.0
1
2
3
4
Years
Ipi + gp100 N=403
Ipi + pbo N=137
gp100 + pbo N=136
1 year
44%
46%
25%
2 year
22%
24%
14%
Survival Rate
Hodi S et al. NEJM 2010;363(8):711-23
(A)
(B)
(C)
p-value
0.0004
0.0026
Study 024: Design
Screening
Previously
Untreated
Metastatic
Melanoma
(N=502)
R
INDUCTION
MAINTENANCE *
Ipilimumab 10 mg/kg
Q3W X4
Ipilimumab 10 mg/kg
Q12W
Dacarbazine 850 mg/m2
Q3W x8
R
Placebo
Q3W X4
Dacarbazine 850 mg/m2
Q3W x8
= blinded
randomization
(1:1)
Placebo
Q12W
* in absence of
progression or doselimiting toxicity
Week 1
Week 12
Baseline
Tumor Assessment
First Scheduled Tumor
Assessment
Wolchok J, et al. Presented at ASCO 2011. Abstract LBA5.
Week 24
Study 024:Ipi in 1st line Overall Survival
1.0
0.
Proportion Alive
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
1
3
4
Years
Estimated Survival Rate
1 Year
2 Year
3 Year*
Ipilimumab + DTIC
n=250
47.3
28.5
20.8
Placebo + DTIC
n=252
36.3
17.9
12.2
*3-year survival was a post-hoc analysis
Wolchok J, et al. Presented at ASCO 2011. Abstract LBA5.
Ipilimumab.
FDA Approval March 2011. EMA Approval August 2011
In USA in prima e seconda linea alla dose di 3 mg /kg
In Europa in seconda linea
14 Gennaio 2012 si è interrotto l’expanded access in
attesa dell’approvazione AIFA…………
MELANOMA TARGETS
PATHWAY
MOLECULAR
BRAF Kinase
An important mediator of cellular proliferation
Growth Factors
Normal
signaling
Oncogenic
signaling
RAF
BRAFV600E
RTK
Membrane
Y-P
Y-P
Ras
GTP
RG7204 selectively inhibits
oncogenic BRAF
MEK
P
MEK
P
Other Effectors
ERK
BRAF mutations are exclusive to
tumors
> 50% malignant melanomas
~10% of CRC
~8% all solid tumors
P
Nuclear Translocation
Gene Expression
ERK
P
Abnormal Cellular
Proliferation
The first-in-human trial of RO5185426 was a Phase I dose
escalation study (PLX06-02) in patients with solid tumors.
RG 7204
Efficacy data in BRAF V600E-mutated melanoma
- A total of 26 of the 32 patients had a response (81%), with a complete
response in 2 patients and a partial response in 24 patients.
- The estimated median progression-free survival among all patients was more than 7
months.
Flaherty KT et al NEJM 2010: 363 (9):
RG 7204
Rapid and dramatic tumor shrinkage
Pre-treatment
Cycle 2
Pre-treatment
Week 8
Pre-treatment
Week 8
P Chapman , et al, ESMO 2009, Abstract 6BA
Summary of adverse events in ≥ 10% of patients (n=55)
includes 1120 mg cohort, not ongoing 960 mg cohort
All related
adverse events
Related
Grade ≥ 3
Rash
29 %
2%
Fatigue
24 %
2%
Pruritus
20 %
2%
Photosensitivity reaction
14 %
0%
Nausea
14 %
0%
Anemia
13 %
0%
Cutaneous squamous cell
carcinoma
11 %
11 %
Alopecia
11 %
0%
Adverse event
P Chapman , et al, ESMO 2009, Abstract 6BA
Neoformazioni Verrucose Ipercheratotiche con iperplasia dello strato granuloso
Fattori di
stratificazione
• M1 e livelli di LDH
• Trattamenti
precedenti
• Sesso
R
A
N
D
O
M
DTIC 1000mg/mq g1 q21
RO5185426 bid 960mg
Overall survival (Dec 30, 2010 cutoff)
100
Vemurafenib (N=336)
Est 6 mo survival 84%
90
Overall survival (%)
80
70
60
Dacarbazine (N=336)
