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(1)

PierFranco Conte

Dipartimento di Chirurgia, Oncologia e Gastroenterologia Università di Padova

Oncologia Medica 2 – IOV, IRCCS, Padova

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

(2)

Bridging the gap between bench and bedside

(3)

Miti, illusioni, illusionisti e realtà

• I tumori sono malattie recenti

(4)

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

(5)

Miti, illusioni, illusionisti e realtà

• I tumori sono malattie recenti FALSO

• I tumori sono un problema che riguarda principalmente

i paesi ricchi

(6)

• # new cancers/yr 12.700.000

• # cancer deaths/yr 7.600.000

• # cancers in developing countries 7.100.000

• # cancer deaths in developing countries 4.860.000

Cancer burden worldwide- Globocan 2008

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

(7)

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

(8)

Key events in the investigation of the Cancer Genome

Stratton M. Science 331:1553, 2011

*

* Philadelphia translocation (bcr-abl): t(9;22((q34;q11)

*

* Myc oncogene (chromosome 8) in Burkitt’s lymphoma

(9)

The « Central Dogma »

(10)

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

(11)

PATOGENESI

Mutazione del proto-oncogene c-kit

Attivazione costitutiva del recettore ed autofosforilazione del recettore c-kit

Crescita cellulare incontrollata e inibizione

dell’apoptosi

(12)

Normal KIT Signaling

P P P ADP P

P

P P P ATP

SIGNALING

Kinase domains

Substrate

Effector

• 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

Savage and Antman. N Engl J Med. 2002;346:683.

Scheijen and Griffin. Oncogene. 2002;21:3314.

(13)

Imatinib Mesylate: Mechanism of Action

P

P P P ATP

SIGNALING Imatinib

mesylate

Kinase domains

• 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

Savage and Antman. N Engl J Med. 2002;346:683.

Scheijen and Griffin. Oncogene. 2002;21:3314.

(14)

Tumor biomarkers: Predictive parameter cKIT, PDGFRA and GIST

Verweij J, Lancet 2004

(15)

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 before 2010

(16)

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

Targeted Agents in Oncology approved after 2010

And there is more…

(17)

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

Targeted Agents in Oncology approved after 2010

In gray agents that have received approval by FDA, but not (yet) approved by EMA

(18)

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)

(19)

Jan 18, 2013 1^ LINE CT

Cisplatin plus Pemetrexed (6 cycles)  PR

EGFR mutation analysis by Sequenom:

 Exon 19 deletion

Mutation (2235del15)

delE746-A750

(20)

Dec 05, 2013 PD

Thoracic PD

Dec 12, 2013

TARGETED THERAPY Gefitinib  PR

After 2 months

(21)

Jan 05, 2015 PD

Thoracic progression and brain lesions

CT-guided biopsy:

 Lung adenocarcinoma

 Exons 20 EGFR: T790M mutation

REGIONE DEL VENETO

ISTITUTO ONCOLOGICO VENETO, IRCCS

Dip. di Scienze Chirurgiche, Oncologiche e Gastroenterologiche - Università di Padova U.O.C. IMMUNOLOGIA E DIAGNOSTICA MOLECOLARE ONCOLOGICA

Direttore: Prof. Alberto Amadori

SGQ ISO 9001:2008 Certificato da CERTIQUALITY

Esame n.O-01302-15 FANTE FABIO Pagina 1

Cognome e nome: FANTE FABIO Data di nascita: 15/12/1959 Provenienza: Azienda Ospedaliera Padova - ANATOMIA PATOLOGICA

Richiedente: Prof.ssa Calabrese

Data di accettazione: 05/03/2015 Data di refertazione: 16/03/2015

Esame n. O-01302-15

DNA da Biopsia n. 15-08591

•Ricerca mutazioni del gene EGFR

Analisi esone 18 Non eseguibile (Metodo Analisi di sequenza)

Analisi esone 20 Mutato (Metodo Analisi di sequenza)

Percentuale di cellule tumorali 70 % (*)

Nota

Percentuale di cellule tumorali valutata dall'Anatomia Patologica di provenienza.

Referto interpretativo

L'analisi del DNA ottenuto dalla biopsia mediante PCR quantitativa, ha evidenziato la presenza di una mutazione (T790M) a carico dell'esone 20 del gene EGFR.

Dott. S. Indraccolo Prof. A. Amadori

Rappresentazione di un referto firmato elettronicamente.

Firmato da STEFANO INDRACCOLO in data: 16-03-2015 14:19 Il referto è conservato secondo la normativa in vigore

REGIONE DEL VENETO

Esame n. O-01302-15

Nota

REGIONE DEL VENETO

Esame n. O-01302-15

Nota

(22)

Mar 18, 2015 CLINICAL TRIAL

Rociletinib vs single agent CT

 PR Feb 21, 2015

WHOLE BRAIN RT 30 Gy in 10 fractions

Rociletinib Background

• Inhibits the EGFR gatekeeper mutation

(T790M), a point mutation associated with clinical resistance to erlotinib and gefitinib

• Rociletinib is under evaluation in study CO- 1686-008 in patients with advanced EGFR mutation-positive NSCLC and previous

treatment with an EGFR inhibitor

The “Gatekeeper”

Mutation

After 6 weeks

(23)

CANCER GENOMICS: INTRA-TUMOR HETEROGENEITY

Gerlinger M et al, N Eng J Med 2012

(24)

