added value of the mo ll td t tlecular targeted agents in ... · added value of the mo ll td t...

Added value of the

l l t t d t molecular targeted agents

in oncologygy

Pr Jean-Charles SORIA

U981

Potential conflict of interest:

Occasional honoraria from:

Abbott Amgen Astellas Astra Zeneca Abbott, Amgen, Astellas, Astra Zeneca, BMS, Boehringer Ingelheim, GSK, g gLilly, Pfizer, Merck-Serono, MSD,R h S f ARoche, Sanofi-Aventis

TopicsTopicsContext

EpidemiologicalFinancialFinancialRegulatoryIndustrial

Therapeutic advances in cancerIncremental advancesEmergence of molecular targeted agents (MTA)Emergence of molecular targeted agents (MTA)The use of MTA and the problematic of biomarkers

Added value of MTAHerceptinMabtheraGleevecGleevecTarceva/IressaErbituxA ti S t tAvastin, Sutent

Perspectives

Epidemiological data

CANCER France Europe World

IncidenceMortality

320 000144 000

2 600 0001 600 000

12 000 0007 600 000

Prevalence 900 000 9 000 000 28 000 000

Current smokers in France15 Millions people

MalesFemales

15 Millions people

32%21%21%

IARC 2008; INSERM 2007

Epidemiological Context: Cancer Worldwide Burden (2008 2030)

12.4 million new cases7.6 million deaths28 million living with cancer

26.4 million new cases17 million deaths

82 million living with cancer

5

g

Courtesy of Peter Boyle. IARC

g

Cancer = 2nd cause of expense for chronical diseases for the french healthcare system

Cancer is not the leading cause of expenseCardiovascular disease: 17 Mds €

€

Cardiovascular disease: 17 Mds €Cancer : 14 Mds €Diabetes : 9 Mds€

DéMean annualDépenses moyenne toute pathologie 8700 €

Mean annual expense

(all diseases) = 8700 €

Cardio- Diabetes Cancer Kidney HIV Rheumatoid Multiple Neurological

Source : CNAM previsions (2009) and results (2006)

vasculary

chronicdisease

arthritis sclerosisg

& muscular diseases

… in 2007:

Mean annual amount of expense for patients diagnosed with cancer = 10 557 €Mean annual amount of expense for patients diagnosed with cancer = 10 557 €largely more inferior than those for patients with psychiatric or Alzheimer disease

Moderate increase of the amount of expense between 2004 and 2007 = +7 2%Moderate increase of the amount of expense between 2004 and 2007 = +7,2% as compared with other chronic disease

Mean ann al amo nt of e penses per patient and per disease bet een 2004 and 2007Mean annual amount of expenses per patient and per disease between 2004 and 2007:

Source: French healthcare system, 2008

Cardiovascular Cancer Diabetes Psychiatric Respiratory Alzheimer & dementias

Developmental steps of antineoplastics:

Discoveryy

Formulation~ 7 ans

Evaluation of activity (in vitro and in vivo)

Ph l

7 ans

Pharmacology

ToxicologyCosts =

1,2 Md

Phase I (dose-finding trial)

,USD

Phase II (efficacy trial)

Phase III (comparison with standard agent trial)~ 8 ans

Phase III (comparison with standard agent trial)

Introduction into general medical practice

Several steps are necessary to assess the drug’s potentiality

The earlier stage it can be used, the greater is the benefit

Adjuvant therapyBenefit = months, years,

potential for cure (long-term remission)

Earlier stages of cancerBenefit = many months

L t t diLate stage diseaseBenefit = weeks, a few

months

PlanPlanContext


Therapeutic advances in cancer Incremental advancesEmergenec of molecular targeted agents (MTA)Emergenec of molecular targeted agents (MTA)The use of MTA and the problematic of biomarkers

Added value of MTAHerceptinMabtheraGleevecGleevecTarceva/IressaErbituxA ti t tAvastin, sutent

