Personalized Medicine. Paul Waring Professor of Pathology The University of Melbourne

Transcription

1 Personalized Medicine. Paul Waring Professor of Pathology The University of Melbourne

2 The Wall Street Journal. April 16 th 1999 The Oncologist 1999:4;

3 Herceptin : The Power of Patient Selection Unselected Selected (HER2+) Unselected Selected Target prevalence 25% 100% Expected survival benefit 1.25m (5.7%) 5m (22.7%) Sample size 11,000 1,250 Study duration 349m 52m

4 Chin L et al. Nature Medicine 2011; 17:

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6 Where are we now?

7 Prototypic Cancer Genome Imielinski M et al. Cell 2012: 150(6):

8 Pharmaceutical oncology pipeline Project Initiation Research Clinical Candidate Selection Early Development IND Filing Phase III Decision Phase I Phase II Phase III 800+ new cancer drugs approved for testing in humans

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10 What are we expecting?

11 Matching the right drug to the right patient based on the individual tumour s unique genetic profile.

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13 When will this become a reality?

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15 Roychowdhury S et al. Science Transl Med 2011;3: ra121

16 ?

17 Each tumour is genetically unique and evolves. Gerlinger M et al. NEJM 2012;366:

18 Tumours invariably develop drug resistance and recur. Wagle et al. 2012

19 Are we playing jeopardy with cancer patients?

20 Are the drugs available?

21 Dietrich S et al. NEJM 2012, 366:21

22 Accelerated approval for rare / serious indications using few patients

23 What do we need to do?

24 Focus on the right diseases Rare cancers often have single (or a few) dominant drivers Common solid cancers some common but many infrequent mutations Few pathways to transformation Single oncogene addicted therapeutic targets eg. EGFR lung adenocarcinoma. Single kinase - dependent tumours suitable for targeted monotherapy in 1 st line. Multiple pathways to transformation and resistance Many potential targets but most at a low frequency few new Her2 s, BRAF s Multiple kinase - dependent tumours may be suitable for combination therapy in refractory patients.

25 The right disease subset (indication) Design the right clinical validation studies The right trial The right target The right patients (biomarkers) The right drug

26 Molecularly-directed signal-seeking clinical trials Common indications Large populations Unselected patients Phenotype - based Low response rate Statistical proof Slow development times High failure rate Low cost drugs Less common indications Smaller populations Pre-selected patients Genotype - based High response rate Biological proof Fast development times High success rate High cost drugs

27 Australian Ovarian Cancer Assortment Trial (ALLOCATE) Platinum resistant advanced or metastatic ovarian cancer (all histologies) Analysis of: Mutations mrna expression Copy Number Variation Methylation HR & FA pathway mutations / BRCA1 methylation 51% Functional NHEJ pathway EGFR mutations PIK3CA mutations VHL mutations/ loss of expression HER2 amplification CCNE1 amplification BRAF mutations KIT mutations 2.2% 3% 3.5% 15-20% 20% 2.2% 28- Clear Dysg 37%L cell ca ermin GSOC oa PARP inhibitors (e.g. Olaparib) EGFR inhibitors (e.g. Erlotinib) PIK3CA, AKT, mtor or dual inhibitors of PIK3CA and mtor (e.g. PKI-587) HIFs inhibitors (e.g. Sunitinib) HER2 inhibitor (e.g.trastuzumab ) CDK2 inhibitor (e.g. Dinaciclib) BRAF inhibitor (e.g. Vemurafenib) KIT inhibitor (e.g. Imatinib)

28 Make sure the intervention will have a clear economic benefit. PBS listing ISEL 2L restricted to EGFR + (expected 250 treated pa) AZ submits to PSAC in 1L EGFR + based on IPASS PSAC rejects 1L EGFR + (insufficient evidence of test cost effectiveness) Poor uptake Testing barrier Erlotinib approved 2L in all comers. MSAC approves 2L MSAC PSTC defers applies to MSAC for EGFR testing in 2L (no test cost data) MBS listed MoH approves 2L AZ submits 1L to MSAC as co-dependent technology

29 Acknowledgements Center for Translational Pathology, Melbourne Tiffany Cowie TGx: Graham Taylor, Sebastian Lunke, Arthur Hsu, Clare Love, Kym Pham, Olga Kondrashova, Renate Marquis-Nicholson, Matthew Wakefield MDx: Barney Rudzki, Simon Cliffe, Voula Dimitriadis, Leakhena Leas, Edith Soo, Susan Prescott. Molecular Pathology Michael Christie, Irma Gresshoff Walter and Eliza Hall Institute Clare Scott Royal Melbourne Hospital Jayesh Desai, Peter Gibbs, Ben Tran, Jeanie Tie, Oliver Sieber, Ingrid Winship Peter MacCallum Cancer Centre Grant MacArthur, David Bowtell, Kate Alsop, Linda Mileshkin, Danny Rischin, Andrew Fellows, Andrew Colebatch, Alex Dobrovic, Stephen Fox. Austin Health David Williams, Jonathon Cebon Monash University Neil Watkins Bar Illan University, Israel Izhak Haviv Ventana Medical Systems Tom Grogan, Kandavel Shanmugan, Alisa Tubbs