Le nuove frontiere della lotta contro il cancro
PierFranco Conte
DiSCOG – Università di Padova Istituto Oncologico Veneto, IRCCS
PierFranco Conte
Disclosure of potential conflicts of interests
• Consultant:
Novartis, EliLilly, Astra Zeneca, Tesaro
• Honoraria:
BMS, GSK, Roche, EliLilly, Novartis, AstraZeneca
• Research Funding from profit organizations:
GSK, Novartis, Roche, EliLilly, BMS, Merck-Serono
• Funding from non profit organizations:
National Research Council, Ministry of Education and Research, , Italian Association for Cancer Research, Italian Drug Agency (AIFA), EmiliaRomagna Secretary of Health, Veneto Secretary of Health, University of Padova, Ministry of Health
• 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?
1°Corso Nazionale:
«Giornalisti Medico-Scientifici e Oncologi Medici»
Parma, 18-19 giugno 2015
Progress & Innovation
- Metrics for Progress
Swimming against the stream can be dangerous..
223,4
184,5
381,3 406,6
0 50 100 150 200 250 300 350 400 450 500
Tassi di mortalità e incidenza STANDARDIZZATI per 100 mila abitanti Tutti i tumori maligni
Italia - Femmine
Tasso di mortalità standardizzato (Italia 2001) Tasso di incidenza standardizzato (Italia 2001)
Fonti Mortalità: ISTAT Health For All; Incidenza: AIRTUM- ITACAN
209,3
253,4 417,4
493,0
0 50 100 150 200 250 300 350 400 450 500 550
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Tassi di mortalità e incidenza GREZZI per 100 mila abitanti Tutti i tumori maligni
Italia - Femmine
Tasso di mortalità grezzo Tasso d'incidenza grezzo Fonti Mortalità: ISTAT Health For
All; Incidenza: AIRTUM-ITACAN
439,4
318,3 582,6
579,3
0 50 100 150 200 250 300 350 400 450 500 550 600 650 700
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Tassi di mortalità e incidenza STANDARDIZZATI per 100 mila abitanti Tutti i tumori maligni
Italia - Maschi
Tasso di mortalità standardizzato (Italia 2001) Fonti Mortalità: ISTAT Health For
315,2 336
532,7
609,8
0 50 100 150 200 250 300 350 400 450 500 550 600 650 700
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Tassi di mortalità e incidenza GREZZI per 100 mila abitanti Tutti i tumori maligni
Italia - Maschi
Tasso di mortalità grezzo Tasso d'incidenza grezzo Fonti Mortalità: ISTAT Health For
We do not treat «standardised» people
but «to day» patients….
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
Progress, Innovation & Clinical Value
- Metrics for Progress:
a Pyrrhus’ victory?
- Innovation and Clinical Value
Swimming against the stream can be dangerous..
Not all victories are the same…
Innovation & Cancer Medicine
How innovative is innovation?
Is innovation a guarantee of clinical value?
Is innovation affordable?
Is access to innovation an issue?
Pyrrhus 318-272 BC
EMA Approvals from 2009 to 2013: 48 new cancer drugs for 68 indications.
35% resulted in prolonged OS (median 2.7 months); among these only 48%
(17% of all indications) are clinically meaningful according to ESMO standard.
10% resulted in improved QoL.
Overall only 51% resulted in improved OS or QoL.
Innovation, Clinical Value & Sustainability
42 RCTs resulting in drug approval from 2006 to 2015
Drug costs increased from 30.447$ in 2006 to 161.141$ in 2015 Clinical benefit measured according to ASCO & ESMO scores
R Saluja et al, JOP 2018
Innovative anticancer drugs: cost/patient/yr 1995-99 3.850 €
2010-14 45.000 €
2018-20 70.000-100.000 €
Mario Melazzini ,2018
2018
12/2017 adiuvante 03/2018 09/2017
06/2017 08/2017
02/2017 02/2017 04/2017 02/2017 2017
11/2016 11/2016
03/2016 05/2016 03/2016 04/2016 04/2016 05/2016
2016 01/2016
10/2015 11/2015 06/2015 01/2016 07/2015
03/2015
2015 10/2015*
12/2014
2014
Mono O+Y
Sq-NSCLC
NonSq-
NSCLC Kidney HL H&N Bladder HCC
MSI-H CRC Melanoma
Access to innovation: Nivolumab
* 10/15 BRAF Wild Type , 01/16 all comers
FDA EMA AIFA
Cnn
Time from FDA to access in Italy: 12-16+ mo.
Time from EMA to access in Italy: 6-10+ mo.
Based on data from clinical trials, IO might
prevent/delay ~ 12% of cancer deaths in Italy
- Metrics for Progress:
a Pyrrhus’ victory?
- Innovation and Clinical Value
new drugs are not always innovative
clinical value of innovative drugs is not always granted costs of new drugs are not related to their clinical value delayed access to innovation is an issue
Progress, Innovation & Clinical Value
Swimming against the stream can be dangerous..
