Le nuove frontiere della lotta contro il cancro -...

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..

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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

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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

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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

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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


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





What is “true” innovation?

Is “true” innovation affordable?

Pyrrhus 318-272 BC

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Overa

ll S

urv

ival (%

)

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

B

RA

F

mu

tati

on

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 PD (peritoneum) DVT

stop Bev After 4 cycles

FOLFOX

8 cycles

SD After 4 cycles 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







true innovation is for limited numbers of patients only

overtreatment is unaffordable





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







true innovation is for limited numbers of patients only

overtreatment is unaffordable

quality of care is the result of a multi-dimensional approach



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


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


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


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


Muldisciplinary Approach

(Cancer Care Plan) Diagnosis Surgery +/-

Radiotherapy AntiCancer

Drugs Follow up

Access to screening Delayed diagnosis

Misdiagnosis

Survivorship Palliative

Care

MTB Staging

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 OncologicaLombarda

ROLi RETE

ONCOLOGICA

LIGURIA


Scientific

Societies

• From shopping lists to recommendations (place in therapy!)

• Real World Data

• Patient-centered trials


Media

Survival increased by 23%

Risk of dying decreased by 19%

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Time, months

Su

rviv

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pro

bab

ilit

yErlotinib + 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

https://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwjng63b2dnZAhWKDewKHYveDf4QjRx6BAgAEAU&url=https://www.imperialbulldog.com/2014/09/02/i-salmoni-fanno-lautostop/&psig=AOvVaw1EraMMn3KCQ1tGwJYGGGii&ust=1520494544349798

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

Le nuove frontiere della lotta contro il cancro -...

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