1. The Role Of Molecular Diagnostics (biomarkers) In The Treatment Decisions Of Tumor Therapy (primarily with mAbs)
„ the journey from bench to bedside”
dr Dóra Mathiász
ONCOMPASS MEDICINE HUNGARY

2. Agenda
1.Precision medicine and personalised treatment,targeted therapies 2.Evolution of the precision medicine 3. New drugs used for the targeted therapies in oncology 4. Biomarkers in tumor therapy 5. Basis of the treatment decisions in oncology 6. The role of the molecular tumor boards 7.Importance of the new IT tools for the treatment decision

3. Precision Medicine
Precision medicine (PM) is a medical model , a complex approach that proposes the customization of  healthcare, with medical decisions, practices, and/or products being tailored to the individual patient on the basis of a person’s genes, lifestyle and environment
Characteristics:
diagnostic testing for selecting appropriate and optimal therapies based on the context of a patient’s genetic content or other molecular or cellular analysis
treatment tools employed in precision medicine can include molecular diagnostics, imaging, and analytics/software
creating patients ’sub-groups based on genetic profile
preventive and treatment strategy based on individual characteristics of the patient
Timmerman, Luke (4 February 2013). "What's in a Name? A Lot, When It Comes to 'Precision Medicine'". Xconomy

4. Evolution of the precision medicine
Development of the molecular pathology
New laboratory technologies
Acceleration of the clinical developments of new drugs
Revolution of the IT background

5. Treatment in the „ post-genomic” era
2003
2013
2016<
30,000 genes
604 cancer genes
138 „drivers”
> 3 millions of
mutations
350< targeted drugs

8. STATE OF THE UNION 2015: PRECISION MEDICINE INITIATIVE
„Tonight, I'm launching a new Precision Medicine Initiative to bring us closer to curing
diseases like cancer and diabetes — and to give all of us access to the personalized information
we need to keep ourselves and our families healthier.”
President Barack Obama, State of the Union Address, January 20, 2015

10. Targeted cancer therapies
Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules ("molecular targets") that are involved in the growth, progression, and spread of cancer.( "molecularly targeted drugs," "molecularly targeted therapies," "precision medicines„)
Targeted therapis
Cytostatics
Act on specific molecular targets
Act on all rapidly dividing cells
Selected or designed to interact with their target
Identified because kills cells
Are often/could be cytostatic
Are always cytostatic

11. Types of targeted therapies available
Hormone therapies  -Tamoxifen blocks the estrogen from binding to the oestrogen receptors, preventing the oestrogen sensitive breast cancer from growing.
Signal transduction inhibitors Some kinases are membrane bound, and others reside in the cytoplasm. Thus, development of agents to modify kinase activities has included antibodies targeted to the extracellular portion of the membrane-bound kinase, eg, trastuzumab, Herceptine as well as small molecules that act in the cytoplasm, eg, imatinib mesylate. Imatinib
Immunotherapies  trigger the immune system to destroy cancer cells. Some immunotherapies are monoclonal antibodies that recognize specific molecules on the surface of cancer cells. Binding of the monoclonal antibody to the target molecule results in the immune destruction of cells that express that target molecule. Other monoclonal antibodies bind to certain immune cells to help these cells better kill cancer cells.-checkpoint inhibitors Nivolumab (Opdivo®)This drug targets PD-1.
Angiogenesis inhibitors -VEGF inhibitors- Bevacizumab
Gene expression modulators 
Apoptosis inducers- PD-1- inhibitor Keytruda

12. Historical review of the development and clinical use of monoclonal antibodies
It was not untill in the 1970s that clinically useful amount of single specific antibodies could be generetad
The effectiveness of many early mAbs of non-human origin was low
Recombinant DNA methods, transgenic technology and improved antibody engineering have generated increasing effective mAbs for the treatment of cancer
A common mechanism by which an mAb may effect the killing of a tumor cell is through engagements of surface receptors on the cell and the delivery of an apoptopic signal
mAbs could be coupled to cytotoxic agents or radioisotopes