Perspectives

In metastatic colorectal setting,incremental survival gains are functionincremental survival gains are function

of drugs’ approvals

Best supportive care

Bolus 5-FU/LV

Infusional 5 FU/LV 12 1

11.3

4-6 1980

Infusional 5-FU/LV

Irinotecan + bolus 5-FU/LV 14.8

12.1

13.2capecitabine 1995

Irinotecan + infusional 5-FU/LV

Bolus 5-FU/LV + oxaliplatin or irinotecan

I i t b l 5 FU/LV b i b

17.4

17.6

Oxaliplatin + infusional 5-FU/LV (N9741) 19.5

21.5Irinotecan (FOLFIRI)/oxaliplatin (FOLFOX) sequencing

Irinotecan + bolus 5-FU/LV + bevacizumab 20.3

25.1Irinotecan + bolus 5-FU/LV + bevacizumab 2010

Adapted from Grothey A et al. J Clin Oncol. 2004;22:1209-1214; Kalofonos HP et al. Ann Oncol. 2005;16:869-877;

Survie globale (mois)0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

11

dap ed o G o ey e a J C O co 00 ; 09 ; a o o os e a O co 005; 6 869 8 ;Venook A. Oncologist. 2005;10:250-261.

Advances in RH- breast cancer stage IV

50Median overal survival (mois)Objective responses

50% 50%

30

4040%

35%45%

20

3030%

1010

15-17 22 25 26-27 31-3210% 12

01970-80 1980-90 1990-2000 2000-2005 2005-2008

First line BSC CMF anthracylin Taxane + Trastuzumab + bevacizumab + Trastuzumab +

Before 1970 First line BSC CMF anthracylin Taxane +

anthracyclinTrastuzumab +

standard Ctbevacizumab +

standard CtTrastuzumab +

standard Ct

Second line

- - + capecitabine Capecitabine+ tratsuzumab

Capecitabine+/- vinorelbine

Capecitabine + lapatinib

Third line

- - - - Trastuzumab + ChT

+ +

Bottenbal et al JCO 2005; Miller et al NEJM 2007; Slamon et al NEJM 2001; Geyer et al, NEJM 2006; Miles et al, JCO 2008;

50Added value of antineoplastic drugs in metastatic lung cancer

40

50

40%

50%Median overall survival (mois)One-year survival rate(%)

30

25%

35%40%

10

20

15%

25%

10

0 2-41970 1980

6

1980 1990

7.5 9 10 1210%

1990 2000 2000 2005 2005 2007 2007 20081970-1980 1980-1990 1990-2000 2000-2005 2005-2007 2007-2008

PlanPlanContext


Therapeutic advances in cancer Incremental advancesEmergence of molecular targeted agents (MTA)Emergence of molecular targeted agents (MTA)The use of MTA and the problematic of biomarkers


Perspectives

Molecular targeted agents (MTA)

• this terminology refers to:

therapeutic strategies

Treatments directed against moleculartargets implicated in tumor growthtargets implicated in tumor growth

• old example: endocrine therapyp py

Cell biology in 1979Cell

NucleusNucleus ??

CytoplasmCytoplasm

Cell biology in the 2000’

Hanahan D,Weinberg RA, Cell,2000

Anti HER

Therapeutical progress in oncologyoverview of the molecular tageted agents in 2011

Anti-HERTarceva (erlotinib), Iressa (gefitinib): lung cancer, pancreatic cancerErbitux (cetuximab): colorectal cancer, head and neck cancerPanitumumab (Vectibix): colorectal cancerPanitumumab (Vectibix): colorectal cancerLapatinib: breast cancerHerceptin (trastuzumab): breast and gastric cancer

More than 500 drugs under investigation

Anti-angiogenicsNexavar (sorafenib): renal cell carcinoma, hepatocarcinomaSutent (sunitinib): renal cell carcinoma GIST

g

Sutent (sunitinib): renal cell carcinoma, GISTAvastin (bevacizumab): colorectal cancer, lung cancer, breast, ovarian cancer

AutresAutresGlivec (imatinib): GIST, CMLRituxan (rituximab): B Cell LymphomaSprycel (dasatinib): CMLSprycel (dasatinib): CMLAfinitor (everolimus): renal cell carcinoma, NE of the pancreasTorisel (temsirolimus): renal cell carcinoma, mantle cell lymphoma

