Emma Bridgewater

3rd Session
MELANOMA
V EUROPEAN CONFERENCE
ON SURVIVORS AND CHRONIC
CANCER PATIENTS
6 7
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June
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2014
Palazzo Vermexio - Siracusa, Italy
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Michele La Greca
Francesco Ferraù
www.oncologicicronici.it
Dipartimento III Livello Oncologia
UOC Oncologia Medica
Ospedale “S.Vincenzo”
Taormina
MELANOMA CUTANEO E PROGNOSI
MELANOMA “SOTTILE”
(Breslow <1 mm.)
DUE
GRUPPI
• BRESLOW> 3 mm.
• LOCALIZZAZIONI
LINFONODALI
• METS SINCRONE
Comparison of different schedules of systemic treatment
(41 TRIALS) in disseminated melanoma
RESPONSE RATE
OVERALL SURVIVAL
TK Eigentler et al., The Lancet Oncology 2003
LA RIVOLUZIONE BIOLOGICA
First DTIC
study
Principali capisaldi terapeutici nel
melanoma metastatico
Studies on associations
therapies to improve
overall survival
1971
1980s
Interferon  is
approved by FDA
Ipilimumab approved
by FDA e EMA
1995
2011
2011/
1975
DTIC is approved by FDA for
metastatic melanoma
1980s-1990s
Fotemustine studies on
brain mets
1998
Interleukin- 2 is
approved by FDA
2013
2012
Dabrafenib
Vemurafenib approved
approved by FDA
by FDA and EMA
Burke PJ, et al. Cancer 1971;27:744–50.
Mouawad R, et al. Crit Rev Oncol Hematol 2010;74:27–39.
Khayat D, et al. Cancer Invest 1994;12:414–20.
National Cancer Institute. Melanoma treatment (PDQ®): stage III melanoma. Available on www.cancer.gov
US Food and Drug Administration. FDA news release: FDA approves new treatment for a type of late-stage skin cancer [press release]. Available on www.fda.gov
European Medicines Agency recommends approval of first-in-class treatment for metastatic or unresectable melanoma. Available on www.ema.europa.eu
4
SECONDA DECADE DEGLI ANNI 2000
LE DUE GRANDI NOVITA’
FARMACI INIBITORI DI
CHECK-POINTS IMMUNITARI
(Ipilimumab – Nivolumab/Pembrolizumab – anti CD137 –
etc)
FARMACI AD ATTIVITA’
TARGETED “GENETIC-DRIVEN”
(BRAFi – MEKi)
Modulation of T-cell function
T-cell activation occurs through the
interaction with an APC
Additional signals occur through
interactions of costimulatory
molecules
T-cell functions are tightly regulated
through various costimulatory and
inhibitory molecules
Modulation of T-cell activation by
targeting these regulatory molecules
is an area of active research
CTLA-4 were developed as anticancer therapies under the
theory that through blockade of the CTLA-4-mediated
inhibitory signal, the activity of T-cells may be activated
against tumor antigens and their activity harnessed for
treatment of cancer.3,13
Frequently asked questions:
mechanism of action
Ipilimumab, CTLA-4 Blocking mAb, augments TThe mechanism of action of ipilimumab differs from those
Cell
Activation
of traditional
chemotherapy or small-molecule inhibitors,
A
T-cell activation
T-cell inhibition
T-cell remains activ ated
CTLA-4
Activation
TCR
TCR
CD28 Activation
CD28
B7
MHC
TCR
Activation
TCR: MHC antigen
MHC
APC
CD28: B7
T-cell activatio n
CTLA-4
Activation
CD28
B7
B7
MHC
APC
B
CTLA-4 Inhibition
APC
CTLA-4: B7
T-cell inhibition
Ipilimumab
blocks
CTLA-4
lpilimumab
CTLA-4 blockade/ T-cell
proliferation
Figure 1 (A and B) Role of CTLA-4 in T-cell responses and the impact of CTLA-4 blockade with ipilimumab. Ipilimumab mechanism of action (A) and “brake and pedal”
analogy (B) as used to explain the mechanism to patients and caregivers.
Abbreviations: CTLA, cytotoxic T-lymphocyte antigen; APC, antigen-presenting cell; MHC, major histocompatibility complex; TCR, T-cell receptor.
Ledezma B, Cancer Manag Res 2014
The target: BRAF kinase
An important mediator of cellular proliferation
RTK
RAS
BRAF
RafV600E
ATP
Vemurafenib
Dabrafenib
MEK
ATP
ERK
Cellular
proliferation
Vemurafenib / Dabrafenib
co-structure with the kinase
domain of BRAFV600E
(Bollag et al., Nature 2010)
o ni v e
Pr o p or t iAl
Ipilimumab Study 024: Overall Survival
1. 0
Ipilimumab + DTIC
0. 9
Placebo + DTIC
0. 8
0. 7
0. 6
0. 5
0. 4
0. 3
0. 2
0. 1
0. 0
0
1
2
Ye a r s
3
4
Estimated Survival Rate
1 Year
2 Year
3Year
4 Year*
Ipilimumab + DTIC
n=250
47.3
28.5
20.8
19
Placebo + DTIC
n=252
36.3
17.9
12.2
9.6
*M.Maio, ESMO Meeting 2012
Overall survival rates with ipilimumab at 10 mg/kg
Survival rate, % (95% CI)
Study
1-year
2-year
3-year
4-year
5-year
*
CA 184-008
47.2
32.8
23.3
19.7
18.2
CA 184-022
48.6
30.4
25.4
21.5
21.5
CA 184-007
55.9
41.1
38.7
36.2
36.2
EAP 10 mg
34.8
23.5
20.9
20.9
Lebbè C, ESMO2012
CAMBIAMENTI CULTURALI
• VALUTAZIONE DELLE RISPOSTE (irCR di
Wolchok)
• CONTROLLO DI MALATTIA POST-TREATMENT
• SD DURATURE E SOPRAVVIVENZA UGUALE
AI PAZ IN RISPOSTA OBIETTIVA
• GESTIONE DEGLI EVENTI AVVERSI A MEDIOLUNGO TERMINE
• TERAPIE COMBINATORIE BEN TOLLERATE
(antiBRAF+antiMEK; anti-CTLA4+antiPD1)
Ipilimumab 4846 Pts (ESMO ECCO 2013):
ORR 7-15%
plateau OS in 17-25% dopo 3 anni,
prolungata fino a 10 aa.
