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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
Melanoma of skin (C43) 4,219 9.7 39.4 1 in 24 385 2.3 3.4 6,790
Lung, bronchus & trachea (C33–C34) 3,270 7.5 29.3 1 in 24 2,526 15.0 22.3 34,770
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
Unknown primary site (C26, C39, C76–C80) 1,592 3.7 13.6 1 in 54 1,741 10.4 14.5 17,635
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
All cancers (C00–C97(a), D45–D47(e)) 43,466 100.0 395.4 1 in 3 16,819 100.0 145.8 229,483
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
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
Melanoma of skin (C43) 4,219 9.7 39.4 1 in 24 385 2.3 3.4 6,790
Lung, bronchus & trachea (C33–C34) 3,270 7.5 29.3 1 in 24 2,526 15.0 22.3 34,770
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
Unknown primary site (C26, C39, C76–C80) 1,592 3.7 13.6 1 in 54 1,741 10.4 14.5 17,635
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
All cancers (C00–C97(a), D45–D47(e)) 43,466 100.0 395.4 1 in 3 16,819 100.0 145.8 229,483
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
Australian Institute of Health and Welfare; Cancer Australia; Pharmaceutical Industry
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
Rare cancers and age of
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%
Non-HodgkinsLymphoma
2%
Cause of death Cancer deaths
Rare cancers and age of
cancer onset: Gen X (40-59)
Cause of death
0
500
1000
1500
2000
2500
3000
3500
ProstateCancer
Non-HodgkinsLymphoma
Melanoma TrafficIncidents
BowelCancerBreastCancer Suicide LungCancer CoronaryHeartDisease
RareandLessCommonCancers
RareandLessCommonCancers
52%
LungCancer18%
BreastCancer13%
BowelCancer9%
Melanoma4%
Non-HodgkinsLymphoma
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
Australian Institute of Health and Welfare; Cancer Australia; Pharmaceutical Industry
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
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