Not all victories are the same…
Innovation & Cancer Medicine
What is “true” innovation?
Is “true” innovation affordable?
Pyrrhus 318-272 BC
0 1 2 3 4 5 6 7 8 9 10 100
90
80 70
60
0 50
40
30
20
Overall Survival (%) 10
Years
IPI (Pooled analysis)1
NIVO Monotherapy (Phase 3 Checkmate 066)3
N=210
NIVO Monotherapy (Phase 1 CA209-003)2
N=107
N=1,861
1. Schadendorf et al. J Clin Oncol 2015;33:1889-1894; 2. Current analysis; 3. Poster presentation by Dr. Victoria Atkinson at SMR 2015
True & Affordable Innovation
Immune Checkpoint Inhibitors for Patients with Advanced Melanoma
True & Affordable Innovation – AP’s History
50%
RAS mutations
BRAF mutation
RAS/BRAF wild-type
40% 10%
MSI 5%
HER-2 3%
A.P. - December 2013:
Palliative right emicolectomy; intraoperative finding of peritoneal nodules. Mucinous adenocarcinoma, G3, R2 resection, pT4a N2b M1b – Stage IVB –
KRASm G12D
FOLFIRI – Bevacizumab 12 cycles
PR DVT PD (peritoneum)
stop Bev After 4 cycles
FOLFOX 8 cycles
After 4 cycles SD PD (peritoneum, lymph-nodes) courtesy of V Zagonel
Caso clinico
Clinical trials
A.P. - continued
courtesy of V Zagonel
- Anemia with the need for blood transfusions 1-2 times per week
- Uncontrolled pain
- More than 15 kg weight loss in 6 months - Reactive depression
Condizioni cliniche del paziente Trattamenti (II linea)
TRATTAMENTO IN AMBITO DI PROTOCOLLO CA209-142
Basal CT scan After 4 cycles
A.P. - Enrollement in CheckMate 142
26/05/2015: Ipilimumab (3 mg/kg) + Nivolumab (1 mg/Kg) q3w x 4 cycles followed by Nivolumab (3 mg/Kg) q2
After 16 cycles
PS =0 , weight gain of 19 Kg, no need for pain medication, normal Hb, optimal QoL
courtesy of V Zagonel
Rosenberg & Resitifo 2015 (Science)
Gene modified cytotoxic T lymphocytes (CTL) carrying
a chimeric antigen receptor (CAR)
Schuster SJ et al, NEJM 2017
Chimeric Antigen Receptor T cells (CD19 targeted CAR-T) in refractory B cell lymphoma
38 patients enrolled 28 patients treated
5 patients > G3 cytokine release syndrome 3 patients > G3 encephalopathy (1 death)
CAR-Therapies World-Wide Today
“clinicaltrial.gov; searching for “CAR, Active Studies” (April 2018)
Total: >330
Unaffordable Innovation?
Precision Cancer Medicine
(Molecular Biologists’ vs Clinicians’ view) A Target + A Targeted Drug = Precision Biology The Right Drug + The Right Patient = Precision Medicine
- Metrics for Progress:
a Pyrrhus’ victory?
- Innovation and Clinical Value
new drugs are not always innovative
clinical value of innovative drugs is not always granted costs of new drugs are not related to their clinical value delayed access to innovation is an issue
true innovation is for limited numbers of patients only overtreatment is unaffordable
Progress, Innovation & Clinical Value
Swimming against the stream can be dangerous..
Not all victories are the same…
Innovation & Cancer Medicine
Is innovation the main determinant of quality of care?
Pyrrhus 318-272 BC
Multidisciplinary Care in ABC Setting:
Evidence From Clinical Trials
1. Kesson EM, et al. BMJ. 2012;26;344:e2718; 2. Vrijens F, et al. Breast. 2012;21(3):261-266.
Country Population &
Nb Primary Endpoint Results
Scottish study1
14,000 women with breast cancer
BC-specific mortality and all-cause
mortality
18% reduction in BC mortality at 5 years with
multidisciplinary care Belgian
study2
25,178 women with breast cancer
Survival for BC by hospital volume
Improved 5-year survival rates in high-volume versus low- volume hospitals (83.9% vs 78.8%, respectively)
Oncology Pathways & Outcome: MTB for Breast Cancer Patients
Time to Radiotherapy
< 42 days 43-49 days > 50 days
# of pts 9,765 4,735 10,716
Median OS yrs 10.5 8.2 6.5
Multidisciplinary Care in ABC Setting:
Evidence From Clinical Trials
1. Harris JP et al. JAMA Otolaryngol Head Neck Surg, 2018
Country Population & Nb Primary Endpoint NCDB
USA1
25,216 patients with stage III/IV H&N tumors
Median OS according to
time to Radiotherapy after Surgery
Oncology Pathways & Outcome: Time to Radiotherapy for H&N Patients
- Metrics for Progress:
a Pyrrhus’ victory?