Est 6 mo survival 64%
50
40
30
Hazard ratio 0.37
20
(95% CI; 0.26 - 0.55)
Log-rank P<0.0001
10
0
0
1
2
3
4
5
192
266
137
210
98
162
64
111
No. of patients in follow up
Dacarbazine
Vemurafenib
336
336
Chapman et al. ASCO 2011
283
320
6
7
Months
39
80
20
35
8
9
10
9
14
1
6
1
1
11
12
Progression-free survival (Dec 30, 2010
cutoff) Hazard Ratio 0.26
(95% CI; 0.20 - 0.33)
Log-rank P<0.0001
Progression-free survival (%)
100
90
Vemurafenib (N=275)
80
70
Dacarbazine
(N=274)
60
50
40
30
Median 5.3 mos
Median 1.6 mos
20
10
0
0
1
2
3
4
5
274
275
Chapman et al. NEJM
213
268
2011
7
8
9
3
4
0
3
Months
No. of patients in follow up
Dacarbazine
Vemurafenib
6
85
211
48
122
28
105
16
50
10
35
6
16
10
11
12
Number of patients receiving anti-cancer
therapies after initial treatment on BRIM-3
Subsequent
anti-cancer therapy
Dacarbazine
(n=338)
Vemurafenib
(n=337)
149 (44%)
122 (36%)
Ipilimumab
73 (22%)
60 (18%)
Dabrafenib
5 (1.5%)
0
Crossover to
vemurafenib
83 (25%)
–
Any
Chapman P. et al. abs 8502
ASCO Ann. Meeting Chicago 2012
Summary of overall survival data
ASCO 2011
ASCO 2012
(post-hoc)
Median follow-up, months
Median OS, months
DTIC
Vemurafenib
DTICa
Vemurafenib
2.3
3.8
9.5
12.5
9.7
13.6
Not reliably estimated
6-month survival, %
64
84
66
84
12-month survival, %
–
–
44
56
Hazard ratio, OS
0.37
0.70
% reduction in
risk of death
63
30
aCensored
at crossover
Chapman P. et al. abs 8502
ASCO Ann. Meeting Chicago 2012
Patterns of disease progression and role for
continuous dosing in a Phase 1 study of
vemurafenib (PLX4032, RG7204) in patients
with metastatic melanoma
K Kim, K Flaherty, P. Chapman, J Sosman, A Ribas, G. McArthur, R
Amaravadi, R Lee, K Nolop, I. Puzanov
M. D. Anderson Cancer Center; Massachusetts General Hospital Cancer Center;
Memorial Sloan-Kettering Cancer Center; Vanderbilt University; University of
California, Los Angeles; Peter MacCallum Cancer Centre; Abramson Cancer
Center; Roche Pharmaceuticals; Plexxikon Inc.
Clinical outcome
Outcome
Duration of treatment postprogression
All patients
N=48)
>30 days
(N=20)
<30 days
(N=24)
P-value
Median PFS, months
(range)a
6.6
(2.8–16.9)
6.3
(0.9–23.8)
0.729
7.0
(0.9–26.0)
Median treatment duration
beyond initial PD, months
(range)
3.8
(1.1–14.8)
–
–
–
Median survival beyond
initial PD, months (range)
>9.1
(1.9–24.3)
3.4
(0–19.6)
0.008
6.0
(0–24.3)
Median OS, months
(range)a
>25.2
(7.6–28.8)
11.2
(1.1–34.8)
0.054
14.9
(1.1–34.8)
aCalculated
from the start of vermurafenib therapy
PFS, progression-free survival; OS, overall survival
Vemurafenib (Zelboraf) expanded access study
• Open-label, multicenter expanded access study of RO5185426
in patients with metastatic melanoma harboring the BRAF
V600 mutation
• Approximately 3000 patients recruited into this study
• 140 Centers in 30 Countries
Roche MO25515
FDA and EMA Approval
August 2011 and February 2012
• The FDA has approved Zelboraf™ (vemurafenib) for
the treatment of BRAF V600 mutation-positive
unresectable (inoperable) or metastatic melanoma.