PlanPlanContext


Therapeutic advances in cancer Incremental advancesEmergence of molecular targeted agents (MTA)Emergence of molecular targeted agents (MTA)The use of MTA and the problematic of biomarkers


Perspectives

MTAMTA

Best supportive care + CT 50 MTA

ogy

Surgery + CT40

%)on

colo

RT ± CT 30

20tient

s (%

MTA

in

20

10

Pat

se o

f M

0Localised Regional Distant

U

RT = radiotherapyCT = chemotherapy

Localised Regional Distant

Importance of the biomarkers Importance of the biomarkers when prescribing MTA

MTA should be delivered only to patients whose tumor express the target

Situations in current practice:Optimal situations (precription directed by biomarkers)

• HER2 & Herceptin (trastuzumab)• CD20 & Rituxan (rituximab)• EGFR mutation & Iressa (gefitinib)(g )

Intermediate situations• EGFR mutation & Tarceva (erlotinib)• RAS Mutation & Erbitux (cetuximab) or Vectibix (panitumumab)• RAS Mutation & Erbitux (cetuximab) or Vectibix (panitumumab)• HER2 & Tykerb (lapatinib)• KIT mutation & Gleevec (imatinib)

S b ti l it ti ( i ti ith t bi k )Sub-optimal situations, (prescription without biomarker)• All the antiangiogenic drugs (avastin, sutent, nexavar)• mTOR inhibitors (afinitor, torisel)

PlanPlanContext


Therapeutic advances in cancer Advances step by stepEmergence of molecular targeted agents (MTA)Emergence of molecular targeted agents (MTA)The use of MTA and the problematic of biomarkers


Perspectives

Mechanism of action of Trastuzumab

HER2 receptorTrastuzumab

Subdomain IV of HER2

• Trastuzumab continually suppresses HER2 activity

• Flags cells for destruction by the immune system (ADCC)

• Prevents HER2 activation by ECD shedding

Trastuzumab: incremental integration in the therapeutic arsenal against HER2+ cancerstherapeutic arsenal against HER2+ cancers

Phase III

adjuvant BCApproval

EU/USPhase III

Gastric CancerPhase III

adjuvant BCPhase III

mBC 1st line various combinations

BC 2 d liPhase II Phase III Approval US/EU

mBC 1st linePhase II Phase III Approval US/EU

91/92 93-95 95-97 98/99 2000 2002 2006Phase I Phase II Phase III Approval US/EU

mBC 2nd line

2009/10

Added-value of MTATrastuzumab and Early Breast Cancer

Systematic decrease of the mortality risk Systematic decrease of the mortality risk ( one third decrease in all studies)( one third decrease in all studies)

Median follow-up, yearsOverall survival benefit

B-31 / N9831 AC PH 3

HERA CTx H 1 year 2

B-31 / N9831 AC PH 3

BCIRG 006 AC DH 3

BCIRG 006 DCarboH 3

0 1 2FavoursHerceptin

Favours noHerceptin

Hazard ratio

Slamon et al 2006;Perez et al 2007; Smith et al 2007

Added-value of MTATrastuzumab and Early Breast Cancer

28,000 patients projection upon a 10 year period in the five leading european countries

Incidence of MBC without HerceptinIncidence of MBC following introduction of HerceptinPatients,n

20,000Herceptin introduced

No. of patients prevented from developing metastases

18,000

16,000

14,000

Herceptin introduced

27,73712,000

10,000

8000

6000

4000

2000

02000 2005 2010 2015

Weisgerber-Kriegl et al 2008

2000 2005 2010 2015Year

MBC, metastatic breast cancer

Trastuzumab and Metastatic breast cancer significative majoration of overall survival with first linesignificative majoration of overall survival with first line metastatic breast cancer

H0648g(IHC 3+)

P alone

PH

M77001D alone

DH

BCIRG 007DCarboH

DH

US Oncology(IHC 3+)