- Innovation and Clinical Value
new drugs are not always innovative
clinical value of innovative drugs is not always granted costs of new drugs are not related to their clinical value delayed access to innovation is an issue
true innovation is for limited numbers of patients only overtreatment is unaffordable
quality of care is the result of a multi-dimensional approach
Progress, Innovation & Clinical Value
Swimming against the stream can be dangerous..
Why Pyrrhus lastly went back home …
Pyrrhus defeated the Romans at Heraclea and Asculum.
According to Plutarch, in both battles, the roman losses were twice higher than those of Pyrrhus’s army.
Pyrrhus however, lost most of his officiers and elephants.
After Asculum battle Pyrrhus muttered:
“If we are victorious in one more battle with the Romans, we shall be utterly ruined.”
Pyrrhus 318-272 BC
From Pirrhus’ victory to true victory:
a new alliance against cancer
Patient Advocacy
Physicians NHS
Media Pharma Industry Investigators
Regulatory Agencies
Scientific
Societies
Pharma Industry
A new alliance against cancer
World military expenditures in 2016 : 1.6 trillion $ World drug sales in 2016: 1.3 trillion $
Pharmaceuticals & Biotech Industry Global Report
Pharma companies estimate a spending for R&D of 2.7 billion USD to bring to the market one single cancer drug.
A recent independent study has calculated the median costs of developing 10 anticancer drugs based on SEC filing.
Median cost is 648 million USD.
Median revenue for these drugs, at a median of 4 years after FDA approval, is 1,658 million USD.
Prasad V and Mailakody S, JAMA Int Med 2017
Regulatory Agencies
A new alliance against cancer
CHECKMATE 017 (ph III)
CHECKMATE 057 (ph III)
KEYNOTE 010 (ph II-III)
POPLAR (ph II)
Treatments Nivo 3mg/kg Doc 75mg/m2
Nivo3 mg/kg Doc75mg/m2
Pembro 2mg/kg Pembro 10mg/kg Doc 75mg/m2 q3w
Atezolizumab 1200 mg Doc 75 mg/m2 Inclusion criteria
Histology Prior treat PS
Squamous 1 Pt-based (+TKI) 0-1
Non-squamous 1 Pt-based (+TKI) 0-1
NSCLC
> 1 Pt-based (+TKI) 0-1
PDL1> 1%
NSCLC
>1 pt-based 0-1
Median OS (m) HR
9.2 vs 6 0.59
12.2 vs 9.4 0.73
10.4 vs 12.7 vs 8.5 0.71 (2mg/kg) 0.61 (10mg/kg)
12.6 vs 9.7 0.73
Choice of comparator HTA
NNT/NNH
Investigators
A new alliance against cancer
100 TNBC pts treated with NACT 50 pCR 50 no pCR
45 (90%) no relapse
5 (10%) relapse
25 (50%) No relapse
25 (50%) relapse
Immunotherapy
Assuming a HR of 0.60 in all patients, number of relapses will decrease from 5 to 3 .
NNT = 25
Assuming a HR of 0.60 in all patients, number of relapses will decrease from 25 to 15.
NNT= 5
A new alliance against cancer
Regulatory Agencies Pharma
Industry
Investigators
cfDNA as “LIQUID BIOPSY”:
• Screening and diagnosis
• Prognostic evaluation
• Monitoring of minimal residual disease
• Monitoring of response/resistance
• Assessment of molecular heterogeneity
• Molecular evolution
NHS
A new alliance against cancer
Muldisciplinary Approach (Cancer Care Plan)
Diagnosis Surgery +/-
Radiotherapy AntiCancer
Drugs Follow up
Access to screening Delayed diagnosis
Misdiagnosis
Survivorship Palliative Care
Staging MTB Molecular Profile
Delayed/inadequate surgery Delayed/inadequate RadioRx
Delayed access Place in Therapy Patient selection Compliance
Intensive Non risk-adapted
Adherence
Setting Guidelines Rehabilitation Long term Tx sequelae
Home Care Hospice Care givers
Rete Oncologica Lombarda
ROLi
RETE ONCOLOGICA LIGURIA
A new alliance against cancer
Scientific Societies
• From shopping lists to recommendations (place in therapy!)
• Real World Data
• Patient-centered trials
A new alliance against cancer
Media
Survival increased by 23%
Risk of dying decreased by 19%
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)
Erlotinib + gemcitabine
Placebo + gemcitabine Median survival, months 6.37
(2 wks improvement)
5.95
Swimming against the stream can be dangerous…
………but only salmons swimming upstream can breed
Acknowledgements
V Guarneri MV Dieci
J Menis G Tasca E Di Liso
C Ghiotto L Bonanno G Faggioni C Falci
T Giarratano C Giorgi MG Ghi E Mioranza O Nicoletto G Pasello G Zago
A Bortolami F Marchese L McMahon V Pozza C Pupo S Tognazzo
