What is the problem, and how big is it?

Rare cancers

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 New cases Per cent of total Rate(b) Risk(c) Number Per cent of total Rate(b) PYLL(d) Cancer site/type (ICD-10 codes) Number 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 Deaths 20,023: 20.4% 11,090: 28.8% 160,563: 30.6% Australian Institute of Health and Welfare

Collective Impact of Rare Cancers on the Community New cases 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) 1:100,000 = 2,224 1,642 Australian 3.0 17.9deaths 1 in 39 each 589year 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 6/100,000 = 14,000 deaths 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 Deaths Australian Institute of Health and Welfare

ICD Code Incidence C39 Other and ill-defined sites in the respiratory system and intrathoracic organs 0 C58 Placenta 6 C33 Trachea 11 C75 Other endocrine glands and related structures 24 C63 Other and unspecified male genital organs 28 C96 Other and unspecified cancers of lymphoid, haematopoietic and related tissue 29 C94 Other leukaemias of specified cell type 30 C76 Other and ill-defined sites 35 C47 Peripheral nerves and autonomic nervous system 38 C68 Other and unspecified urinary organs 41 C70 Meninges 41 C08 Other and unspecified major salivary glands 42 C72 Spinal cord, cranial nerves and other parts of 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 of unspecified cell type 77 C52 Vagina 77 C14 Other and ill-defined sites in the lip, oral 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 of limbs 114 C41 Bone and articular cartilage of other and unspecified sites 115 C11 Nasopharynx 120 C05 Palate 130 C66 Ureter 142 C57 Other and unspecified female genital organs 149 C06 Other and unspecified parts of mouth 151 C04 Floor of mouth 181 C26 Other and ill-defined digestive organs 185 D45 Polycythaemia vera [WARNING: Incomplete time series] 196 C48 Retroperitoneum and peritoneum 203 Total for Super Rare (2.89% of all cancer diagnosed in Australia in 2011) 3,439 C07 Parotid gland 245 C01 Base of 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 of tongue 430 C24 Other and unspecified parts of biliary tract 433 D47 Other cancers of 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% of all cancer diagnosed in Australia in 2011) 10,154 Total for Rare and Super Rare (11.45% of 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 other 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 of 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% of all cancer diagnosise in Australia in 2011) 28,981 Total for RLC (35.86% of all cancer diagnosed in Australia n 2011) 42,574

Rare and less common cancers Australian Institute of Health and Welfare; Cancer Australia; Pharmaceutical Industry

Incidence to mortality ratios 0.6 0.5 0.4 Common Cancers 0.3 0.2 Rare Cancers Linear (Common Cancers) Linear (Rare Cancers) 0.1 0 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Australian Institute of Health and Welfare; Cancer Australia; Pharmaceutical Industry

Rare cancers and age of cancer onset 90 80 70 60 50 40 30 20 10 0 Common Cancers Accidental Poisoning Accidental Drowning Traffic Incidents Rare and Less Common Cancers Cause of death for Australian children aged 0-14, in 2012

Rare cancers and age of cancer onset: Gen Y (20-39) 1200 Lung Cancer 3% Non-Hodgkins Lymphoma 2% 1000 800 600 Melanoma 10% 400 200 0 Prostate Cancer Non-Hodgkins Lymphoma Lung Cancer Melanoma Breast Cancer Bowel Cancer Coronary Heart Disease Assault Rare and Less Common Accidental Poisoning Traffic Incidents Suicide Breast Cancer 11% Bowel Cancer 13% Rare and Less Common Cancers 61% Cause of death Cancer deaths

Rare cancers and age of cancer onset: Gen X (40-59) 3500 3000 2500 2000 Non-Hodgkins Lymphoma Melanoma 3% 4% Bowel Cancer 9% Prostate Cancer 1% 1500 1000 Breast Cancer 13% Rare and Less Common Cancers 52% 500 0 Prostate Cancer Non-Hodgkins Lymphoma Melanoma Traffic Incidents Bowel Cancer Breast Cancer Suicide Lung Cancer Coronary Rare and Less Heart Disease Common Cancers Lung Cancer 18% Cause of death Cancer deaths

Evidence and clinical practice

Research funding

Cancer research funding in Victoria 2005 <0.5% 1.3%

Investment in rare and less common cancers Australian Institute of Health and Welfare; Cancer Australia; Pharmaceutical Industry

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

Progression-free survival (%) McConaill et al 100 90 80 70 60 50 40 30 20 10 0 Median 1.6 mos Dacarbazine (N=274) Vemurafenib (N=275) Median 5.3 mos 0 1 2 3 4 5 6 7 8 9 10 11 12 Months

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 Phase 2 Phase 3 and beyond Low-cost therapies No mechanism Low response rates Large populations Slow development times Toxicities severe Therapeutic pessimism High-cost therapies Rational design High response rates Smaller populations Fast development times Lower toxicities Therapeutic optimism Community awareness Phase 1/2/3 design

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

Challenges in drug development IND NDA Costing > $1B Average per patient cost now getting towards $100K

Annual Growth Rate Protocol development and costs 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 6.5% 8.7% 10.5% 12.1% Compensation per Procedure Number of Unique Procedures Frequency of Procedures Execution Burden Number of Eligibility Criteria -7.9% Represents 10,038 industry protocols; provided by Fast Track Systems Work effort values based on Medicare s RVU methodology 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 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 Molecular Tumour Board: assign to substudy by molecular target/biomarker Advanced/metastati c cancer of any histologic type, focus: rare types (n = 1000) Eligibility screening: biospecimen suitable for treatment no established treatment or further standard therapy Molecular Screening Gene Panel, IHC Existing therapy or trial Targeted Treatments Signal-seeking clinical trials (12 substudies, n=13-16) Outcomes Clinical activity (ORR, TTP) Safety Biology (eg biomarkers) Evaluation of modular trial design + screening platform

Substudies in development Molecular Screening Actionable mutation No actionable mutation Molecularly targeted therapy Immunotherapy Substudy CDK4/6 inhibitor Substudy PARP inhibitor Substudy Immune checkpoint inhibitors Defects in Rb pathway: CCND1/2/3, CDK4, CDKN2A mut/ampl Palbociclib Approved (Pfizer) 1 substudy Defects in HR DNA repair: BRCA complex mut/del Eg., Talazoparib Stratification by TILs+PD-L1 Durvalumab + Tremelimumab Approved (Astrazeneca) 4 substudies

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 Novel, creative approaches to bring bench to bedside Bring safe and effective drugs to underserved patient populations faster Public health Increased and early drug access to patients with unmet need Pharmaceutical industry More efficient target discovery, shared risk, structured compassionate drug access

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

A health care system in evolution 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