rare cancers - garvan institute of medical research

Rare cancers

What is the problem, and how

big is it?

Rare (orphan) diseases

NIH Office for Rare Diseases •Prevalence less than 5/10 000 in the community

•In the US <200 000 cases

Eurodis (European Organisation for Rare Diseases) •5-8 000 distinct conditions

•Affect 6-8% of the population

Cancer •EUROCARE working group definition of ‘very rare’ diseases

Annual crude incidence rates <2/100 000 for both sexes

combined (Gatta et al 2006 Lancet Oncology 7:132)

•Rare = <6/100,000

•Less common = 6-12/100,000

•>186 cancer types

Collective Impact of Rare Cancers on the Community

Cancer site/type (ICD-10 codes) Number

Per cent

of total Rate(b) Risk(c) Number

Per cent

of total Rate(b) PYLL(d)

Males

Prostate (C61) 15,759 28.7 163.4 1 in 5 2,792 12.9 33.0 20,560

Colorectal (C18–C20) 7,160 13.0 75.1 1 in 10 2,196 10.1 23.8 30,770

Lung, bronchus & trachea (C33–C34) 5,826 10.6 61.6 1 in 11 4,733 21.8 50.8 64,090

Melanoma of skin (C43) 5,503 10.0 56.6 1 in 15 815 3.8 8.7 14,868

Lymphoma (C81–C85, C96) 2,352 4.3 24.3 1 in 33 803 3.7 8.8 12,260

Unknown primary site (C26, C39, C76–C80) 1,700 3.1 18.5 1 in 40 1,781 8.2 19.7 23,385

Bladder (C67) 1,642 3.0 17.9 1 in 39 589 2.7 6.8 5,308

Leukaemia (C91–C95) 1,578 2.9 16.8 1 in 47 833 3.8 9.3 12,148

Kidney (C64) 1,395 2.5 14.2 1 in 55 497 2.3 5.3 7,670

Stomach (C16) 1,275 2.3 13.6 1 in 52 720 3.3 7.9 9,818

Other 10,680 19 111 NA 5,911 27 64 94,205

All cancers (C00–C97(a), D45–D47(e)) 54,870 100.0 573.4 1 in 2 21,670 100.0 237.5 295,080

Females

Breast (C50) 12,126 27.9 112.8 1 in 9 2,664 15.8 23.8 48,910

Colorectal (C18–C20) 5,817 13.4 51.5 1 in 14 1,872 11.1 16.0 21,798



Lymphoma (C81–C85, C96) 1,920 4.4 17.5 1 in 46 736 4.4 6.3 8,725

Uterus, body (C54) 1,718 4.0 15.8 1 in 52 202 1.2 1.8 2,510


Ovary (C56) 1,246 2.9 11.4 1 in 73 851 5.1 7.6 13,083

Thyroid (C73) 1,128 2.6 10.9 1 in 103 51 0.3 0.4 555

Leukaemia (C91–C95) 1,087 2.5 9.8 1 in 83 612 3.6 5.2 8,350

Other 9,343 21 83 NA 5,179 31 44 66,358


New cases Deaths

Australian Institute of Health and Welfare

20,023: 20.4% 11,090: 28.8% 160,563: 30.6%

Collective Impact of Rare Cancers on the Community

Cancer site/type (ICD-10 codes) Number

Per cent of

total Rate(b) Risk(c) Number

Per cent of

total Rate(b) PYLL(d)

