How to faster integrate new technologies into clinical practice 31JAN2017 Jens Bjørheim, CMO Ultimovacs Nordic Trial Alliance Stakeholders meeting
2 Oncology New drugs Landscape The current buzz Basket Studies Precision Medicine Stratified Medicine Companion Diagnostics Multiplex Diagnostics Next Generation Sequencing Theranostics Multi-drug Studies Molecularly Matched Umbrella Studies Personalised Healthcare Hyper-segmentation Patient Selection Immune therapy
3 Oncology Landscape Science is showing the way Enhanced disease understanding Move towards molecular classification 60 yrs...disease of the blood... ~0 % 50 yrs 40 yrs Chronic leukaemia Acute leukaemia Preluekaemia Leukaemia or Lymphoma Indolent lymphoma Aggressive lymphoma 5 yr survival Tissue of Origin Today ~ 38 Leukaemia s... ~ 51 Lymphoma s... Acute myeloid (~12 types) Acute lymphoblastic (2 types) Acute promyelocytic (2 types) Acute monocytic (2 types) Acute erythroid (2 types) Acute megakaryoblastic Acute myelomoncytic (2 types) Chronic myeloid Chronic myeloproliferative disorders (5 types) Myelodysplastic syndromes (6 types) Mixed myeloproliferative/myelodysplas ticsyndromes (3 types) Mature B-cell (~14 types) Mature T-cell (15 types) Plasma cell neoplasm (3 types) Immature (precursor) (2 types) Hodgkin s (5 types) Immunodeficiency associated (~5 types) Other haematolymphoid neoplasms (~7 types) 70% Molecular Pathway
4 Oncology Landscape Growing understanding of stratification 1 3 Breast Central nervous system Endocrine Gastrointestinal Gynaecologic Head and neck Haematologic Skin Soft tissue Thoracic Urologic 2 4 Etc...
Oncology Landscape Drugging the hallmarks 5 Hallmarks of Cancer: The Next Generation. Douglas Hanahan & Robert A. Weinberg. Cell 144, March 4, 2011
Oncology Landscape Targeted therapeutics are improving survival 6 Example: NSCLC is an evolving landscape Where we re going... Overall Survival (months) 30 20 10 0 1980 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010 2015 2020 1970 1980 2000 2010 2020 1998 2004 2009 2011 2012 2013
7 Oncology Landscape Biomarkers in clinical development... Hallmarks of Cancer: The Next Generation. Douglas Hanahan & Robert A. Weinberg. Cell 144, March 4, 2011
8 HER Signalling Is Altered In Cancer We have a small molecule inhibitor... Inhibitor Adapted from KinaseChem.com (Copyright 2013 Kinasechem.LTD.) Now pick a biomarker
Reality Of Drug Development Precision and cost 9 ABPI Delivering Value in the UK Report 2014
Stratified Medicine Why should we be interested? 10 Drivers for stratified medicine... Society: effective and sustainable healthcare systems, medicines faster to market Patient/physician: scientific/technological advances new disease classification Pharmaceutical industry: challenges better medicines, better precision, lower cost, diagnosis
11 Stratified Medicine Requires Portfolio Approach Lung adenocarcinoma squamous
12 Linkage, efficacy biomarkers, patient selection...
13 Oncology Landscape Transforming environment August 2011... FDA approves crizotinib with companion diagnostic for a type of late-stage lung cancer Key genetic driver abnormal anaplastic lymphoma kinase gene The drug had accelerated approval due to clear efficacy and ability to treat only those patients likely to respond
14 Oncology Landscape The current buzz Basket Studies Precision Medicine Stratified Medicine Companion Diagnostics Multiplex Diagnostics Next Generation Sequencing Theranostics Multi-drug Studies Molecularly Matched Umbrella Studies Personalised Healthcare Hyper-segmentation Patient Selection
15 Stratified Medicine In Drug Development Basket studies offer a practical solution Choosing the patient for the trial Baskets choose the trial for the patient Trial 1 Trial 2 Trial 3 Basket portfolio, multidrug, umbrella, etc...
16 Basket Studies In Lung Cancer MATRIX National Lung Trial CRUK MATRIX National Lung Cancer Trial Cancer Research UK Outline protocol NSCLC, >1L Ph.2a, signal seeking, single arm, mono-tx 2-stage Bayesian design (total n=30 pts), using ORR and PFS National screening programme screening 2,000 pts/year rolling Modular design, over-arching protocol Allows drop-in and drop-out Illumina NGS plus bespoke tissue pathology for screening Screening delivered via 3 technical hubs, routine clinical molecular pathology service Currently includes up to 12 AZ compounds, 2 compounds from Pfizer
Basket Studies In Lung Cancer MATRIX National Lung Trial CRUK 17 Adenocarcinoma MATRIX National Lung Cancer Trial Cancer Research UK PI3K/AKT deregulation AKT1 FGFR LKB1 TSC1/2 CDK4 amplification CCND1 amplification KRAS MET amplification ROS1 gene fusions EGFRm+ & T790M+ NF1 NRAS No actionable change A3 A6 B1 C1 C2 D2 D3 D4 E1 E2 F1 G2 G3 H1 Starting line-up... AZD5363 AZD4547 AZD2014 Palbociclib Crizotinib AZD9291 Selumetinib + Docetaxel MEDI4376 Squamous cell carcinoma PIK3CA PIK3CA amplification PTEN PTEN loss AKT1 FGFR LKB1 TSC1/2 Rb-wildtype and homozygous p16 loss CDK4 amplification CCND1 amplification MET amplification ROS1 gene fusions EGFRm+ & T790M+ NF1 NRAS No actionable change A1 A2 A4 A5 A6 B2 C1 C2 D1 D2 D3 E1 E2 F1 G1 G3 H1 AZD5363 AZD4547 AZD2014 Palbociclib Crizotinib AZD9291 Selumetinib + Docetaxel MEDI4376
18 Diagnostics A Changing Landscape Single assays are becoming obsolete... Consider Many molecular segments, accurate diagnosis requires multiple markers Running multiple, serial or parallel assays impractical / impossible Limits of tissue less with line of therapy What order Etc...
19 Diagnostics A Changing Landscape Next Generation Sequencing (NGS)...
20 Conclusion 1. Innovative clinical trials to more effectively and efficiently identify patients who are predicted to be responders Trial designs Diagnostics Drug development 2. Allow wider (and earlier) patient access to novel therapeutics from multiple Pharma companies 3. Leverage cutting-edge diagnostics to robustly identify the right patients with more efficient use of biopsy material 4. Exploit new types of dataset in regulatory approval process 5. Enable patient access through new and more robust diagnostic standards To faster integrate new technologies into clinical practice