Un aiuto dalle terapie biologiche.

Il Carcinoma della Tiroide: un aiuto dalle Terapie Biologiche
Giorgio Bonciarelli
Dipartimento Funzionale di Oncologia Clinica
Ospedale Madre Teresa di Calcutta, Padova Sud, Monselice
2 Ottobre 2015
Dichiarazione di conflitto di interessi
Dichiaro nessun conflitto di
interessi nella realizzazione di
questo intervento
Chemioterapia nel ca. della tiroide: the
past?!
E’ indicata nelle forme diffuse,
differenziate, in rapida crescita,
fortemente
sintomatiche
e
non
suscettibili di altro trattamento. I
farmaci di scelta sono l’Adriblastina,
il Cisplatino, il Taxolo con tassi di
risposta
(quasi
esclusivamente
parziali) che si attestano intorno al 3040% ma senza incidere positivamente
sulla OS.
Busaidy NL, J Thyroid Res 2012
Haugen BR, Semin. Surg. Oncol. 1999
The problem: RAI-Refractory
Disease
• 25-50% of metastatic Thyroid cancers lose
ability to take up Iodine
• Limited
treatments
options
for
unresectable thyroid cancer refractory to
RAI
Marcia S. Brose MD, 2009
Concetto di «Druggable Target»
Abbiamo capito (tantissimo ancora rimane da
fare!) che lo sviluppo di una neoplasia è
dovuto all’accumulo di mutazioni di specifici
geni
che
inducono
proliferazione
incontrollata,
resistenza
a
segnali
antiproliferativi,
resistenza
all’apoptosi,
induzione
della
neo-angiogenesi,
metastasizzazione.
Occorre quindi attuare il “Disinvestment”
ossia abbandonare, se possibile, pratiche
obsolete ed individuare, dirigere risorse
per l’accesso all’ innovazione.
Main oncogenic Pathways
RAS MUTATION IS ASSOCIATED WITH
TUMOR RECURRENCE AND LOSS OF
RESPONSE TO RADIOIODINE THERAPY
OBIETTIVO DELL’ ONCOLOGO MEDICO
Terapia personalizzata:
identificare il 10%
dei pts con sicure alterazioni molecolari per
ottenere il 100% delle risposte ma……
attenzione alle nuove tossicità che sono diverse
da quelle della CHT e talora subdole!
Nuovi farmaci Biotech in Oncologia Medica
(attualmente circa 50% ed in crescita)
Clinicamente grandi speranze ma
anche “dilemmi etici”: i loro
vantaggi terapeutici, talora non
così rilevanti, possono giustificare
gli alti costi?
L’Oncologia Medica paradigma di
insostenibilità economica ?!
Thyroid cancer has three main sub-types and MTC is
clearly distinguishable from other
Differentiated
American Cancer Society 2008
Undifferentiated
What have we learned recently at molecular processes of
thyroid cancer ?
New compounds (TKIs, antiVEGFR…) have been tested
and preliminary evidence indicates that they may help treat
Thyroid cancer cells with mutations in certain genes as
RAS/BRAF and RET and they may have important clinical
benefit.
Brilli L. Future Oncol 2011
Smallridge RC, Endocr Relat Cancer 2009)
Sorafenib (Nexavar)
Sunitinib (Sutent)
Pazopanib (Votrient)
Cabozantinib (Cometriq)
Motesanib (AMG 706)
Axitinib (Inlyta)
Vandetanib (Caprelsa)
Vemurafenib (Zelboraf)
Dabrafenib (Trafinlar) and Selumetinib
Partial summary of main Phase ll and lll clinical
trials of TKIs in DTC
•
Sorafenib
•
Lenvatinib
(Brose MS, Oncol Res Treat 2014) Decision trial, Phase lll,
417 pts (si indicazione, ma NON
rimborsabilità).
(Schlumberger M, JCO 2014)
Select trial, Phase lll 392 pts
•
•
•
Sunitinib
Axitinib
Pazopanib
(Carr LL, Clin Cancer Res 2010)
(Sherman SI, NEJM 2007)
(Bible KC, Lancet Oncol 2010)
•
Vemurafenib (Kim KB, Thyroid2013)
•
…………..
