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Roma 22 Settembre 2012La terapia medica del melanoma
metastatico
Paola QueiroloDept. 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
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)
1Korn EL et al. J Clin Oncol 2008;26(4):527-34.2Dummer 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.
Time (months)
Prop
ortio
n al
ive
Due to the lack of efficacious therapy, the preferred treatment for metastatic melanoma remains the inclusion in a clinical trial
Adapted from Korn 2008
0
5
10
15
20
25
RR 20 24 18 13 15 14,5 13 17 17
DTIC FTM BCNU CCNU CDDP TAX Alc.V IFNa2 IL-2
Metastatic Melanoma : Single Agent Options
Overall responses with monotherapy
Khayat, Educational Book, ASCO 2000
CT/BioCT AND RRPhase II trials
Authors Regimen N. Pts
RR Survival(month)
LeghaCancer J Sci Am ‘97
CVD+IL-2+IFN 115 60% 12
ComellaEur J Cancer ‘97
FTM+DTIC+IFN 43 40% 5.7
LeghaJCO ‘98
CVD+IL-2+IFN 53 64% 11.8
AtkinsClin Cancer Res ‘02
CV+TMZ+IL-2+IFN 48 47% 7.5
CT/BioCT AND RR
Authors Regimens N. Pts
RR Survival(month)
RosenbergJCO ‘99
CDDP+DTIC+TamCD+IL-2+IFN+Tam
5250
27%44%
1510
EtonJCO ‘02
CVDCVD+IL-2+IFN
9291
25%48% s
911
AvrilJCO ‘04
DTICFotemustine
112117
6.8%15.2% s
5.67.3
KaufmannJCO ‘05
TmzTmz+IFN
134137
13%24% s
89
BedikianJCO ‘06
DTICDTIC+Oblimersen
385386
7.5%13.5% s
7.89
Keilholz CVDI-Il-2 23 9(JCO ‘05) vs. 363
CVDI 21 9
Atkins CVD-bio 17 9(JCO ‘08) vs. 416
CVD 12 9
Author Regimen No. of pts
RR OS
Metastatic Melanoma: Phase III Biochemo vs Chemo
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 bloodBx: inflammatory colitis
• Skin toxicity: Rash, pruritus and vitiligo
• Endocrine Toxicity:Hypophysitis; Thyroiditis
• 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
Pituitary Insufficiency in a patient with metastatic melanoma
Endocrinopathies
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
-9 -3 3 9 15 21 27 33 39 45 51
Relative week from first dose date
Chan
ge fr
om b
asel
ine
SPD
(%)
SPD (m
m2)
2,8942,5562,2181,8811,5431,206868530193-145-482
50
25
0
-25
-50
-75
-100
-125
Response in baseline lesions
PD
PR
CR
5.2 months
'Stable disease' with slow, steady decline in total tumor volume
-9 -3 3 9 15 21 27 33 39 45 51
• Stable disease
Chan
ge fr
om b
asel
ine
SPD
(%)
2,8102,4822,1541,8261,4981,171843515187-140-468
50
25
0
-25
-50
-75
-100
-125
9 months
150125100
755025
0-25-50-75
-100-125
19,373
17,242
15,111
12,980
10,849
8,718
6,587
4,456
2,325
194
-1,937
SPD (m
m2)
Relative week from first dose date
50
25
0
–25
–50
–75
–100
–125
Chan
ge fr
om b
asel
ine
SPD
(%) 1,272
1,124
975
827
678
530
382
233
85
-64
-212
SPD (m
m2)
Chan
ge fr
om b
asel
ine
SPD
(%)
-9 -3 3 9 15 21 27 33 39 45 51
-9 -3 3 9 15 21 27 33 39 45 51
Response after initial increase in total tumor volume
6 months
9.4 months
Response in index and new lesions At or after the appearance of new lesions
“Non conventional” response
• Response in index lesions and new lesions after the appearance of new
• Response after initial increase in total tumour volume
Example of conventional pattern of response: response in baseline lesions
Baseline Week 12
Anti CTLA4 . Esempio di risposta
Screening
Week 12Initial increase in total tumour burden (mWHO PD)
Week 16Responding
Week 72Durable & ongoing response without signs of IRAEs
Courtesy of K. Harmankaya
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
Prop
ortio
n al
ive
Years
lpi + Gp100 (A)lpi Alone (B)Gp100 Alone (C)
Survival Rate Ipi + gp100 N=403 Ipi + pbo N=137 gp100 + pbo N=136
1 year 44% 46% 25%
2 year 22% 24% 14%
Kaplan-Meier Analysis of Survival
Comparison HR p-value Arms A vs. C 0.68 0.0004 Arms B vs. C 0.66 0.0026
Hodi S et al. NEJM 2010;363(8):711-23
Baseline Tumor Assessment
First Scheduled Tumor Assessment
Screening
Ipilimumab 10 mg/kgQ12W
Ipilimumab 10 mg/kgQ3W X4
Week 12 Week 24Week 1
INDUCTION MAINTENANCE *
* in absence of progression or dose-limiting toxicity
Dacarbazine 850 mg/m2
Q3W x8
PreviouslyUntreatedMetastaticMelanoma
(N=502)
PlaceboQ3W X4
PlaceboQ12W
R
R = blindedrandomization(1:1)
Dacarbazine 850 mg/m2
Q3W x8
Study 024: Design
Wolchok J, et al. Presented at ASCO 2011. Abstract LBA5.
