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

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

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

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

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

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

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

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

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

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

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

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.

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  

ERA OF PRECISION ONCOLOGY (2016) MDAnderson Cancer Center 400-500 genes San Diego Cancer Center 400-500 genes Intermountain Hospital/HMO 100 genes Sloan Kettering Cencer Center 400-500 genes Columbia University 400-500 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 300-400 genes (covered for 70 million people) Switzerland 50 gene Belgium 50 genes

META-ANALYSIS OF MATCHING VS NON-MATCHING PHASE II TRIALS OF TARGETED THERAPIES Meta-analysis :570 phase II, single-agent studies ; 32.149 patients, (1.Jan 2010 -31.Dec 2012) Schwaederle M, et al. J Clin Oncol. 2015 Aug 24.

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,

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

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. 2014 Jun;20(6):682-8.

CHALLENGES IN CLINICAL DEVELOPMENT

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. 2014 Jun;20(6):682-8. WWW.ONCOMPASSMEDICINE.COM WWW.REALTIMEONCOLOGY.COM

New Design Of Clinical Studies

Umbrella design http://www.roche.com/media/store/roche_stories/asco-2015-overview/asco-2015-story-2.htm 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

Basket /Bucket Study Design http://www.roche.com/media/store/roche_stories/asco-2015-overview/asco-2015-story-2.htm 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). www.sciencedaily.com/releases/2015/08/150819211344.htm

Adaptive Study Design gives flexibility to the investigators http://www.roche.com/media/store/roche_stories/asco-2015-overview/asco-2015-story-2.htm gives flexibility to the investigators based on the reactions of the subjects to treatment investigator could change the desig/treatment arms

Enrichment Or The Targeted Structure: parallel development of the drug candidate with the companion diagnostic http://meetinglibrary.asco.org/content/11500141-156

Recent publications in the medical press Diabet Med. 2016 Jun; 33(6): 712–717.Published online 2016 May 19.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879510/ Diabet Med. 2016 Jun; 33(6): 712–717. Published online 2016 May 19. doi:

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

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

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

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

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

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