Males

Prostate (C61) 15,759 28.7 163.4 1 in 5 2,792 12.9 33.0 20,560

Colorectal (C18–C20) 7,160 13.0 75.1 1 in 10 2,196 10.1 23.8 30,770



Lymphoma (C81–C85, C96) 2,352 4.3 24.3 1 in 33 803 3.7 8.8 12,260


Bladder (C67) 1,642 3.0 17.9 1 in 39 589 2.7 6.8 5,308

Leukaemia (C91–C95) 1,578 2.9 16.8 1 in 47 833 3.8 9.3 12,148

Kidney (C64) 1,395 2.5 14.2 1 in 55 497 2.3 5.3 7,670

Stomach (C16) 1,275 2.3 13.6 1 in 52 720 3.3 7.9 9,818

Other 10,680 19 111 NA 5,911 27 64 94,205


Females

Breast (C50) 12,126 27.9 112.8 1 in 9 2,664 15.8 23.8 48,910

Colorectal (C18–C20) 5,817 13.4 51.5 1 in 14 1,872 11.1 16.0 21,798



Lymphoma (C81–C85, C96) 1,920 4.4 17.5 1 in 46 736 4.4 6.3 8,725

Uterus, body (C54) 1,718 4.0 15.8 1 in 52 202 1.2 1.8 2,510


Ovary (C56) 1,246 2.9 11.4 1 in 73 851 5.1 7.6 13,083

Thyroid (C73) 1,128 2.6 10.9 1 in 103 51 0.3 0.4 555

Leukaemia (C91–C95) 1,087 2.5 9.8 1 in 83 612 3.6 5.2 8,350

Other 9,343 21 83 NA 5,179 31 44 66,358


New cases Deaths

Australian Institute of Health and Welfare

1:100,000 = 2,224 Australian deaths each year

6/100,000 = 14,000 deaths

ICDCode Incidence

C39Otherandill-definedsitesintherespiratorysystemandintrathoracicorgans 0

C58Placenta 6

C33Trachea 11

C75Otherendocrineglandsandrelatedstructures 24

C63Otherandunspecifiedmalegenitalorgans 28

C96Otherandunspecifiedcancersoflymphoid,haematopoieticandrelatedtissue 29

C94Otherleukaemiasofspecifiedcelltype 30

C76Otherandill-definedsites 35

C47Peripheralnervesandautonomicnervoussystem 38

C68Otherandunspecifiedurinaryorgans 41

C70Meninges 41

C08Otherandunspecifiedmajorsalivaryglands 42

C72Spinalcord,cranialnervesandotherpartsofcentralnervoussystem 49

C38Heart,mediastinumandpleura 49

C37Thymus 52

C13Hypopharynx 56

C31Accessorysinuses 68

C46Kaposisarcoma 69

C74Adrenalgland 75

C93Monocyticleukaemias 75

C95Leukaemiasofunspecifiedcelltype 77

C52Vagina 77

C14Otherandill-definedsitesinthelip,oralcavityandpharynx 83

C88Immunoproliferativecancers 89

C12Pyriformsinus 91

C10Oropharynx 95

C55Uterus,partunspecified 97

C60Penis 108

C30Nasalcavityandmiddleear 109

C03Gum 109

C40Boneandarticularcartilageoflimbs 114

C41Boneandarticularcartilageofotherandunspecifiedsites 115

C11Nasopharynx 120

C05Palate 130

C66Ureter 142

C57Otherandunspecifiedfemalegenitalorgans 149

C06Otherandunspecifiedpartsofmouth 151

C04Floorofmouth 181

C26Otherandill-defineddigestiveorgans 185

D45Polycythaemiavera[WARNING:Incompletetimeseries] 196

C48Retroperitoneumandperitoneum 203

TotalforSuperRare(2.89%ofallcancerdiagnosedinAustraliain2011) 3,439

C07Parotidgland 245

C01Baseoftongue 259

C69Eyeandadnexa 266

C65Renalpelvis 273

C84PeripheralandcutaneousT-celllymphomas 275

C51Vulva 318

C23Gallbladder 339

C09Tonsil 361

C21Anusandanalcanal 369

C02Otherandunspecifiedpartsoftongue 430

C24Otherandunspecifiedpartsofbiliarytract 433

D47Othercancersoflymphoid,haematopoieticandrelatedtissue 440

C17Smallintestine 442

C32Larynx 590

C49Otherconnectiveandsofttissue 604

C81Hodgkinlymphomas 606

C45Mesothelioma 690

C62Testis 732

C44Skin-Non-melanoma,excludingBCCandSCC 769

C53Cervix 801

C00Lip 912

TotalForRare(8.55%ofallcancerdiagnosedinAustraliain2011) 10,154

TotalforRareandSuperRare(11.45%ofallcancerdiagnosedinAustraliain2011) 13,593

D46Myelodysplasticsyndromes[WARNING:Incompletetimeseries] 1,309

C56Ovary 1,330

C15Oesophagus 1,395

C22Liverandintrahepaticbileducts 1,446

C92Myeloidleukaemias 1,457

C90Multiplemyelomaandotherplasmacellcancers 1,533

C91Lymphoidleukaemias 1,654

C71Brain 1,724

C16Stomach 2,093

C73Thyroidgland 2,098

C54Bodyofuterus 2,140

C67Bladder 2,404

C25Pancreas 2,748

C80Unknownprimarysite 2,802

