Nuovi target e nuove prospettiv e terapeutiche
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Nuovi target e nuove prospettive
terapeutiche
Massimo Di Maio
Unità Sperimentazioni Cliniche
Istituto Nazionale Tumori Fondazione G.Pascale – IRCCS
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Nuovi target e nuove prospettive terapeuticheAlcuni spunti da Sidney 2013
• Sempre più dati dall’analisi genomica
• I progressi terapeutici ci sono stati…
• …ma non guariamo ancora nessuno
• La teoria darwiniana applicata ai tumori
• Nella futura (futuribile) pratica clinica?
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Matthew Meyerson. What can we learn from lung cancer sequencing?Sidney 2013
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Matthew Meyerson. What can we learn from lung cancer sequencing?Sidney 2013
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Peter Hammerman, Novel targets in squamous cell lung cancerSidney 2013
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Matthew Meyerson. What can we learn from lung cancer sequencing?Sidney 2013
Lawrence et al, Nature 489, 519–525 (27 September 2012)
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Matthew Meyerson. What can we learn from lung cancer sequencing?Sidney 2013
Lawrence et al, Nature 489, 519–525 (27 September 2012)
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Matthew Meyerson. What can we learn from lung cancer sequencing?Sidney 2013
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Nuovi target e nuove prospettive terapeuticheAlcuni spunti da Sidney 2013
• Sempre più dati dall’analisi genomica
• I progressi terapeutici ci sono stati…
• …ma non guariamo ancora nessuno
• La teoria darwiniana applicata ai tumori
• Nella futura (futuribile) pratica clinica?
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Mark KrisPL03.07Sidney 2013
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Ben Solomon, Sidney 2013
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Mark Kris, PL03.07 , Sidney 2013
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Mark Kris, PL03.07 , Sidney 2013
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Alcuni risultati negativi…
Drug Mechanism of action
Selection Author (abstract)
Necitumumab Anti-EGFR Non-squamous Paz-Ares(O03.02)
Phase III:Cis/Pem +/- Neci
Farletuzumab Anti-Folate receptor alpha
FRA+ Maltzman (P1.11-19 )
Phase II random:Platinum-based +/-farletuzumab
Cixutumumab Anti-IGF-1R Non-squamous Scagliotti(P1.11-018 )
Phase II random:Cis/Pem +/- Cix
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1° line treatment:Cis/Pem +/- cixutumumab
(anti IGF-1R)
Scagliotti, P1.11-018 , Sidney 2013
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Qualche risultato promettente…Drug Mechanism of
actionAuthor (abstract)
Nivolumab Anti-PD1 Brahmer (MO18-03)
Overall survival data of the phase I trial
MK3475 Anti-PD1 Garon(MO18-02)
Preliminary activity data; predictive role of PD-L1
Trametinib MEK1 / MEK2 inhibitor
Mazieres (MO18-10)Bennouna(MO18-11)
Fase Ib + pem o doc: activity in KRAS mut & wt, anche in squamosi
Ganetespib HSP90 inhibitor Ramalingam (O03.01)
Fase II random: biomarkers & subgroups
AUY922 HSP90 inhibitor Barlesi (P1.11-037)
Fase II in EGFRmut+ pretreated: strong evidence of activity
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Ramalingam (O03.01), Sidney 2013
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Ramalingam (O03.01), Sidney 2013
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Ramalingam (O03.01), Sidney 2013
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Ramalingam (O03.01), Sidney 2013
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Nuovi target e nuove prospettive terapeuticheAlcuni spunti da Sidney 2013
• Sempre più dati dall’analisi genomica
• I progressi terapeutici ci sono stati…
• …ma non guariamo ancora nessuno
• La teoria darwiniana applicata ai tumori
• Nella futura (futuribile) pratica clinica?
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Tony Mok, Sidney 2013
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Estimation of survival in patients of EGFR mutation (IPASS)
Estimate of 20% survival rate at 4
yrs
Estimate of 20% survival rate at 4
yrs
Fukuoka et al JCO 2009
75% long term survival is curable20% long term survival is not curable!!!
