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 30-40% 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 Undifferentiated American Cancer Society 2008
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 (Brose MS, Oncol Res Treat 2014) Decision trial, Phase lll, 417 pts (si indicazione, ma NON rimborsabilità). Lenvatinib (Schlumberger M, JCO 2014) Select trial, Phase lll 392 pts Sunitinib (Carr LL, Clin Cancer Res 2010) Phase ll Axitinib (Sherman SI, NEJM 2007) Phase ll Pazopanib (Bible KC, Lancet Oncol 2010) Phase ll Vemurafenib (Kim KB, Thyroid2013) 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) Direct antitumour effects Indirect antitumour effects EGFR signalling RET signalling VEGFR signalling EGFR signalling VEGFR signalling Tumour cells VEGF Endothelial cells 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
Study objectives Primary endpoint: PFS Based on RECIST (1.0) assessments as read by central independent review >80% di potenza per rilevare una hazard ratio (HR) <0.50 Secondary assessments included: Objective response rate Disease control rate at 24 weeks Biochemical response (decreases in serum levels of CT and CEA) Overall survival Time to worsening of pain Safety and tolerability (CTCAE 3.0) Wells et al. JCO 2012
Vandetanib significantly prolonged PFS (primary endpoint) Progression-free survival At risk (n) Vandetanib Placebo 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 Hazard ratio = 0.46 (0.31 0.69); P<0.0001 Hazard ratio <1 favours vandetanib Vandetanib 300 mg Placebo Median PFS: 19.3 months (placebo), not reached Vandetanib (modello Weibull si può predire una mediana di 30.5 mesi) (Appl Mech Trans) 6 12 18 24 30 36 Time (months) 231 198 171 141 42 1 0 100 72 57 45 13 0 0 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 V=47/137 (34.3%) P=27/50 (54.0%) RET mutation status negative V=1/2 (50.0%) P=5/6 (83.3%) Unknown RET mutation status V=25/92 (27.2%) P=19/44 (43.2%) CTN doubling time 24 months V=39/124 (31.5%) P=27/46 (58.7%) CTN doubling time >24 months V=23/83 (27.7%) P=19/43 (44.2%) Unknown CTN doubling time V=11/24 (45.8%) P=5/11 (45.5%) CEA doubling time 24 months V=25/69 (36.2%) P=26/33 (78.8%) CEA doubling time >24 months V=28/119 (23.5%) P=14/48 (29.2%) Unknown CEA doubling time V=20/43 (46.5%) P=11/19 (57.9%) High baseline p-vegf V=41/115 (35.7%) P=25/51 (49.0%) Low baseline p-vegf V=25/101 (24.8%) P=20/42 (47.6%) Unknown baseline p-vegf V=7/15 (46.7%) P=6/7 (85.7%) High baseline p-vegfr2 V=40/155 (25.8%) P=26/69 (37.7%) Low baseline p-vegfr2 V=26/61 (42.6%) P=19/24 (79.2%) Unknown baseline p-vegfr2 V=7/15 (46.7%) P=6/7 (85.7%) High baseline p-bfgf V=39/107 (36.4%) P=26/49 (53.1%) Low baseline p-bfgf V=27/108 (25.0%) P=19/43 (44.2%) Unknown baseline p-bfgf V=7/16 (43.8%) 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
Vandetanib significantly improved the objective tumour and biochemical response rate Secondary Endpoint Caprelsa arm (n=231) Placebo arm (n=100) Statistics Objective response rate 45% 13% Odds ratio: 5.48 95% CI 2.99 to 10.79 p=<0.0001 Biochemical response: serum calcitonin Biochemical response: serum CEA Decrease in serum calcitonin: 69% Decrease in serum CEA: 52% Decrease in serum calcitonin: 3% Decrease in serum CEA: 2% Odds ratio: 72.9 95% CI 26.2 to 303.2 p=<0.0001 Odds ratio: 52.0 95% CI 16.0 to 320.3 p=<0.0001 12 of 13 responses in the placebo arm began during treatment with open-label vandetanib 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%) 0 Rash 8 (3%) 1 (1%) Asthenia 6 (3%) 1 (1%) Dyspnoea 4 (2%) 3 (3%) Back pain 1 (0.4%) 3 (3%) Syncope 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
ZETA Trial: conclusions Vandetanib demonstrated efficacy in this Phase III study of patients with advanced metastatic MTC, a disease for which there is currently no effective therapy Wells et al. JCO 2012
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