Schadendorf D et Al, abst # 241BA
Vemurafenib (BRIM 3)
ORR 53 % (RC 6%),
m OS 13,6 mesi
Dabrafenib (BREAK 3)
ORR 50% (RC 3%),
m OS 18,2 mesi
Pooled overall survival data from 1861
ipilimumab-treated patients in 12 clinical trials
1.0
0.9
0.8
Median OS, months (95% CI): 11.4 (10.7–12.1)
Proportion
Alive
0.7
0.6
3-year OS rate, % (95% CI): 22 (20–24)
0.5
0.4
0.3
0.2
0.1
Ipilimu
mab
CENSORED
0.0
0
1861
12
24
36
48
60
Months
72
84
96
108
120
5
0
 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
Schadendorf D, et al. Presented at ECC 2013: oral presentation 24LBA
Pooled overall survival analysis including
Expanded Access Program data: 4846 patients
1.0
Median OS, months (95% CI): 9.5 (9.0–10.0)
Proportion Alive
0.9
0.8
0.7
0.6
3-year OS rate, % (95% CI): 21 (20–22)
0.5
0.4
0.3
0.2
0.1
Ipilimumab
CENSORED
0.0
0
1
2
2
4
3
6
4
8
6
0
7
2
8
4
9
6
108
120
2
6
1
5
5
0
Months
Schadendorf D, et al. Presented at ECC 2013: oral presentation 24LBA
“… immunologic agents induce long-lasting complete
responses in a limited number of patients, to the point
where
the question of “cure”
in these cases must be entertained.”
Paul Chapman
ASCO Educational Book, 2014
Paziente vivente in RC, 19 mesi di terapia con vemurafenib
La persistenza della memoria, Salvador Dalì
OLTRE IPILIMUMAB: MoAb ANTI-PD-1
PEMBROLIZUMAB, 135 pts:
RO (recist): 38%
Hamid O, NEJM 2013
PEMBROLIZUMAB, 411 pts: RO (recist): 40% IPI naive
RO (recist): 28% IPI previous
mOS not reached
sopravv.1 anno: 71%
AEs GIII-IV: 12% Ribas A, ASCO 2014
OLTRE IPILIMUMAB: MoAb ANTI-PD-1
NIVOLUMAB, 107 pts:
RO (recist): 31%, durata mediana 22 mesi
OS mediana: 17 mesi
sopravv. 1 anno: 62%
sopravv. 2 anni: 43%
Sznol M, ASCO 2013
NIVOLUMAB, 107 pts:
-
RO (recist): 32%, durata mediana 23 mesi
46% mantiene risposta oltre sei mesi
sopravv. 2 anni: 48%
sopravv. 3 anni: 41%
 PFS e OS per PD-L1 pos.
Hodi FS, ASCO 2014
OLTRE IPILIMUMAB: MoAb ANTI-PD-1
NIVOLUMAB + IPILIMUMAB, 53 Pts concurrent, 33 Pts sequential
•RO (Recist): 40%
•Clinical Activity (RO, irR): 65%
•quasi tutte risposte con regressione dell’ 80%
•AEs GIII-IV: 53%
Wolchock JD, NEJM 2013
Melanoma Immunotherapy:
Future Directions
 Targeted monoclonal antibody therapy
– Anti–CTLA-4 therapy
– Dose, schedule, toxicity
– Novel antibodies: anti–PD-1, anti-CD137, anti-CD40
 Adoptive-cell therapy
– Combined use of CD4+ and CD8+ T cells
– Combination therapy with anti–CTLA-4/anti–PD-1 antibodies
– Stimulating transferred lymphocytes with new/better combinations
of agents
 Combinatorial immunotherapy with targeted therapy,
antiangiogenic agents, and chemotherapy
NUOVI SCENARI
Per il Chirurgo: Elettrochemioterapia;
Metastasectomia di melanoma oligometastatico
(NCCN 2014).
Per l’Oncologo: trattamento neoadiuvante,
adiuvante e delle sequele a lungo termine.
Per lo Psicologo: trattamento dell’ansia
cronica.
CONCLUSIONI
• Il Paziente con melanoma avanzato inizia ad avere
miglior qualità di vita e spravvivenza prolungata
• Risposte obiettive significative, miglior controllo
del dolore, prolungamento della “dormant phase”
• L’oncologo inizia a focalizzare l’attenzione su
problematiche “croniche”
• Format psico-assistenziale per Pazienti con
particolare autocoscienza di malattia
Grazie per l’attenzione

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