Phase ll
Phase ll
Phase ll
Phase l
TKIs et al., improved PRR, PFS, SD rates but OS has not been
well documented . There are contrasting evidence probably due to
the drug resistance! (Haugen BR, Endocr Rev 2013)
Carcinoma midollare (MTC)
• Aggressivo, sintomatico, ad alto rischio di
metastasi con rapido deterioramento delle
condizioni cliniche e radiologiche
• Deriva dalle cellule C Parafollicolari
• Non risponde alla terapia con 131Iodio Radioattivo
• Pazienti con urgente bisogno di trattamento
Sporadic MTC represents 75-80%
Sporadic (75%)
Hereditary (25%)
MEN 2A e MEN 2B
• Occurs in absence of family history
• Typically presents in the fifth or sixth decade of life
• In ~50% of sporadic cases and 100% of Hereditary
there is a somatic mutation in RET (Rearranged during
Transfection), a tirosin - chinase protein.
Marsh et al 1996, Eng et al 1996
The American Thyroid Association (ATA) Guidelines state that:
“The use of standard chemotherapy agents
should not be considered as first-line
therapy for patients with persistent or
recurrent MTC”
Kloos et al. Thyroid 2009
Martins RG, Clin Oncol 2006
RAS proto-oncogene in Medullary Thyroid
Carcinoma
• Other oncogenes
commonly involved in the
pathogenesis of human cancers have also investigated
in MTC
• The prevalence of RAS mutations in sporadic MTC
occurring usually in tumors with WT RET suggesting that
activation of these oncogenes represents alternative
genetic events in sporadic MTC tumorgenesis.
Thus, the assessment of RAS mutation status can be
useful to define therapeutic strategies in RET WT MTC
M.M. Moura, Endocrine Related Cancer
Vandetanib (Zeta trial, 331 pts) and Cabozantinib
(Exam trial, 330 pts)
New multitarget TKI for the treatment of
metastatic medullary thyroid carcinoma
(MTC)
Elisei R Jco 2013 – Wells JCO 2012
Vandetanib shows a doubled effect on tumour
(Wells SA, JCO 2012)
Indirect antitumour effects
Direct antitumour effects
EGFR signalling
RET signalling
Tumour
cells
VEGFR
signalling
EGFR
signalling
VEGFR
signalling
Endothelial cells
VEGF
Inhibition of EGFR and RET blocks tumour cell growth, proliferation and secretion of pro- angiogenic
factors
• EGFR is overexpressed in MTC (Wang W, 1997) and in particular in its metastasis (Rodriguez-Antona
C, 2010)
Inhibition of VEGFR blocks endothelial cell proliferation, migration and survival, and vascular
permeability
• VEGFR-1, and VEGFR-2 are overexpressed in MTC (Capp C, 2010)
• Microvessels, expression of neo-angiogenesis, are more represented in MTC than in other thyroid
tumors (Fontanini, 1996)
17
ZETA: an International, randomized, placebocontrolled Phase III trial
Patients with unresectable locally advanced or metastatic
hereditary or sporadic MTC (N=331)
2:1 randomization
Vandetanib 300 mg/day
n=231
Placebo
n=100
Follow for progression
Follow for progression
Discontinue blinded treatment at progression
Optional open-label vandetanib 300 mg/day
Follow for survival
Wells et al. JCO 2012
Vandetanib significantly prolonged PFS (primary
endpoint)
Hazard ratio <1 favours vandetanib
Progression-free survival