Whole genome CGH array (gene copy

numbers) Sanger sequencing

hot spots PIK3CA/AKT1

Identification of a targetable Genomic Alteration by a multicentric multidisciplinary

team Targeted therapy

according to the genomic profile at the

time of PD

Biopsy metastases in patients PR/SD

under treatment 2 Frozen samples

1 FFPE sample

SAFIR01: Study Flow

(25)

biopsy

CGH array + Mutations PIK3CA/AKT DNA extraction +

quality control

Molecular MDT

Identification of a potential Clinical

Trial

SAFIR01: Clinical Operations

18 Investigational centers

SAFIR01: Clinical Operations

(26)

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%)

(27)

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

(28)

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 before 2010

(29)

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

Targeted Agents in Oncology approved after 2010

And there is more…

(30)

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

Targeted Agents in Oncology approved after 2010

In gray agents that have received approval by FDA, but not (yet) approved by EMA

(31)

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?

(32)

Male Female

Trends in mortality from cancer in Europe:

age-standardised rate (W) per 100,000

www.who.int/gho

(33)

Cancer is a global challenge that will be met by global participation

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

(34)

• What is scientific evidence?

• What is clinically relevant (for the patient !)

• New drugs and sustainability

• Targeted therapies: beginning of the end?

• The new challenges

Innovation in Oncology

There is a method to madness

(35)

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 Reimbursement Payers

(AIFA)

Cost effectiveness Value for money (QALY)

Access Scientific societies Local boards

Comparative effectiveness GRADE of

recommendation

Use Physicians (and

patients)

Benefit for the patient Cure Survival

Symptom control

End points of Efficacy

There is a method to the madness!

(36)

Efficacy for Investigators - Proofs of Concept

BEFORE STUDY TREATMENT AFTER STUDY TREATMENT

Objective Response

Ki67

0 10 20 30 40 50 60 70 80 90

baseline surgery

Molecular Response

Metabolic Response

(37)

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 Reimbursement Payers

(AIFA)

Cost effectiveness Value for money (QALY)

Access Scientific societies Local boards

Comparative effectiveness GRADE of

recommendation

Use Physicians (and

patients)

Benefit for the patient Cure Survival

Symptom control

End points of Efficacy

There is a method to the madness!

(38)

0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0

0 6 12 18 24

Time, months

Survival probability

Erlotinib + gemcitabine (n = 261) Placebo + gemcitabine (n = 260)

† Adjusted for PS and extent of disease at randomization

Erlotinib for Pancreatic Cancer Overall Survival

HR = 0.81 (95% CI: 0.67, 0.98), p = 0.028

^†

Erlotinib + gemcitabine

Placebo + gemcitabine

Median survival, months 6.37 5.95

1-year survival 23% 17%

 23% increase in survival

(39)

39

Pertuzumab plus Trastuzumab plus

Docetaxel for MBC

(40)

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 Reimbursement Payers

(AIFA)

Cost effectiveness Value for money (QALY)

Access Scientific societies Local boards

Comparative effectiveness GRADE of

recommendation

Use Physicians (and

patients)

Benefit for the patient Cure Survival

Symptom control

End points of Efficacy

There is a method to the madness!

(41)

B Jonsson, CCR 2013

AFFORDABILITY

After D Cameron

(42)

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 Reimbursement Payers

(AIFA)

Cost effectiveness Value for money (QALY)

Access Scientific societies Local boards

Comparative effectiveness GRADE of

recommendation

Use Physicians (and

patients)

Benefit for the patient Cure Survival

Symptom control

End points of Efficacy

There is a method to the madness!

(43)

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 Reimbursement Payers

(AIFA)

Cost effectiveness Value for money (QALY)

Access Scientific societies Local boards

Comparative effectiveness GRADE of

recommendation

Use Physicians (and

patients)

Benefit for the patient Cure

Survival prolongation Symptom control

End points of Efficacy

There is a method to the madness!

(44)

• Median survival increased by 2 weeks

• Survival increased by 23%

• Risk of dying decreased by 19%

Efficacy end points in Oncology

What does it really mean for the patient?

(45)

0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0

0 6 12 18 24

Time, months

Survival probability

Erlotinib + gemcitabine (n = 261) Placebo + gemcitabine (n = 260)

† Adjusted for PS and extent of disease at randomization

Erlotinib for Pancreatic Cancer Overall Survival

HR = 0.81 (95% CI: 0.67, 0.98), p = 0.028

^†

Erlotinib + gemcitabine

Placebo + gemcitabine

Median survival, months 6.37 5.95

1-year survival 23% 17%

 23% increase in survival

(46)

• What is scientific evidence?

• What is clinically relevant (for the patient !)

• New drugs and sustainability

• Targeted therapies: beginning of the end?

• The new challenges

Innovation in Oncology

There is a method to madness

(47)

(48)

TARGETED THERAPIES:

RESPONSE TO TREATMENT

 INITIAL DISEASE PROGRESSION WITH IMMUNOTHERAPY

(49)

IPILIMUMAB in metastatic melanoma

C Robert et Al, N Engl J Med, 2011

IPI+DTIC median OS:

11.2 m vs 9.1 m (p=0.0009)

HR 0.72 (0.59-0.87)

(50)

NIVOLUMAB and lung cancer (Checkmate 017)

First immunotherapy approved for lung cancer

(51)