C64Kidney,exceptrenalpelvis 2,847

TotalForLessCommon(24.34%ofallcancerdiagnosiseinAustraliain2011) 28,981

TotalforRLC(35.86%ofallcancerdiagnosedinAustralian2011) 42,574

Rare and less common

cancers

Australian Institute of Health and Welfare; Cancer Australia; Pharmaceutical Industry

Incidence to mortality ratios


0

0.1

0.2

0.3

0.4

0.5

0.6

19921993199419951996199719981999200020012002200320042005200620072008200920102011

CommonCancers

RareCancers

Linear(CommonCancers)

Linear(RareCancers)

Rare cancers and age of

cancer onset

0

10

20

30

40

50

60

70

80

90

CommonCancers AccidentalPoisoningAccidentalDrowning TrafficIncidents RareandLessCommonCancers

Cause of death for Australian children aged 0-14, in 2012


cancer onset: Gen Y (20-39)

0

200

400

600

800

1000

1200

ProstateCancer

Non-HodgkinsLymphoma

LungCancer

Melanoma

BreastCancer

BowelCancer

CoronaryHeartDisease

Assault

RareandLessCommon

AccidentalPoisoning

TrafficIncidents

Suicide

RareandLessCommonCancers61%BowelCancer

13%

BreastCancer11%

Melanoma10%

LungCancer3%


2%

Cause of death Cancer deaths


cancer onset: Gen X (40-59)

Cause of death

0

500

1000

1500

2000

2500

3000

3500

ProstateCancer


Melanoma TrafficIncidents

BowelCancerBreastCancer Suicide LungCancer CoronaryHeartDisease

RareandLessCommonCancers

RareandLessCommonCancers

52%

LungCancer18%

BreastCancer13%

BowelCancer9%

Melanoma4%


3%

ProstateCancer1%

Cancer deaths

Evidence and clinical practice

Research funding

Cancer research funding in Victoria 2005

1.3% <0.5%

Investment in rare and less

common cancers


Ductal

Melanoma

SCC

RAF

Her2

BRCA

ER/PR

GIST KIT

Histopathology Molecular pathology

Breast

Bowel

Skin

Bone

Lobular

Ewing

Osteo

Anatomy

100

90

80

70

60

50

40

30

20

10

0

Pro

gre

ss

ion

-fre

e s

urv

iva

l (%

)

0 1 2 3 4 5 6 7 8 9 10 11 12

Months

Dacarbazine

(N=274)

Vemurafenib (N=275)

Median 1.6

mos

Median 5.3

mos

McConaill et al

Orphanet –testing and therapies 2013 200 new therapies

by 2020

50 000 and 150 000 people (receiving 51% of all orphan designations). 48% of orphan medicinal products in the EU treat less than 1 in 10 000 patients

Courtesy of Mark Caulfield

Clinical trials design

Phase 1/2/3 design

Low-cost therapies

No mechanism

Low response rates

Large populations

Slow development times

Toxicities severe

Therapeutic pessimism

Phase 1 Phase 2 Phase 3 and

beyond

Clinical trials design

High-cost therapies

Rational design

High response rates

Smaller populations

Fast development times

Lower toxicities

Therapeutic optimism

Community awareness

Phase 1/2/3 design

Low-cost therapies

No mechanism

Low response rates

Large populations

Slow development times

Toxicities severe

Therapeutic pessimism

Phase 1 Phase 2 Phase 3 and

beyond

Evolution of clinical trials

1980s

• Protocol 10 pages

• Protocol development weeks

• Cost per patient < 3K

• Time from submission to

opening 2 weeks

• Consent form 3 pages

2010

• Protocol 150 pages

• Protocol development years

• Time from submission to

opening 20 months

• 370 preactivation steps

• Consent form 30 pages

• Cost per patient >120K

• Average Phase 2 study costs

$10M

• Average Phase 3 study costs

$40M

IND NDA

Costing > $1B

Average per patient cost now getting towards $100K

Challenges in drug

development

Courtesy of Kevin Lynch, Celgene

8.7%10.5%

12.1%

-7.9%

6.5%

Number of Unique

Procedures

Frequency of

Procedures

Execution Burden Number of

Eligibility Criteria

An

nu

al

Gro

wth

Rate

Compensation per Procedure

CRF pages increased from 55 to 180 in the same period (2000-2006)