1.0
0.9
Vandetanib 300 mg
0.8
Placebo
0.7
0.6
0.5
0.4
0.3
Hazard ratio = 0.46 (0.31–0.69); P<0.0001
0.2
Median PFS: 19.3 months (placebo), not reached Vandetanib (modello
Weibull si può predire una mediana di 30.5 mesi) (Appl Mech Trans)
0.1
0
0
6
12
18
Time (months)
24
30
36
198
72
171
57
141
45
42
13
1
0
0
0
At risk (n)
Vandetanib 231
Placebo 100
Wells et al. JCO 2012
Vandetanib benefited all patient groups
in a predefined subgroup analysis of PFS
Overall
V=73/231 (31.6%)
P=51/100 (51.0%)
RET mutation status positive
RET mutation status negative
Unknown RET mutation status
V=47/137 (34.3%)
V=1/2 (50.0%)
V=25/92 (27.2%)
P=27/50 (54.0%)
P=5/6 (83.3%)
P=19/44 (43.2%)
CTN doubling time ≤24 months
CTN doubling time >24 months
Unknown CTN doubling time
V=39/124 (31.5%)
V=23/83 (27.7%)
V=11/24 (45.8%)
P=27/46 (58.7%)
P=19/43 (44.2%)
P=5/11 (45.5%)
CEA doubling time ≤24 months
CEA doubling time >24 months
Unknown CEA doubling time
V=25/69 (36.2%)
V=28/119 (23.5%)
V=20/43 (46.5%)
P=26/33 (78.8%)
P=14/48 (29.2%)
P=11/19 (57.9%)
High baseline p-VEGF
Low baseline p-VEGF
Unknown baseline p-VEGF
V=41/115 (35.7%)
V=25/101 (24.8%)
V=7/15 (46.7%)
P=25/51 (49.0%)
P=20/42 (47.6%)
P=6/7 (85.7%)
High baseline p-VEGFR2
Low baseline p-VEGFR2
Unknown baseline p-VEGFR2
V=40/155 (25.8%)
V=26/61 (42.6%)
V=7/15 (46.7%)
P=26/69 (37.7%)
P=19/24 (79.2%)
P=6/7 (85.7%)
High baseline p-bFGF
Low baseline p-bFGF
Unknown baseline p-bFGF
V=39/107 (36.4%)
V=27/108 (25.0%)
V=7/16 (43.8%)
P=26/49 (53.1%)
P=19/43 (44.2%)
P=6/8 (75.0%)
0.0625
0.25
1.0
4.0
16.0
64.0
A HR <1 favors vandetanib
The analyses were performed using a log-rank test with treatment as the only factor
Wells et al. JCO 2012
Most common grade 3+ adverse events (> 2%
incidence in either arm)
Vandetanib 300 mg
(n=231)
Placebo
(n=99)
Diarrhoea
25 (11%)
2 (2%)
Hypertension
20 (9%)
1 (1%)
ECG QTc prolonged
18 (8%)
1 (1%)
Fatigue
13 (6%)
1 (1%)
Decreased appetite
10 (4%)
Rash
8 (3%)
1 (1%)
Asthenia
6 (3%)
1 (1%)
Dyspnoea
4 (2%)
3 (3%)
Back pain
1 (0.4%)
3 (3%)
Syncope
0
0
2 (2%)
Wells et al. JCO 2012
Attenta selezione del paziente!
• Vandetanib non deve essere somministrato in pazienti
con:
– Sindrome congenita del QTc lungo
– Precedenti episodi di torsione di punta, a meno che
la causa scatenante non sia stata individuata e
corretta
– Bradiaritmie o scompenso cardiaco non
compensato
• Inoltre, l’utilizzo di vandetanib non è stato valutato in
pazienti con aritmie ventricolari e infarto del miocardio
recente
Considerazioni conclusive
• I progressi ottenuti nel trattamento biologico del tumore
avanzato
della
tiroide
possono
definirsi
“oncologicamente intriganti”.
• In futuro, verosimilmente, si disegneranno trials con
l’impiego di ‘combinazioni di target agents’ con
l’obiettivo di migliorare gli outcomes.
• Parlando di sperimentazioni cliniche, il problema etico
rimane di fondamentale importanza cosi come la
multidisciplinarietà e l’Oncologo Medico si pone come
protagonista di un nuovo modo di fare ricerca e come
garante dell’indipendenza scientifica.
GRAZIE DELL’ATTENZIONE