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1°Corso Nazionale: «Giornalisti Medico-Scientifici e Oncologi Medici» Parma, 18-19 giugno 2015 Divulgare in modo corretto i successi (anche parziali) della lotta contro il cancro PierFranco Conte Dipartimento di Chirurgia, Oncologia e Gastroenterologia Università di Padova Oncologia Medica 2 – IOV, IRCCS, Padova Bridging the gap between bench and bedside Miti, illusioni, illusionisti e realtà • I tumori sono malattie recenti Cancer has always been with us (even before we were here……) Bone tumors found in vertebrae of : 29/97 Hadrosauran dinosaurs 0/ 611 non Hadrosauran dinosaurs Possible explanation of different epidemiology: stomach content of Hadrosaurs include conifers; this diet is unique to Hadrosaurs Miti, illusioni, illusionisti e realtà • I tumori sono malattie recenti FALSO • I tumori sono un problema che riguarda principalmente i paesi ricchi Cancer burden worldwide- Globocan 2008 • • • • # new cancers/yr # cancer deaths/yr # cancers in developing countries # cancer deaths in developing countries 12.700.000 7.600.000 7.100.000 4.860.000 Probabilità di sviluppare un tumore in Italia sede tumorale maschi femmine tutte le sedi 2 3 mammella - 9 cute, non melanomi 7 14 prostata 8 - polmone 9 37 colon-retto 10 17 vescica 25 187 stomaco 25 42 retto 28 56 Miti, illusioni, illusionisti e realtà • I tumori sono malattie recenti FALSO • I tumori sono un problema che riguarda principalmente i paesi ricchi FALSO • La lettura del genoma umano consente di identificare tutti i passaggi chiave della cancerogenesi Key events in the investigation of the Cancer Genome * * * Philadelphia translocation (bcr-abl): t(9;22((q34;q11) * Myc oncogene (chromosome 8) in Burkitt’s lymphoma Stratton M. Science 331:1553, 2011 The « Central Dogma » © 2010 Nature Education All rights reserved. Miti, illusioni, illusionisti e realtà • I tumori sono malattie recenti FALSO • I tumori sono un problema che riguarda principalmente i paesi ricchi FALSO • La lettura del genoma umano consente di identificare tutti i passaggi chiave della cancerogenesi VERO • Le terapie mirate (terapie “intelligenti”) alle alterazioni genomiche “chiave” sono l’arma finale PATOGENESI Mutazione del proto-oncogene c-kit Attivazione costitutiva del recettore ed autofosforilazione del recettore c-kit Crescita cellulare incontrollata e inibizione dell’apoptosi Normal KIT Signaling • The KIT kinase domain activates a substrate protein, eg, PI3 kinase, by phosphorylation • This activated substrate initiates a signaling cascade culminating in cell proliferation and survival Substrate Effector Kinase domains ADP P PPP ATP PPP SIGNALING Savage and Antman. N Engl J Med. 2002;346:683. Scheijen and Griffin. Oncogene. 2002;21:3314. Imatinib Mesylate: Mechanism of Action • Imatinib mesylate occupies the ATP binding pocket of the KIT kinase domain • This prevents substrate phosphorylation and signaling • A lack of signaling inhibits proliferation and survival Kinase domains P ATP PPP Imatinib mesylate Savage and Antman. N Engl J Med. 2002;346:683. Scheijen and Griffin. Oncogene. 