Estimated Survival Rate 1 Year 2 Year 3 Year*
Ipilimumab + DTICn=250
47.3 28.5 20.8
Placebo + DTICn=252 36.3 17.9 12.2
*3-year survival was a post-hoc analysis
Pro
po
rtio
nA
live
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.
1.0
Years0 1 3 4
Study 024:Ipi in 1st line Overall Survival
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 /kgIn Europa in seconda linea
14 Gennaio 2012 si è interrotto l’expanded access in attesa dell’approvazione AIFA…………
MOLECULAR TARGETSMELANOMA PATHWAY
Membrane RTK
Y-PY-P Ras GTP
Other Effectors
Growth Factors
RAF
MEK
ERK
P
P
Nuclear TranslocationGene Expression
Normal signaling
Oncogenic signaling
BRAFV600E
MEK
P
ERK
P
Abnormal CellularProliferationARRESTED
RG7204 selectively
inhibits oncogenic BRAF
BRAF KinaseAn important mediator of cellular proliferation
BRAF mutations are exclusive to tumors
> 50% malignant melanomas
~10% of CRC
~8% all solid tumors
The first-in-human trial of RO5185426 was a Phase I dose escalation study (PLX06-02) in patients with solid tumors.
- A total of 26 of the 32 patients had a response (81%), with a completeresponse 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 Efficacy data in BRAF V600E-mutated
melanoma
RG 7204 Rapid and dramatic tumor shrinkage
Pre-treatment
Week 8Cycle 2
Pre-treatment
P Chapman , et al, ESMO 2009, Abstract 6BA
Pre-treatment
Week 8
Summary of adverse events in ≥ 10% of patients (n=55) includes 1120 mg cohort, not ongoing 960 mg cohort
Adverse event
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 %
P Chapman , et al, ESMO 2009, Abstract 6BA
Neoformazioni Verrucose Ipercheratotiche con iperplasia dello strato granuloso
RANDOM
Fattori di stratificazione
• M1 e livelli di LDH• Trattamenti
precedenti• Sesso
DTIC 1000mg/mq g1 q21
RO5185426 bid 960mg
100
90
80
70
60
50
40
30
20
10
0
Ove
rall
surv
ival
(%)
No. of patients in follow upDacarbazineVemurafenib
0 1 2 3 4 5 6 7 8 9 10 11 12
Vemurafenib (N=336)Est 6 mo survival 84%
Months
336336
283320
192266
137210
98162
64111
3980
2035
16
11
Dacarbazine (N=336)Est 6 mo survival 64%
914
Hazard ratio 0.37 (95% CI; 0.26 - 0.55)Log-rank P<0.0001
Overall survival (Dec 30, 2010 cutoff)
Chapman et al. ASCO 2011
100
90
80
70
60
50
40
30
20
10
0
Prog
ress
ion-
free
sur
viva
l (%
)
No. of patients in follow upDacarbazineVemurafenib
0 1 2 3 4 5 6 7 8 9 10 11 12
Hazard Ratio 0.26 (95% CI; 0.20 - 0.33)Log-rank P<0.0001
Months
274275
213268
85211
48122
28105
1650
1035
616
34
03
Dacarbazine (N=274)
Vemurafenib (N=275)
Progression-free survival (Dec 30, 2010 cutoff)
Median 1.6 mos Median 5.3 mos
Chapman et al. NEJM 2011
Number of patients receiving anti-cancer therapies after initial treatment on BRIM-3
Subsequent anti-cancer therapy
Dacarbazine (n=338)
Vemurafenib (n=337)
Any 149 (44%) 122 (36%)
Ipilimumab 73 (22%) 60 (18%)
Dabrafenib 5 (1.5%) 0
Crossover to vemurafenib 83 (25%) –
Chapman P. et al. abs 8502 ASCO Ann. Meeting Chicago 2012
Summary of overall survival dataASCO 2011 ASCO 2012
(post-hoc)
DTIC Vemurafenib DTICa Vemurafenib
