for the patient

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for the patient
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

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