Costs of trials have doubled every 9 years for the past 50 years Average time from concept to study opening 2+ years

Average number of regulatory steps 300-600

Sources: Tufts CSDD; Getz et al. Assessing the Impact of Protocol Design Change on Clinical Trial Performance. American Journal of Therapeutics. 2008 15(5); 450 - 457

Represents 10,038 industry protocols; provided by Fast Track Systems

Work effort values based on Medicare’s RVU methodology

Protocol development and costs

Courtesy of Kevin Lynch, Celgene

Success rate low

Kola and Landis, Nat Rev Drug Disc Vol 3(8) 711-715, 2004. Courtesy of Kevin Lynch, Celgene

The number of drugs invented per billion dollars

R&D invested has halved every nine years for half

a century

Scannell et al. Nature Reviews Drug Discovery 2012

Kantarjian et al JCO, 2013; Steensma, JCO, 2014; Ward, MJA, 2014

Baskets and umbrellas

One drug, many diseases

[B2225]

Different drugs, different

mutations, single type of

cancer [BATTLE]

NCI-MATCH

25% rare cancers

Personalised medicine

Lancet Oncology 2015

Hormone receptor pathway

PI3KCA pathway

RAF/MEK pathway

MoST program design

Advanced/metastatic

cancer of any histologic type,

focus: rare types (n = 1000)

Molecular Screening Targeted Treatments

Eligibility screening: biospecimen suitable for treatment no established

treatment or further standard therapy

Existing therapy or trial

Signal-seeking clinical trials (12 substudies, n=13-16)

Gene Panel, IHC

Outcomes Clinical activity (ORR, TTP) Safety Biology (eg biomarkers) Evaluation of modular trial design + screening platform

Molecular Tumour Board: assign to substudy by molecular target/biomarker

Substudies in development

Molecular Screening

Substudy CDK4/6 inhibitor

Defects in Rb pathway:

CCND1/2/3, CDK4, CDKN2A mut/ampl

Palbociclib

Approved (Pfizer)

1 substudy

Substudy PARP inhibitor

Defects in HR DNA repair:

BRCA complex mut/del

Eg., Talazoparib

Substudy Immune checkpoint inhibitors

Stratification by TILs+PD-L1

Durvalumab + Tremelimumab

Approved (Astrazeneca) 4 substudies

Molecularly targeted therapy Immunotherapy

Actionable mutation No actionable mutation

Substudy prioritisation criteria

Unmet need

Clearly testable hypothesis

Strong and novel rationale

Feasibility (eg. population size, response rate, treatment administration)

Suitable drug (past phase I, non-toxic)

Commitment of pharmaceutical partner

Key partnerships

Academic and clinical research

Pharmaceutical industry

Public health

Novel, creative approaches to bring bench to bedside

More efficient target discovery, shared risk, structured compassionate drug access

Increased and early drug access to patients with unmet need

Bring safe and effective drugs to underserved

patient populations faster

Centralisation is key

Centralisation

• Expertise

– Pathology (20% diagnoses incorrect on

central review)

– Clinical care

• Surgical outcomes and caseload

• Putting up your hand to take responsibility

– Advocacy

• Clinical trials

PBAC and drug approvals

Since 2010:

• 85 positive recommendations

• 56 for common cancers

• 6 for rare solid cancers (2 for Herceptin

expansion to male breast cancer, HER2+

gastric cancer)

• But some rare cancers have received

approval—DFSP, GCTB, GIST &c

Ecology of cancer rests on

the social determinants of

health. We have failed to

manage the negative

health consequences of

development

Purushotham A & Sullivan R. Darwin,

medicine and cancer. Annals Oncol 2010,

21: 199-203

Hughes & Hunter. Disease and Development

in Africa. Soc Sci Med 1970: 443-93

A health care system in evolution

rare cancers - garvan institute of medical research

Documents