PCarboH

H

Median survival (months)0 10 20 30 40 50

P = paclitaxel; H = trastuzumab D = docetaxel; Carbo = carboplatin Smith, et al. Anticancer Drugs 2001; Marty, et al. JCO 2005

Robert, et al. JCO 2006; Pegram, et al. ASCO 2007

Trastuzumab completely reversed the poor prognosis associated with HER2+ metastatic breast cancerassociated with HER2+ metastatic breast cancer

ility

1.0HER2 –HER2+/no trastuzumab

pro

bab 0.8

0.6

/ o t astu u abHER2+/trastuzumab

surv

ival

0.4

Ove

rall

0.2

00 12 24 36 48 60

Months from diagnosis

Dawood, et al. ASCO 2008

g

PlanPlanContext


Therapeutic advances in cancer Advances step by stepEmergence of molecular targeted agents (MTA)Emergence of molecular targeted agents (MTA)To measure the target of MTA remains problematic


Perspectives

CD20 antigenspecific biomarker of B lymphocytes

» 297 AA phosphoprotein (33–35 kD) Extra-cellular domain

» Restricted to the B lineage

Expression in > 95% lymphomatous cells– Expression in > 95% lymphomatous cells

– Absence of expression in stem cells, in B

progenitors or in mature B plasmocytes

Trans-membrane domain

progenitors or in mature B plasmocytes

» Absence of rapid modulation during the

binding with the anti-CD20 antibody

Cytoplasm

Rituximab

hi i ( i h ) l l tib d di t dchimeric (murine human) monoclonal antibody directed against CD20 antigen

Variable domain (Fab) = (murine part)» directed against CD20 antigen

Constant domain (Fc) = (human part) lgG1» prolonged half-life as compared to fully

murine antibody» initiate early effectors of the immune

response» Limits the generation of anti-chimeric

antibodies (HACA)

Mc Laughlin P et al. J Clin Oncol 1998 ; 16(8) : 2825-33.

Rituximab its clinical developement completely changed strategies in t ti h t l i li itreating hematologic malignancies

Maintenance relapse /refractory

ASMR I

Maintenance

ASMR notable ASMR II

Maintenance relapse /refractory follicular NHL responding to the induction with/without Mabthera (EORTC 20981)

ASMR I

Maintenance1st line NHL follicular(PRIMA ‐ Q1 2010)

follicular NHLstage III‐IVpivotal trial

follicular NHL stage III‐IVInduction 1st line

Associated with CVP (M39021)

Follicular lymphoma stage III‐IV1st line, associated with chemotherapy

(GLSG’00, OSHO‐39, FL2000)

2002 2009

1998 2006 20082004

ASMR I

2010

ASMR: in process

Diffuse large B‐cell lymphomaassociated with CHOP (LNH98.5)

ASMR in process

CLL 1st lineAssociated with chemotherapy (CLL8)

CLL relapse/refractoryAssociated with CT (REACH)

LNH: non hodgkin lymphomaLLC: chronic lymphoid leukemiaASMR: clinical added value (french healthcare scoring sytem: I, major added value V, absence of added value)

Rituximab and lymphomashistorical break in the disease specific mortality

Cisplatin Etoposide Fludarabine Rituximab

historical break in the disease specific mortality

Cisplatin Etoposide Fludarabine Rituximab(1978) (1983) (1991) (1997)

15

10

0,00

0*

-2,8% / year+1,6% / year

5

Rat

e pe

r 100

LNH mortality

R

(SEER Program, USA)

1975 1980 1985 1990 1995 2000 2005 20100

Molina A, et al. Ann Rev Med 2008; 59:237–250.*Age adjusted to 2000 US standard population

PlanPlanContext




Perspectives

Added value of gleevec in the treatment of Added value of gleevec in the treatment of GIST

1) Revolution in metastatic GISTs: Overal survival increased three timesLow toxicity rate, Occupational reintegration

2) necessity of a long term treatment2) necessity of a long term treatment

3) decrease of the relapse risk in adjuvantHowever relapses might be delayedHowever, relapses might be delayedLong terme treatment for high risk of relapse adjuvant situations

