Transcript Selezione dei pazienti affetti da melanoma

Selezione dei
pazienti affetti da
melanoma
Vanna Chiarion Sileni
Melanoma and Skin Cancer Unit
IOV-IRCCS , Padova
Prognostic factors in metastatic melanoma
1362 pts enrolled in 8 studies ECOG in the last 25 years
Median OS 6.4 months (CI 6.1-6.9)
•
Multiple metastases RR= 1.3
•
ECOG PS >1 RR = 1.49
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GI metastases RR =1.49
•
Liver metastases = 1.44
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Pleural metastases RR =1.35
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LDH  RR = 1.89
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FAL  RR = 1.76
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Previous immunotherapy RR = 0.84
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Female gender RR = 0.87
•
Response to the treatment RR = 0.4
J Manola JCO 18; 3782-3793,2000
LDH is the most important prognostic factor
C. Balch. JCO 27:6199,2009
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
Patient selection
Factors to recommend high-dose IL-2 or
immunotherapies
• Good PS (ECOG 0-1)
• Normal LDH
• Cutaneous or subcutaneous metastases only or less
than three organs involved
• No brain metastases
BO 84 y protocol Ca184 EAP
Courtesy V Chiarion Sileni
BO anni 84 Ipi 3 mg/kg q 21d x 4
EORTC Protocol 16032 (Coso 059)
Jun 2005
Sep 2005
Nov 2005
EORTC Protocol 16032 (C0s0 059)
courtesy V. Chiarion Sileni
Aug 2005
Nov 2005
Jan 2006
Different incidence of Braf mutation with age and sun exposure
JCO 2011
IOV-IRCCS
Cancer 2011
MELANOMA
MOLECULAR
TARGETSPATHWAY
Overall survival (March 31, 2011 cutoff)
1.0
Overall survival (%)
0.9
Vemurafenib (N=337)
Est 6 mo survival 83%
Median follow-up 6.2 mo
0.8
0.7
0.6
0.5
0.4
Hazard ratio 0.44
0.3
(95% CI; 0.33 - 0.59)
Dacarbazine
median OS
7.9 mo
0.2
0.1
Dacarbazine* (N=338)
Est 6 mo survival 63%
Median follow-up 4.5 mo
0
0
1
2
3
4
5
No. of patients at risk
Dacarbazine
Vemurafenib
338 302 268 232
337 336 334 317
186 145
285 218
6
7
8
9
Time (months)
111
178
83
125
43
82
26
54
10
11
12
13
14
12
22
5
11
0
4
0
2
0
0
Post-progression use of ipilimumab: 17% dacarbazine patients vs 6% vemurafenib patients
*Dacarbazine patients who received vemurafenib after the IA (by DSMB recommendation; N=50) were
censored at the date of crossover
Confirmed objective response rates (RECIST 1.1) across
vemurafenib clinical trial programme
Vemurafenib
(95% CI)
Dacarbazine
(95% CI)
BRIM-3 ORR
(final analysis
at OS IA, 30 Dec
2010)
PLX 06-02
Phase I
BRIM 2
56.0%
53.0%
48.4%
(38–74)
(44–62)
(42–55)
–
–
5.5%
(3–9)
Clinical case 1
F 21-y old Nov 2005 NM on the left arm : pT4bN2aM0
HDI 1 month iv and 6 months LDI sc Feb ‘06 Oct ‘06
Feb ‘09 subcutaneous multiple recurrences: Sur
Jan ’10 subcutaneous multiple lesions: S + RT
Mar ’10 recurrence in axillary lymph-node and iliac: DTIC+DDP x
4 NC (CT and PET scan)
Jul ’10 FMT only induction: plt G4 toxicity and pelvic PD
Nov ’10 ipilimumab 3 mg/kg x 4 well tolerated: PD
April’11 surgical resection of pelvic mass (symptomatic) and left
ovary
Aug’ 11 started vemurafenib 960 mg x 2 on protocol M025515
ongoing
Tolerance: photosensitization ,weight loss, dry skin, curly hair
Aug 2011
Oct 2011
Dec 2011
Mar 2012
V. Chiarion Sileni courtesy
May 2012
V. Chiarion Sileni courtesy
Clinical case 1
resection and DC vaccination ?
radical resection alone or continuing vemu ?
ECT and to continue vemu ?
Clinical case 2
M 30-y old, May 2004 SSM in the back High IM and axillary mets
pT2a N1aM0
adjuvant HDI for 1 y regular FU till Jan ‘11
Lung bilateral recurrence and mediastinal node: evaluation for S
excluded
Apr ’11 he started DTIC for 8 cycles: SD followed by PD lung and
bone
Oct 2011 Vemurafenib + zoledronic acid: ongoing in Sep ’12
Toxicity: photosensitization and plantar hyperkeratosis ( G2)
Oct 2011
Dec 2011
Apr 2012
Jul 2012
V.Chiarion Sileni courtesy
Clinical case 2
Options:
Continue treatment without any change ?
Stop Vemu and restart it at PD ?
Ipilimumab asap or at PD ?
Clinical case 3
F 29-y old: NM on the shoulder Mar 2010 pT4bN0
Jan ’11 lung multiple mets: DDP+DTIC x 6 Cycles:
SD- PD
Sep ’11 evaluation for protocol M025515
screen failure due to elevated LFT
Jan 2011 retested, started vemuradenib
Jan 2012
Mar 2012
May 2012
V. Chiarion Sileni courtesy
Jun 2012
Aug 2012
Sep 2012
V. Chiarion Sileni courtesy
Clinical case 3
In pts who develop CNS mets during vemu
should the treatment be stopped ?
Feb 2011
Aug 2011
Rochet N, NEJM 2011
B. Neyns Mel Res 2012
Conclusions (1)
•
•
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After 30 years of extensive researches two new
different drugs showed an increase of OS in
metastatic melanoma
The effect of ipilimumab is not directly related to the
tumor response, need time and a good PS, seems
independent from disease extension and location
Ipilimumab exerts some activity also in metastatic
mucosal and ocular melanoma and in brain metastases
when asymptomatic
Conclusions (2)
BRAFi exert their effect rapidly and in a large
proportion of patients arboring BRAF mutation
BRAFi showed efficacy in brain metastases
Combination of BRAFi with MEKi seems to prolong
response duration
Efficacy in the adjuvant setting, activity and safety in
combination with other target therapies, with
other immuno-modulating agents and with antiangiogenetic agents are undervaluation