75% long term survival is curable20% long term survival is not curable!!!
Tony Mok, Sidney 2013
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Lung CancerLung Cancer
“ME TOO” strategy in the war against lung cancer
GenetechGenetech
Academic + InvestigatorsAcademic + Investigators
MerckMerck NovartisNovartis Eli LillyEli Lilly AVEOAVEOPharmaceutical industry + Academic + InvestigatorsPharmaceutical industry + Academic + Investigators
Tony Mok, Sidney 2013
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Lung CancerLung Cancer
“ME TOO” strategy in the war against lung cancer
GenetechGenetech
Academic + InvestigatorsAcademic + Investigators
MerckMerck NovartisNovartis Eli LillyEli Lilly AVEOAVEOPharmaceutical industry + Academic + InvestigatorsPharmaceutical industry + Academic + Investigators
Tony Mok, Sidney 2013
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To avoid the “Me Too” strategy
• Pharmaceuticals should develop better ways to eliminate pipeline drugs
• To establish an external tribunal (scientists, academic researchers, investigators, FDA/EMEA representatives) to evaluate the entire panel of drugs against a specific target, and advise the respective pharmaceuticals
Need global efforts to avoid the “Me Too” strategy
Need global efforts to avoid the “Me Too” strategy
Tony Mok, Sidney 2013
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Nuovi target e nuove prospettive terapeuticheAlcuni spunti da Sidney 2013
• Sempre più dati dall’analisi genomica
• I progressi terapeutici ci sono stati…
• …ma non guariamo ancora nessuno
• La teoria darwiniana applicata ai tumori
• Nella futura (futuribile) pratica clinica?
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Charlie Swanton, Sidney 2013
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Implications for Therapy and Outcome
Burrell, Mcgranahan, Bartek and Swanton Nature 2013
Intertumour Heterogeneity Intratumour Heterogeneity Intercellular Heterogeneity
Review principles of intratumour heterogeneity learned from Renal CancerApply methods to study cancer evolution in Non-Small Cell Lung Cancer
Charlie Swanton, Sidney 2013
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Charlie Swanton, Sidney 2013
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Yap, Gerlinger, Pusztai, Futreal and Swanton Sci Trans Med 2012Charlie Swanton, Sidney 2013
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Target Tumour Phylogenetic Trunks and Resolve Branches
Trunk Genetic Events Present inEvery Cancer Cell
DEFINE TRUNK DRIVERS
Branched Genetic Events Present inSome Cancer Cells not others
Dynamic during disease course
Monitor subclonal events to define drug resistance mechanisms
Charlie Swanton, Sidney 2013
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Una strategia potrebbe essere la combinazione di farmaci con differente meccanismo d’azione…
Giaccone et al (MO07.07), Sidney 2013
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Giaccone et al (MO07.07), Sidney 2013
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Giaccone et al (MO07.07), Sidney 2013
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Tony Mok, What is Cure and How We May Achieve that with Molecular Targeted Therapy?Sidney 2013
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Nuovi target e nuove prospettive terapeuticheAlcuni spunti da Sidney 2013
• Sempre più dati dall’analisi genomica
• I progressi terapeutici ci sono stati…
• …ma non guariamo ancora nessuno
• La teoria darwiniana applicata ai tumori
• Nella futura (futuribile) pratica clinica?
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Solomon, Sidney 2013
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Solomon, Sidney 2013
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Solomon, Sidney 2013
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Solomon, Sidney 2013
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Solomon, Sidney 2013
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La re-biopsia: routine nella (futura) pratica clinica?
Vergnenegre, Sidney 2013
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Nuovi target e nuove prospettive terapeuticheAlcuni spunti da Sidney 2013
• Sempre più dati dall’analisi genomica
• I progressi terapeutici ci sono stati…
• …ma non guariamo ancora nessuno
• La teoria darwiniana applicata ai tumori
• Nella futura (futuribile) pratica clinica?
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Grazie per l’attenzione!
Massimo Di Maio
Unità Sperimentazioni Cliniche
Istituto Nazionale Tumori Fondazione G.Pascale – IRCCS