13. Monoclonal antibodies currently FDA-approved in oncology.
Andrew M. Scott et al. Cancer Immun 2012;12:14
© 2012 by Andrew M. Scott

14. FDA APPROVED 2015
Oncology
Alecensa (alectinib); Roche; ALK-positive, metastatic NSCLC , App December 2015
Cotellic (cobimetinib) ; Genentech; BRAF V600E or V600K melanoma, App Nov 2015
Darzalex (daratumumab); Janssen Biotech; multiple myeloma, App November 2015
Empliciti (elotuzumab); Bristol-Myers Squibb; multiple myeloma who have received prior th, App Nov 2015
Farydak (panobinostat); Novartis; multiple myeloma, App Feb 2015
Ibrance (palbociclib); Pfizer; ER-positive, HER2-negative breast cancer, App Feb 2015
Imlygic (talimogene laherparepvec) ; Amgen; unresectable recurrent melanoma, App. Oct 2015
Lenvima (lenvatinib); Eisai; thyroid cancer, App February 2015
Lonsurf (trifluridine and tipiracil); Taiho Oncology; metastatic colorectal cancer, App Sept 2015
Ninlaro (ixazomib); Millennium Pharmaceuticals; multiple myeloma, App November 2015
Odomzo (sonidegib); Novartis; locally advanced basal cell carcinoma, July 2015
Onivyde (irinotecan liposome inj); Merrimack; met pancreatic cc following gemcitabine-based th, App Oct 2015
Opdivo (nivolumab); Bristol-Myers Squibb; metastatic squamous NSCLC App March 2015
Portrazza (necitumumab) ; Eli Lilly; metastatic squamous NSCLC, App November 2015
Tagrisso (osimertinib); AstraZeneca; EGFR T790M mutation positive NSCLC , App Nov 2015
Unituxin (dinutuximab); United Therapeutics; pediatrics with high-risk neuroblastoma, App March 2015
Varubi (rolapitant); Tesaro; prevention of delayed nausea and vomiting associated with ChTx, App Sept 2015
Yondelis (trabectedin); Janssen; liposarcoma or leiomyosarcoma, App October 2015

15. The clinical use of biomarkers To help diagnose conditions, as in the case of identifying early stage cancers (Diagnostic) To forecast how aggressive a condition is, as in the case of determining a patient's ability to fare in the absence of treatment (Prognostic) To predict how well a patient will respond to treatment (Predictive)
Rhea, Jeanne; Ross J. Molinaro (March 2011). "Cancer Biomarkers: Surviving the journey from bench to bedside". Medical Laboratory Observer. Retrieved 26 April 2013.

16. Molecular biomarkers in oncology
Tumor Type
Biomarker
Breast
HER-2, ER/PR,
PIK3CA,EGFR,MET,FGFR,ALK,ROS1
Colorectal
KRAS,RAS, NRAS, BRAF, EGFR,PIK3CA,
HER-2,MET,ALK,FGFR,ROS1
Lung
ALK,EGFR,ROS1,BRAF,MET,HER,
KRAS,PIK3CA,FGFR,EGFR

17. ERA OF PRECISION ONCOLOGY (2016)
MDAnderson Cancer Center genes
San Diego Cancer Center genes
Intermountain Hospital/HMO 100 genes
Sloan Kettering Cencer Center genes
Columbia University genes
Dana-Farber Cancer Center/Harvard University OncoPanel 305 genes
Mayo Clinic CANCP, Solid Tumor Targeted Cancer Gene Panel 50 genes
Washington University UW-OncoPlex™ 194 genes
Foundation Medicine Foundation One /Heme genes (covered for 70 million people)
Switzerland 50 gene
Belgium 50 genes

18. META-ANALYSIS OF MATCHING VS NON-MATCHING
PHASE II TRIALS OF TARGETED THERAPIES
Meta-analysis :570 phase II, single-agent studies ; patients, (1.Jan Dec 2012)
Schwaederle M, et al. J Clin Oncol Aug 24.

