Rare cancers What is the problem, and how big is it? Rare (orphan) - - PowerPoint PPT Presentation

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Rare cancers

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What is the problem, and how big is it?

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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

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Collective Impact of Rare Cancers on the Community

Cancer site/type (ICD-10 codes) Number Per cent

• f total

Rate(b) Risk(c) Number Per cent

• f 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%

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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

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ICD Code Incidence C39 Other and ill-defined sites in the respiratory system and intrathoracic

• rgans

C58 Placenta 6 C33 Trachea 11 C75 Other endocrine glands and related structures 24 C63 Other and unspecified male genital

• rgans

28 C96 Other and unspecified cancers

• f

lymphoid, haematopoietic and related tissue 29 C94 Other leukaemias

• f

specified cell type 30 C76 Other and ill-defined sites 35 C47 Peripheral nerves and autonomic nervous system 38 C68 Other and unspecified urinary

• rgans

41 C70 Meninges 41 C08 Other and unspecified major salivary glands 42 C72 Spinal cord, cranial nerves and

• ther

parts

• f

central nervous system 49 C38 Heart, mediastinum and pleura 49 C37 Thymus 52 C13 Hypopharynx 56 C31 Accessory sinuses 68 C46 Kaposi sarcoma 69 C74 Adrenal gland 75 C93 Monocytic leukaemias 75 C95 Leukaemias

• f

unspecified cell type 77 C52 Vagina 77 C14 Other and ill-defined sites in the lip,

• ral

cavity and pharynx 83 C88 Immunoproliferative cancers 89 C12 Pyriform sinus 91 C10 Oropharynx 95 C55 Uterus, part unspecified 97 C60 Penis 108 C30 Nasal cavity and middle ear 109 C03 Gum 109 C40 Bone and articular cartilage

• f

limbs 114 C41 Bone and articular cartilage

• f
• ther

and unspecified sites 115 C11 Nasopharynx 120 C05 Palate 130 C66 Ureter 142 C57 Other and unspecified female genital

• rgans

149 C06 Other and unspecified parts

• f

mouth 151 C04 Floor

• f

mouth 181 C26 Other and ill-defined digestive

• rgans

185 D45 Polycythaemia vera [WARNING: Incomplete time series] 196 C48 Retroperitoneum and peritoneum 203 Total for Super Rare (2.89%

• f

all cancer diagnosed in Australia in 2011) 3,439

• C07

Parotid gland 245 C01 Base

• f

tongue 259 C69 Eye and adnexa 266 C65 Renal pelvis 273 C84 Peripheral and cutaneous T-cell lymphomas 275 C51 Vulva 318 C23 Gallbladder 339 C09 Tonsil 361 C21 Anus and anal canal 369 C02 Other and unspecified parts

• f

tongue 430 C24 Other and unspecified parts

• f

biliary tract 433 D47 Other cancers

• f

lymphoid, haematopoietic and related tissue 440 C17 Small intestine 442 C32 Larynx 590 C49 Other connective and soft tissue 604 C81 Hodgkin lymphomas 606 C45 Mesothelioma 690 C62 Testis 732 C44 Skin

• Non-melanoma,

excluding BCC and SCC 769 C53 Cervix 801 C00 Lip 912 Total For Rare (8.55%

• f

all cancer diagnosed in Australia in 2011) 10,154 Total for Rare and Super Rare (11.45%

• f

all cancer diagnosed in Australia in 2011) 13,593

• D46

Myelodysplastic syndromes [WARNING: Incomplete time series] 1,309 C56 Ovary 1,330 C15 Oesophagus 1,395 C22 Liver and intrahepatic bile ducts 1,446 C92 Myeloid leukaemias 1,457 C90 Multiple myeloma and

• ther

plasma cell cancers 1,533 C91 Lymphoid leukaemias 1,654 C71 Brain 1,724 C16 Stomach 2,093 C73 Thyroid gland 2,098 C54 Body

• f

uterus 2,140 C67 Bladder 2,404 C25 Pancreas 2,748 C80 Unknown primary site 2,802 C64 Kidney, except renal pelvis 2,847 Total For Less Common (24.34%

• f

all cancer diagnosise in Australia in 2011) 28,981

• Total

for RLC (35.86%

• f

all cancer diagnosed in Australia n 2011) 42,574

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Rare and less common cancers

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

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Incidence to mortality ratios

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

0.1 0.2 0.3 0.4 0.5 0.6 19921993199419951996199719981999200020012002200320042005200620072008200920102011 Common Cancers Rare Cancers Linear (Common Cancers) Linear (Rare Cancers)

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Rare cancers and age of cancer onset

10 20 30 40 50 60 70 80 90 Common Cancers Accidental Poisoning Accidental Drowning Traffic Incidents Rare and Less Common Cancers

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

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Rare cancers and age of cancer onset: Gen Y (20-39)

200 400 600 800 1000 1200 P r

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• Rare

and Less Common Cancers 61% Bowel Cancer 13% Breast Cancer 11% Melanoma 10% Lung Cancer 3% Non-Hodgkins Lymphoma 2%

Cause of death Cancer deaths

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Rare cancers and age of cancer onset: Gen X (40-59)

Cause of death

500 1000 1500 2000 2500 3000 3500 Prostate Cancer Non-Hodgkins Lymphoma Melanoma Traffic Incidents Bowel CancerBreast Cancer Suicide Lung Cancer Coronary Heart Disease Rare and Less Common Cancers

Rare and Less Common Cancers 52% Lung Cancer 18% Breast Cancer 13% Bowel Cancer 9% Melanoma 4% Non-Hodgkins Lymphoma 3% Prostate Cancer 1%

Cancer deaths

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Evidence and clinical practice

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Research funding

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Cancer research funding in Victoria 2005

1.3% <0.5%

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Investment in rare and less common cancers

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

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Ductal

Melanoma

SCC RAF Her2 BRCA ER/PR GIST KIT Histopathology Molecular pathology Breast Bowel Skin Bone Lobular Ewing Osteo Anatomy

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100 90 80 70 60 50 40 30 20 10 Progression-free survival (%) 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

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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

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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

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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

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Evolution of clinical trials

1980s

• Protocol 10 pages
• Protocol development weeks
• Cost per patient < 3K
• Time from submission to
• pening 2 weeks
• Consent form 3 pages

2010

• Protocol 150 pages
• Protocol development years
• Time from submission to
• pening 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

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Evolution of clinical trials

1980s

• Protocol 10 pages
• Protocol development weeks
• Cost per patient < 3K
• Time from submission to
• pening 2 weeks
• Consent form 3 pages

2010

• Protocol 150 pages
• Protocol development years
• Time from submission to
• pening 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

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IND NDA

Costing > $1B Average per patient cost now getting towards $100K

Challenges in drug development

Courtesy of Kevin

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8.7% 10.5% 12.1%

• 7.9%

6.5% Number of Unique Procedures Frequency of Procedures Execution Burden Number of Eligibility Criteria

Annual Growth 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

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Success rate low

Kola and Landis, Nat Rev Drug Disc Vol 3(8) 711-715, 2004.

Courtesy of Kevin Lynch, Celgene

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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

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

SLIDE 29

Baskets and umbrellas

One drug, many diseases [B2225] Different drugs, different mutations, single type of cancer [BATTLE]

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NCI-MATCH

25% rare cancers

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Personalised medicine

Lancet Oncology 2015

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Hormone receptor pathway PI3KCA pathway RAF/MEK pathway

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MoST program design Advanced/metastati c 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

• r 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

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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

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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

SLIDE 39

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

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Centralisation is key

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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

SLIDE 42

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

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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