4) better selection of the patients suitable for imatinib in 4) better selection of the patients suitable for imatinib in adjuvant setting (KIT mutation driven strategy)

Overall survivalOverall survivalHi t i l iHi t i l i

PoofPoof of of

90

100Historical comparisonHistorical comparison

KITKITPDGFRPDGFR

the conceptthe concept

70

80

90Glivec®Glivec®

PDGFRPDGFR

ABLABL

40

50

60

20

30

40DoxorubinDoxorubin--basedbased

(months)0

10

20

0 6 12 18 24 30O N Number of patients at risk : Treatment

273 946 850 786 638 39379 86 57 31 19 14

Kinase Mutations in GISTsKinase Mutations in GISTs

“Wild“Wild--type”type”

Exon 9Exon 9

PDGFRAPDGFRA

Exon 9Exon 9

Exon 18Exon 18

KITKIT

Exon 11Exon 11

Heinrich et al.Heinrich et al. J Clin Oncol 21:4342J Clin Oncol 21:4342--4349, 20034349, 2003Agaram et al. Genes, Chromosomes & Cancer 47:853Agaram et al. Genes, Chromosomes & Cancer 47:853––859, 2008859, 2008Agaimy et al. J Clin Pathol 2009;62:613Agaimy et al. J Clin Pathol 2009;62:613––616, 2009616, 2009

Phase III TrialsPhase III TrialsGenotype and PFSGenotype and PFS

EORTC/ISG/AGITGEORTC/ISG/AGITGSWOG S0033SWOG S0033

Heinrich et al. J Clin Onc Heinrich et al. J Clin Onc 2008, 26(33):53602008, 26(33):5360--7 7

DebiecDebiec--Rychter et al. Eur J Cancer Rychter et al. Eur J Cancer 2006, 42(8):10932006, 42(8):1093--103 103

PlanPlanContext




Perspectives

PerspectivesPerspectivesMTA are progressively integrated to therapeutic strategies in oncologySuch integration starts in the metastatic setting and is then being expanded to other situationsexpanded to other situationsMTA result in major added value in adjuvant setting in few tumor types (e g HER2 + Breast cancer and Trastuzumab)types (e.g. HER2 + Breast cancer and Trastuzumab)Some MTA deepely changed tumors’ natural history:

Rituximab and B lymphomasTrastuzumab and HER2+ Breast CancersGleevec and CML or GISTAntiangiogenics and Renal cell carcinomag g

MTA represent 0,6% of the total amont of the french healthcare system expenses

PerspectivesPerspectives

MTA also highlight biology in vivo since these drugs modulate transversal biological process.

The use MTA expands beyond the oncology fieldRituximab and auto-imune pathologiesAntiangiogenics and ARMD

The MTA pricing should be based on the clinical added value produced rather than on the « succes storys » of this class of produced rather than on the « succes storys » of this class of agents

With the exception of severe pathologies in which few weeks or months gains represents true advances( e.g. pancreatic cancer, lung cancer, glioblastoma)MTA are always tested at first in metastatic setting

phase II trial testing Rituximab in type I diabetes (NEJM 26 nov 2009)

Vestibular schwannomas cause hearing gloss in neurofibromatosis type 2

Avastin led to tumour shrinkage, with associated decreases in vascular permeability and blood flow

Plotkin, et al. NEJM 2009

– hearing was improved in four of seven evaluable patients

Antiangiogenic drugs Aptamer Anti-VEGF/ Macugen®p g

Baseline 20/63Baseline 20/63( 60 letters( 60 letters))

Year 1 20/40Year 1 20/40(70 letters)(70 letters)

Year 2 20/20Year 2 20/20(84 letters)(84 letters)( )( )

Tumor type with oncogenic addiction e.g. Hedgehog inhibitors in BCC

The last wave of MTA reinforces the global positive trend

(PTCH mutations), B‐RAF inhibitors in melanoma (B‐RAFmutations), ALK inhibitors in NSCLC (ALK translocation) – i.e. “superstars”!

»(New Engl J. Med 2010)

»(New Engl J. Med 2010)

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