2002;21:3314. SIGNALING Tumor biomarkers: Predictive parameter cKIT, PDGFRA and GIST Verweij J, Lancet 2004 Targeted Agents in Oncology approved before 2010 YEAR AGENT TARGET DISEASES 1970 Tamoxifen Estrogen receptor Breast cancer 1997 Rituximab CD20 NHL 1998 Trastuzumab Her 2 Breast ca, Gastric ca 2001 Imatinib BCR /ABL, c-kit, PDGFR CML, GIST 2002 Fulvestrant Estrogen receptor Breast cancer 2003 Gefitinib-Erlotinib EGFR NSCLC 2004 Letrozole - Anastrazole Aromatase enzyme Breast cancer 2005 Exemestane Aromatase enzyme Breast cancer 2005 Bevacizumab VEGF CRC, Breast, RCC, NSCLC, Brain, Ovarian ca 2005 Cetuximab - Panitumumab EGFR CRC, Head and Neck 2006 Sorafenib Raf-k, VEGFR2-3, PDGFR,c-kit Liver ca, RCC 2006 Sunitinib PDGFR, VEGFR1-2-3,c-kit,FLT3 RCC, GIST 2007 Dasatinib BCR /ABL, Src CML 2008 Lapatinib HER2-EGFR Breast cancer 2008 Temsirolimus- Everolimus mTOR RCC, PNET, Breast 2010 Pazopanib VEGFR1-2-3, PDGFRα–β, c-kit RCC, sarcoma dei tessuti molli Targeted Agents in Oncology approved after 2010 YEAR AGENT TARGET DISEASES 2011 Denosumab Rank-ligand Bone mets 2011 Vemurafenib B-RAF Melanoma 2011 Crizotinib EML4/ALK ALK-positive NSCLC 2011 Abiraterone CYP 17A1 Prostate ca 2012 Enzalutamide AR Prostate ca 2012 Pertuzumab HER2 Breast ca 2012 Vismogedib SMO (Hedgehog pathway) Basal cell ca 2012 Axitinib VEGFR1-2-3 RCC 2012 Vemurafenib BRAF BRAF mut melanoma 2012 Vandetanib VEGFR-2, EGFR, RET Medullary thyroid ca 2013 T-DM1 HER2 Breast ca 2013 Aflibercept VEGF-A, VEGF-B, PIGF CRC 2013 Regorafenib VEGFR1-2-3, TIE2, c-kit, RET, PDGFR, FGFR CRC, GIST 2013 Ipilimumab CTLA-4 Melanoma 2013 Dabrafenib RAF kinases BRAF mut melanoma 2013 Afatinib EGFR NSCLC And there is more… Targeted Agents in Oncology approved after 2010 YEAR AGENT TARGET DISEASES 2014 Cabozantinib MET, VEGFR, RET, GAS6R, KIT, FLT3 Medullary thyroid ca 2014 Trametinib MEK BRAF mut melanoma 2014 Ramucirumab VEGFR-2 Gastric cancer, CRC 2014 Olaparib Poly ADP-ribose polymerase (PARP) BRCA mut ovarian ca 2014 Nivolumab PD-1 Melanoma, lung ca 2014 Pembrolizumab PD-1 Melanoma 2014 Ceritinib ALK ALK-positive NSCLC 2015 Palbociclib CdK 4, CdK 6 Breast cancer 2015 Lenvatinib VEGFR2-3 RAI-refractory diff. thyroid ca In gray agents that have received approval by FDA, but not (yet) approved by EMA Male, 53 years old Never smoker Veterinary Roadrunner Not relevant comorbidities Dyspnea during marathon coaching Bronchoscopy with TBNA: Lung adenocarcinoma (TTF1+, p63-) Exons 18-21 EGFR: wt (sanger sequencing; 20% cancer cells) Lung adenocarcinoma T3N3M1a (stage IV) Jan 18, 2013 1^ LINE CT Cisplatin plus Pemetrexed (6 cycles) PR EGFR mutation analysis by Sequenom: Exon 19 deletion Mutation (2235del15) delE746-A750 Dec 05, 2013 PD Thoracic PD Dec 12, 2013 TARGETED THERAPY Gefitinib PR After 2 months CT-guided biopsy: Jan 05, 2015 Lung adenocarcinoma PD REGIONE DEL VENETO Thoracic progression Exons 20 EGFR: T790M REGIONE DEL VENETO ISTITUTO ONCOLOGICO VENETO, IRCCS ISTITUTO ONCOLOGICO VENETO, IRCCS Dip. di Scienze Chirurgiche, Oncologiche e Gastroenterologiche - Università di Padova Dip. dibrain Scienze Chirurgiche, Oncologiche eDEL Gastroenterologiche - Università di Padova and lesions VENETO mutation U.O.C. IMMUNOLOGIA EREGIONE DIAGNOSTICA MOLECOLARE ONCOLOGICA U.O.C. IMMUNOLOGIA E DIAGNOSTICA MOLECOLARE ONCOLOGICA ISTITUTO ONCOLOGICO VENETO, IRCCS Direttore: Prof. Alberto Amadori Direttore: Prof. Alberto Amadori Dip. di Scienze Chirurgiche, Oncologiche e Gastroenterologiche - Università di Padova SGQ ISO Certificato da CERTIQUALITY U.O.C. IMMUNOLOGIA E9001:2008 DIAGNOSTICA MOLECOLARE ONCOLOGICA SGQ ISO 9001:2008 Certificato da CERTIQUALITY Direttore: Prof. Alberto Amadori Cognome e nome: FANTE FABIO Data di nascita: 15/12/1959 SGQ ISO 9001:2008 Certificato da CERTIQUALITY Cognome e nome: FANTE FABIO Data di nascita: 15/12/1959 Provenienza: Azienda Ospedaliera Padova - ANATOMIA PATOLOGICA Provenienza: Azienda Ospedaliera Padova - ANATOMIA PATOLOGICA Richiedente: Prof.ssaFABIO Calabrese Cognome e nome: FANTE Data di