19. Molecular Tumor Boards „from bench-to-bedside”
The molecular tumor board helps to translate the molecular pathology results of the given patient into the treatment options
education, scientific discussions, designing of clinical studies’s
Members are apart of the „traditional members”: geneticians, molecular pathologists, IT specialists, clinical pharmacologists,

20. Tasks Of The Molecular Biological Interpretation Team
Bioinformatic screening of the molecular alterations based on qualitative and quatitative parameters
Functional annotation of the molecular alterations:Select the driver& the passenger mutations from the SNPs and VUSs. Ranking the drivers.
Farmaco-diagnostic interpretation of the molecular alterations: Collecting the evidences which relates to the positive or negative relationship between the alterations and the drug molecules either marketed or under development

21. EVIDENCE-BASED MEDICINE IN PRECISION ONCOLOGY
LEVELS A B C D E
Therapy
There is a validated association between the given alteration and response/resistance to the given agent for the given indication
There is limited clinical evidence (early or conflicting data) for an association between this alteration and response/resistanceto this agent in this tumor type
Clinical evidence with this drug in
another tumor type
There is preclinical evidence for an association between this alteration and response/resistance to this agent
There is an inferential association between this alteration and response/resistance to this agent
Clinical Trials
This alteration is  used or has been  used as an  eligibility criterion for clinical trials of  this agent or class  of agents
There is limited  clinical evidence (early or conflicting  data) for an  association between  this alteration and  response/resistance to this agent or class  of agents in this  tumor type
Clinical evidence with this compound or same class of compounds in another tumor type
Preclinical evidence with this compound or same class of compounds
Indirect computational evidence with this compound or same class of compounds
Mandatory
Complementer
Adapted from Van Allen EM, et al. Nat Med Jun;20(6):682-8.

22. CHALLENGES IN CLINICAL DEVELOPMENT

23. THE CHALLENGE OF PRECISION ONCOLOGY
8-10 (UP TO 8-10 DRIVERS/TUMOR)
3 MILLION (MUTATIONS)
~50% OF DRIVER MUTATIONS OCCUR WITH < 1% FREQUENCY
The typical long-tail distribution of driver genetic alterations
Van Allen et al. Nat Med Jun;20(6):682-8.

24. New Design Of Clinical Studies

25. Umbrella design
Testing drug candidates in one study which targets the same genetic mutation in the given histology
Development time could be shortened with the parallel testing
Sub-grouping patients help to move them in the most fitting sub-groups

26. Basket /Bucket Study Design
1.Basket/Bucket studies are designed to test the effect of a single drug on a single mutation in a variety of cancer types.
2. These trials can also screen multiple drugs across many cancer types.
3. This design provides evidence for pairing a drug with validated biomarker in a specific tumor
4. Basket/Bucket design helps to reach appopriate subject’s number in rare tumors with this mixed patient’s population
5. Basket/Bucket design allows patients with multiple diseases and one or more target to be enrolled in cohorts or groups in one trial (the basket).

27. Adaptive Study Design gives flexibility to the investigators
gives flexibility to the investigators
based on the reactions of the subjects to treatment investigator could change the desig/treatment arms

28. Enrichment Or The Targeted Structure:
parallel development of the drug candidate with the companion diagnostic

29. Recent publications in the medical press
Diabet Med Jun; 33(6): 712–717.Published online 2016 May 19. 
Diabet Med Jun; 33(6): 712–717. Published online 2016 May 19. doi:

30. Need to know the molecular genetic information
Need to learn from all former cases
Need to share the experiences

31. A Precision Medicine Calculator (PMC) new IT platform
PMC Class I medical device EU registered
Genes with mutations evidences
Publisged evidences for treatment options
Targeted therapies
Immune therapies
Clinical studies
Case studies
Registered users

32. Test Calculator
Selecting the most relevant and cost effective gene panels for the diagnosis

33. Molecular Treatment Calculator
Ranks the scientific evidences based on a proprietary algorhytm

34. Profile „matching” for clinical trial
Trial Calculator
Profile „matching” for clinical trial

35. email alert „matching” studies
PMC Alert
alert „matching” studies