Genomic Medicine The Future of Cancer Care. Shayma Master Kazmi, M.D. Medical Oncology/Hematology Cancer Treatment Centers of America

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1 Genomic Medicine The Future of Cancer Care Shayma Master Kazmi, M.D. Medical Oncology/Hematology Cancer Treatment Centers of America

2 Personalized Medicine Personalized health care is a broad term for interventions that are targeted to individuals based on their risk in order to provide a more coherent and focused approach to health care Personalized health care includes preventive, diagnostic and therapeutic interventions, with risk defined through genetics as well as clinical and family histories More technology-focused definition relies on use of molecular testing to define risk, e.g., genetics, genomics, etc. Goals include greater effectiveness and efficiency of health care delivery as well as improved health outcomes and quality of life

3 PRESENTATION OUTLINE Define Personalized Medicine/Genomics progress to date in cancer care Limitations/Challenges Current & future strategies at CTCA to incorporate Personalized Medicine into cancer care 2014 Rising Tide 3

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5 Definitions Genetic testing Testing germline mutations for possible presence of genetic diseases or variability in metabolism of drugs Genomic testing Usually testing somatic mutations in cancer cells to assess for drug targets 2014 Rising Tide 5

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8 Benefits of Personalized Medicine Better matching patients to drugs instead of trial and error Customized pharmaceuticals may eliminate life-threatening adverse reactions Improved efficacy of drugs Reduce costs of clinical trials by Quickly identifying total failures Favorable responses for particular backgrounds 2014 Rising Tide 8

9 Targeted, Personalized, or Precision therapy Not a new concept Hormonal therapy of breast/prostate cancer: Earliest systemic anti-neoplastic strategy ER receptor discovered 40 years ago HER-2 over-expression in breast cancer CML/GIST (profoundly different pathology but similar molecular abnormalities resulting in essentially identical highly effective therapy) Resulting over-simplification of complex biology 2014 Rising Tide 9

10 EGFR (Epidermal Growth Factor Receptor) Major research efforts to develop EGFR receptor inhibitors, known in pre-clinical systems to be relevant in tumor progression Majority of lung cancer patients over-express EGFR receptor 10% of patients with metastatic lung cancer have major response (over 80%) to one EGFR inhibitor Phase 3 randomized trials with this agent (combined with chemotherapy) negative 2014 Rising Tide 10

11 EGFR Receptor Evidence that over-expression of receptor in lung cancer is not clinically relevant, but the presence of particular EGFR mutations predict for clinical activity (approximately 20-25% of patients - more commonly observed in non-smokers, Asian population, women) Definitive evidence in that lung cancer patients with a mutation experience a superior outcome when treated with EGFR inhibitor alone, rather than chemotherapy (Lancet Oncology 2012; 13:239) 2014 Rising Tide 11

12 Other Examples of Effective Precision Therapy ALK rearrangement (4-5% of lung cancer) Crizotinib - FDA approved 8/2011, other ALK inhibitor approved since, more in development BRAF mutation (50% patients with melanoma) Vemurafinib FDA approved 8/2011, more in development Hedgehog pathway inhibitor (basal cell carcinoma locally advanced/metastatic) Vismodegib FDA approved 1/2012 Her-2 antibody drug conjugate Ado-trastuzumab emtansine FDA approved 2/ Rising Tide 12

13 Issues for Future Precision Medicine Drug Development Small subsets of patients: How to prove clinical benefit? Is a phase 3 trial always required? How does a drug achieve FDA approval? Quality of evidence for clinical utility of molecular/biological markers (e.g., individual/ institutional financial conflict-of-interest) Insurers willingness to pay for anti-neoplastic therapy based on molecular test results, rather than on data from phase 3 randomized trials? 2014 Rising Tide 13

14 Aspirin use and survival after the diagnosis of colon cancer (NEJM) Two populations (121,000, Nurses Health Study [1976]; 51,000, Health Professionals Follow-up Study [1986]) - detailed health information 964 pts. developed colon cancer; tumor tested 17% patients PIK3CA mutation In patients with PIK3CA mutations in the tumor 82% reduction in risk of death if took aspirin compared to patients who did not take aspirin No impact of aspirin if normal PIK3CA 2014 Rising Tide 14

15 But The future is here It is possible (today or within less than a year) to sequence the entire genome of a tumor and the corresponding normal genome of an individual cancer patient for < $5,000 (12-15 years ago this would have cost $6,000,000,000) So, the issue is not whether the data will be available to patients, but rather how to optimally convert this massive quantity of raw data into information of genuine value in individual patient management 2014 Rising Tide 15

16 Declining Cost of Sequencing a Human Genome 2014 Rising Tide 16

17 Proposed future research strategy Web-based national/international registry of outcomes (history, validated treatment results) from therapy based on molecularbased management ( N-of-1 research) Results made available to all interested parties (public, patients, regulatory agencies, 3 rd party payers, employers, research community) When robust data available, publication in peer-reviewed literature 2014 Rising Tide 17

18 Targeted Cancer Therapy The best oncology drugs introduced during the last 15 years have been targeted agents, with activity dependent on identification of the appropriate population Assessment of tumors for specific molecular abnormalities (mutations, overexpression, etc) is now a standard part of clinical practice The large majority of drugs in development are targeted, and many are being developed with companion diagnostic tests 2014 Rising Tide 18

19 Molecular Tumor Profiling-Current status in clinical practice Limited practical application Expensive-not consistently reimbursed Considered a research tool 2014 Rising Tide 19

20 Targeted Therapeutics in Cancer. McDermott U et al. N Engl J Med 2011;364:

21 Targeted Cancer Therapy 21

22 New Frontiers in Genomics at CTCA **Signature Trial Program-Novartis Phase II, pipeline drugs **My Pathway Trial-Genentech Phase II, 5 available drugs for broader application 2014 Rising Tide 22

23 Signature Trial FGFR-BGJ398 RAS/RAF/MEK-Binimetinib(MEK162) PI3K/PTEN-Buparlisib(BKM120) ALK/ROS1-Ceritinib(LDK378) RTK-Dovitinib(TKI258) BRAFV600-Encorafenib(LGX818) CDK4/6, Cyclin D1/3 or p16-lee011 PTCHI/SMO- Sonidegib(LDE225) 2014 Rising Tide 23

24 My Pathway An open label phase IIA study evaluating Trastuzumab/Pertuzumab, Erlotinib, Vemurafenib, and Vismodegib in patients who have advanced solid tumors with mutations or gene expression abnormalities predictive of response to one of these agents 2014 Rising Tide 24

25 PRO 02 My Pathway Study Main Schema 25

26 Rapidly accumulating data on the heterogeneity and molecular complexity of the tumor As new markers are validated in clinical trials, they will need progressive integration into routine practice with the help of decision making algorithm On going debate about the tumor sample for mutation analysis, primary versus metastatic tumor versus circulating tumor cells On going debate on FDA approved test vs. laboratory developed test Single test (KRAS, EGFR, HER2) with reflex vs. multiplex testing (panels) (exomes, genomes) Technology advancing at incredible rate, regulatory agencies, government and payers working hard to keep up

27 Targeting Treatment to a Specific Variant in the Melanoma Gene. McDermott U et al. N Engl J Med 2011;364:

28 Thank you Contact information: Dr. Shayma Kazmi