nascita: 15/12/1959 Richiedente: Prof.ssa Calabrese Data di accettazione: 05/03/2015 Data di refertazione: 16/03/2015 Provenienza: Ospedaliera Padova - ANATOMIA PATOLOGICA Data di accettazione: Azienda 05/03/2015 Data di refertazione: 16/03/2015 Esame n. O-01302-15 Richiedente: Prof.ssa Calabrese Esame n. O-01302-15 Data di accettazione: 05/03/2015 Data di refertazione: 16/03/2015 Esame n. O-01302-15 DNA da Biopsia n. 15-08591 DNA da Biopsia n. 15-08591 •Ricerca mutazioni del gene EGFR •Ricerca mutazioni del gene EGFR DNAAnalisi da Biopsia esone 18n. 15-08591 Analisi esone 18 Analisi esone 19 Analisi esone 19 del gene EGFR •Ricerca mutazioni Analisi esone 20 Analisi esone esone 18 20 Analisi Analisi esone 21 21 Analisi esone 19 Percentuale di cellule tumorali Percentuale cellule tumorali Analisi esonedi20 Nota Nota esone 21 Analisi Non eseguibile Non eseguibile Non eseguibile Non eseguibile Mutato Mutato Non eseguibile Non eseguibile Non eseguibile 70 70 Mutato (Metodo Analisi di sequenza) (Metodo Analisi di sequenza) (Metodo Analisi di sequenza) (Metodo Analisi di sequenza) (Metodo Analisi di sequenza) (Metodo Analisi di sequenza) (Metodo Analisi di sequenza) (Metodo Analisi di sequenza) % (*) % (*) Non eseguibile Percentuale di cellule tumorali valutata dall'Anatomia Patologica di provenienza. Percentuale cellule tumorali valutata dall'Anatomia Patologica di (*) provenienza. Percentuale di celluleditumorali 70 % (Metodo Analisi di sequenza) (Metodo Analisi di sequenza) Nota Referto interpretativo RefertoPercentuale interpretativodi cellule tumorali valutata dall'Anatomia Patologica di provenienza. L'analisi del DNA ottenuto dalla biopsia mediante PCR quantitativa, ha evidenziato la presenza di una L'analisi del(T790M) DNA ottenuto dalla biopsia 20 mediante PCR quantitativa, ha evidenziato la presenza di una mutazione a carico dell'esone del gene EGFR. mutazione (T790M) a carico dell'esone 20 del gene EGFR. d Feb 21, 2015 WHOLE BRAIN RT 30 Gy in 10 fractions Mar 18, 2015 CLINICAL TRIAL Rociletinib vs single agent CT PR After 6 weeks CANCER GENOMICS: INTRA-TUMOR HETEROGENEITY Gerlinger M et al, N Eng J Med 2012 SAFIR01: Study Flow Biopsy metastases in patients PR/SD under treatment 2 Frozen samples 1 FFPE sample Whole genome CGH array (gene copy numbers) Sanger sequencing hot spots PIK3CA/AKT1 Targeted therapy according to the genomic profile at the time of PD Identification of a targetable Genomic Alteration by a multicentric multidisciplinary team biopsy DNA extraction + quality control CGH array + Mutations PIK3CA/AKT Molecular MDT Identification of a potential Clinical Trial SAFIR01: Clinical Operations 18 Investigational centers SAFIR project - Results Results n (%) Patients screened 423 Patients biopsied 404 (95%) CGH arrays 287 (68%) Pts with targetable genomic alterations 194 (46%) Patients treated 48 (11%) Objective response 4 (1%) SD>16 weeks 8 (2%) OR + SD>16 weeks 12 (3%) Limiti delle terapie a bersaglio molecolare • Riproducibilità/sensibilità delle tecniche diagnostiche • Rare mutazioni “drivers”; molte mutazioni “passengers” • Mutazioni secondarie (indotte? selezione clonale?) • Eterogeneità della popolazione neoplastica • Difficoltà nel produrre evidenza scientifica Targeted Agents in Oncology approved before 2010 YEAR AGENT TARGET DISEASES 1970 Tamoxifen Estrogen receptor Breast cancer 1997 Rituximab CD20 NHL 1998 Trastuzumab Her 2 Breast ca, Gastric ca 2001 Imatinib BCR /ABL, c-kit, PDGFR CML, GIST 2002 Fulvestrant Estrogen receptor Breast cancer 2003 Gefitinib-Erlotinib EGFR NSCLC 2004 Letrozole - Anastrozole Aromatase enzyme Breast cancer 2005 Exemestane Aromatase enzyme Breast cancer 2005 Bevacizumab VEGF CRC, Breast, RCC, NSCLC, Brain, Ovarian ca 2005 Cetuximab - Panitumumab EGFR CRC, Head and Neck 2006 Sorafenib Raf-k, VEGFR2-3, PDGFR,c-kit Liver ca, RCC 2006 Sunitinib PDGFR, VEGFR1-2-3,c-kit,FLT3 RCC, GIST 2007 Dasatinib BCR /ABL, Src CML 2008 Lapatinib HER2-EGFR Breast cancer 2008 Temsirolimus- Everolimus mTOR RCC, PNET, Breast 2010 Pazopanib VEGFR1-2-3, PDGFRα–β, c-kit RCC, sarcoma dei tessuti molli Targeted Agents in Oncology approved after 2010 YEAR AGENT TARGET DISEASES 2011 Denosumab Rank-ligand Bone mets 2011 Vemurafenib B-RAF Melanoma 2011 Crizotinib EML4/ALK ALK-positive NSCLC 2011 Abiraterone CYP 17A1 Prostate ca 2012 Enzalutamide AR Prostate ca 2012 Pertuzumab HER2 Breast ca 2012 Vismogedib SMO (Hedgehog pathway) Basal cell ca 2012 Axitinib VEGFR1-2-3 RCC 2012 Vemurafenib BRAF BRAF mut melanoma 2012 Vandetanib VEGFR-2, EGFR, RET Medullary thyroid ca 2013 T-DM1 HER2 Breast ca 2013 Aflibercept VEGF-A, VEGF-B, PIGF CRC 2013 Regorafenib VEGFR1-2-3, TIE2, c-kit, RET, PDGFR, FGFR CRC, GIST 2013 Ipilimumab CTLA-4 Melanoma 2013 Dabrafenib RAF kinases BRAF mut melanoma 2013 Afatinib EGFR NSCLC And there is more… Targeted Agents in Oncology approved after 2010 YEAR AGENT TARGET DISEASES 2014 Cabozantinib MET, VEGFR, RET, GAS6R, KIT, FLT3 Medullary thyroid ca 2014 Trametinib MEK BRAF mut melanoma 2014 Ramucirumab VEGFR-2 Gastric cancer, CRC 2014 Olaparib Poly ADP-ribose polymerase (PARP) BRCA mut ovarian ca 2014 Nivolumab PD-1 Melanoma, lung ca 2014 Pembrolizumab PD-1 Melanoma 2014 Ceritinib ALK ALK-positive NSCLC 2015 Palbociclib CdK 4, CdK 6 Breast cancer 2015 Lenvatinib VEGFR2-3 RAI-refractory diff. thyroid ca In gray agents that have received approval by FDA, but not (yet) approved by EMA Miti, illusioni, illusionisti e realtà • • • • • I tumori sono malattie recenti FALSO I tumori sono un problema che riguarda principalmente i paesi ricchi FALSO La lettura del genoma umano consente di identificare tutti i passaggi chiave della cancerogenesi VERO Le terapie mirate (terapie “intelligenti”) alle alterazioni genomiche “chiave” sono l’arma finale FALSO, progressi importanti solo in pochi tumori La “conquista del cancro” è vicina? Trends in mortality from cancer in Europe: age-standardised rate (W) per 100,000 Male Female www.who.int/gho Cancer “Globalization” New Cancer Cases 2000 - 10,000,000 2010 - 15,000,000 2030 - 27,000,000 New Cancer Deaths 2000 - 6,200,000 2010 - 10,000,000 2030 - 17,000,000 Cancer is a global challenge that will be met by global participation Innovation in Oncology There is a method to madness • What is scientific evidence? • What is clinically relevant (for the patient !) • New drugs and sustainability • Targeted therapies: beginning of the end? • The new challenges End points of Efficacy There is a method to the madness! Goal Players Efficacy End Point Parameters Development Scientists Pharma Go/no go testing Proof of principle Approval Regulators (FDA,EMA) Efficacy Surrogate end points Survival Cost effectiveness Value for money (QALY) Reimbursement Payers (AIFA) Access Scientific societies Comparative effectiveness Local boards GRADE of recommendation Use Physicians (and patients) Cure Survival Symptom control Benefit for the patient Efficacy for Investigators - Proofs of Concept AFTER STUDY TREATMENT BEFORE STUDY TREATMENT Objective Response 0 10 20 30 40 50 60 70 80 90 Molecular Response Ki67 baseline Metabolic Response surgery End points of Efficacy There is a method