Median follow-up, months 2.3 3.8 9.5 12.5
Median OS, months Not reliably estimated 9.7 13.6
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 outcomeOutcome Duration of treatment post-
progressionAll 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 therapyPFS, progression-free survival; OS, overall survival
• 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
Vemurafenib (Zelboraf) expanded access study
Roche MO25515
FDA and EMA ApprovalAugust 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
30-40% colon cancer
~30% lung cancer
~20% melanoma
50-60% melanoma
8- 12% colorectal cancer
12% ovarian cancer
36% thyroid cancer
RAS
BRAF
MEK162
Frémin C, Meloche S. J Hematol Oncol. 2010;3:8; Pratilis CA, Solit DB. Clin Cancer Research, 2010;16:3329
MEK inhibitors.Study Design
Arm 1: BRAFV600E/(n = 28)MEK162 45 mg BID
Arm 1: BRAFV600E/(n = 28)MEK162 45 mg BID
Arm 2: NRAS-mutant (n = 26)MEK162 45 mg BID
Arm 2: NRAS-mutant (n = 26)MEK162 45 mg BID
Patients with advanced or metastatic unresectable
cutaneous malignant melanoma harboring
BRAFV600E/NRAS mutation
Patients with advanced or metastatic unresectable
cutaneous malignant melanoma harboring
BRAFV600E/NRAS mutation
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)
*Patients with missing best % change from baseline and unknown overall response are not included.
N=28*Progressive Disease (PD)
Stable Disease (SD)
Partial Response (PR)
Unconfirmed PR
45 mg NRAS
Ongoing pts
PFS – NRAS- /BRAF-mutant
Number of patients at risk
100
PFS
(%)
Median (months) [95% CI]: 3.65 [2.53, 5.39]Median (days) [95% CI]: 111 [77, 164]
Time (days)
0 0214437145 mg
00
20
40
60
61
80
122 183 274 365
Median (months) [95% CI]: 3.55 [2.00, 3.81]Median (days) [95% CI]: 108 [61, 116]
NRASmt
BRAFmt
[TITLE]
Rationale for Combination of BRAFi (GSK436) + MEKi (GSK212) in BRAF Mutant Tumors
1 Kefford et al., SMR 2010; 2 Lewis et al. Perspectives in Melanoma 2011
Tumor Type % BRAF Mutant
Melanoma 50%
Thyroid 50%
Cholangioca 15%
NSCLC 7-8%
Colorectal 5%
Goals of Combination
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
pERK
BRAF
MEK
Proliferation
SurvivalInvasion
Metastasis
BRAFi (GSK436)RR 77%1
Mechanistic toxicity: Hyperproliferative skin AEsMEKi (GSK212)
RR 35%2
Mechanistic toxicity: rash
RAS
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%.
Pre-screening for c-Kit mutation
Pre-screening for c-Kit mutation
ScreeningScreening
Randomization 120 Patients1:1Randomization 120 Patients1:1
DTIC 850 mg/m2
IV q3weeksDTIC 850 mg/m2
IV q3weeks
ProgressionProgression
Tasigna 400 mgb.i.d.
Tasigna 400 mgb.i.d.
ProgressionProgression
Cross-over?Cross-over?
Follow for survivalFollow for survival
Follow for survivalFollow for survival
No
. Studio di fase III randomizzato . NILOTINIB vs DTIC in c-kit mutati
MELANOMA in 2012Setting EMA approval Clinical trials evidence
1° line B-Raf mutated Vemurafenib Ipilimumab +/CT
B-Raf WT CT Ipilimumab +/-CT
2 line B Raf mutated Ipilimumab Ipilimumab ?BRAFi +MTT-CT
B-Raf WT Ipilimumab