Zelboraf is not recommended for use in patients with
wild-type BRAF melanoma
• The agency has also approved the Roche cobas®
4800 BRAFV600 Mutation Test, a diagnostic test
developed to identify patients eligible for treatment
[TITLE]
[TITLE]
[TITLE]
Efficacy and safety of oral MEK162 in
patients with locally advanced and
unresectable or metastatic cutaneous
melanoma harboring BRAFV600 or NRAS
mutations
Paolo A. Ascierto,* Carola Berking, Sanjiv S. Argawala,
Dirk Schadendorf, Carla van Herpen, Paola Queirolo,
Christian U. Blank, Axel Hauschild, J. Thaddeaus Beck,
Angela Zubel, Faiz Niazi, Simon Wandel, Reinhard Dummer
*National Cancer Institute, Naples
Italy
MEK inhibitors: targeting RAS and
BRAF mutations in cancer
70-90% pancreatic cancer
RAS
30-40% colon cancer
~30% lung cancer
~20% melanoma
MEK162
50-60% melanoma
BRAF
36% thyroid cancer
12% ovarian cancer
8- 12% colorectal cancer
Frémin C, Meloche S. J Hematol Oncol. 2010;3:8;
Pratilis CA, Solit DB. Clin Cancer Research, 2010;16:3329
MEK inhibitors.Study Design
Patients with advanced or
metastatic unresectable
cutaneous malignant
melanoma harboring
BRAFV600E/NRAS mutation
Arm 1: BRAFV600E/(n = 28)
MEK162 45 mg BID
Arm 2: NRAS-mutant (n = 26)
MEK162 45 mg BID
Stratification based on metastatic stage (M1a, M1b and M1c), region, and baseline LDH (< 0.8 x
ULN, 0.8–1.1 x ULN, >1.1-2 x ULN)
Best percentage change from baseline and best
overall response (NRAS)
N=28*
45 mg NRAS
Progressive Disease (PD)
Stable Disease (SD)
Partial Response (PR)
Unconfirmed PR
*Patients with missing best % change from baseline and unknown overall response are not included.
Ongoing pts
PFS – NRAS- /BRAF-mutant
100
Median (months) [95% CI]: 3.65 [2.53, 5.39]
Median (days) [95% CI]: 111 [77, 164]
NRASmt
PFS (%)
80
BRAFmt Median (months) [95% CI]: 3.55 [2.00, 3.81]
Median (days) [95% CI]: 108 [61, 116]
60
40
20
0
0
61
122
43
14
183
Time (days)
274
365
0
0
Number of patients at risk
45 mg
71
2
[TITLE]
Rationale for Combination of BRAFi (GSK436) + MEKi
(GSK212) in BRAF Mutant Tumors
RAS
BRAF
MEK
Tumor Type
% BRAF Mutant
Melanoma
50%
BRAFi (GSK436)
RR 77%1
Mechanistic toxicity:
Hyperproliferative skin AEs
Thyroid
50%
Cholangioca
15%
NSCLC
7-8%
MEKi (GSK212)
RR 35%2
Mechanistic toxicity: rash
Colorectal
5%
Goals of Combination
pERK
Proliferation
Survival
Invasion
Metastasis
1 Kefford
1. Improve complete response rate
2. Suppress MAP kinase dependent resistance mechanisms and
improve duration of response
3. Decrease incidence of BRAFi-induced proliferative skin lesions
et al., SMR 2010; 2 Lewis et al. Perspectives in Melanoma 2011
IPILIMUMAB VS VEMERAFENIB PFS
Ipilimumab
Vemurafenib
• Forty-three patients with metastatic melanoma harboring c-Kit
aberrations were enrolled on this phase II trial.
• Each patient received a continuous dose of imatinib 400 mg/d unless
intolerable toxicities or disease progression occurred.
• Fifteen patients who experienced progression of disease were
allowed to escalate the dose to 800 mg/d.
PFS and OS Rates
Median PFS 3.5 months
1-year OS 51.0%.
Studio di fase III randomizzato . NILOTINIB vs DTIC in c-kit mutati
.
Pre-screening for c-Kit
mutation
Screening
Randomization
120 Patients1:1
DTIC 850 mg/m2
IV q3weeks
Tasigna 400 mg
b.i.d.
Progression
Progression
Cross-over?
Follow for survival
No
Follow for survival
MELANOMA in 2012
Setting
EMA approval
Clinical trials evidence
1° line B-Raf mutated
Vemurafenib
Ipilimumab +/CT
B-Raf WT
CT
Ipilimumab +/-CT
B Raf mutated
Ipilimumab
Ipilimumab ?
BRAFi +MTT-CT
B-Raf WT
Ipilimumab
2 line