to the madness! Goal Players Efficacy End point Parameters Development Scientists Pharma Go/no go testing Proof of principle Approval Regulators (FDA,EMA) Efficacy Surrogate end points Survival Cost effectiveness Value for money (QALY) Reimbursement Payers (AIFA) Access Scientific societies Comparative effectiveness Local boards GRADE of recommendation Use Physicians (and patients) Cure Survival Symptom control Benefit for the patient Erlotinib for Pancreatic Cancer Overall Survival 1,0 0,9 HR = 0.81 (95% CI: 0.67, 0.98), p = 0.028† Survival probability 0,8 23% increase in survival 0,7 0,6 0,5 Erlotinib + gemcitabine (n = 261) Placebo + gemcitabine (n = 260) 0,4 0,3 0,2 0,1 0,0 0 6 12 18 24 Time, months Erlotinib + gemcitabine Placebo + gemcitabine Median survival, months 6.37 5.95 1-year survival 23% 17% † Adjusted for PS and extent of disease at randomization Pertuzumab plus Trastuzumab plus Docetaxel for MBC 39 End points of Efficacy There is a method to the madness! Goal Players Efficacy End point Parameters Development Scientists Pharma Go/no go testing Proof of principle Approval Regulators (FDA,EMA) Efficacy Surrogate end points Survival Cost effectiveness Value for money (QALY) Reimbursement Payers (AIFA) Access Scientific societies Comparative effectiveness Local boards GRADE of recommendation Use Physicians (and patients) Cure Survival Symptom control Benefit for the patient AFFORDABILITY B Jonsson, CCR 2013 After D Cameron End points of Efficacy There is a method to the madness! Goal Players Efficacy End point Parameters Development Scientists Pharma Go/no go testing Proof of principle Approval Regulators (FDA,EMA) Efficacy Surrogate end points Survival Cost effectiveness Value for money (QALY) Reimbursement Payers (AIFA) Access Scientific societies Comparative effectiveness Local boards GRADE of recommendation Use Physicians (and patients) Cure Survival Symptom control Benefit for the patient End points of Efficacy There is a method to the madness! Goal Player Efficacy End point Parameter Development Scientists Pharma Go/no go testing Proof of principle Approval Regulators (FDA,EMA) Efficacy Surrogate end points Survival Cost effectiveness Value for money (QALY) Reimbursement Payers (AIFA) Access Scientific societies Comparative effectiveness Local boards GRADE of recommendation Use Physicians (and patients) Cure Survival prolongation Symptom control Benefit for the patient Efficacy end points in Oncology What does it really mean for the patient? • Median survival increased by 2 weeks • Survival increased by 23% • Risk of dying decreased by 19% Erlotinib for Pancreatic Cancer Overall Survival 1,0 0,9 HR = 0.81 (95% CI: 0.67, 0.98), p = 0.028† Survival probability 0,8 23% increase in survival 0,7 0,6 0,5 Erlotinib + gemcitabine (n = 261) Placebo + gemcitabine (n = 260) 0,4 0,3 0,2 0,1 0,0 0 6 12 18 24 Time, months Erlotinib + gemcitabine Placebo + gemcitabine Median survival, months 6.37 5.95 1-year survival 23% 17% † Adjusted for PS and extent of disease at randomization Innovation in Oncology There is a method to madness • What is scientific evidence? • What is clinically relevant (for the patient !) • New drugs and sustainability • Targeted therapies: beginning of the end? • The new challenges TARGETED THERAPIES: RESPONSE TO TREATMENT INITIAL DISEASE PROGRESSION WITH IMMUNOTHERAPY IPILIMUMAB in metastatic melanoma IPI+DTIC median OS: 11.2 m vs 9.1 m (p=0.0009) HR 0.72 (0.59-0.87) C Robert et Al, N Engl J Med, 2011 NIVOLUMAB and lung cancer (Checkmate 017) First immunotherapy approved for lung cancer
