Dr. Chirag Desai , MD, DM (Oncology) Hemato -oncology Clinic, Vedanta, Ahmedabad

1. Biotechnology in Fighting Fatal Disease – CancerNational Biotechnology Symposium 2012Innovations in Biotechnology: From Education to IndustrySep 1, 2012, AMA, Ahmedabad Dr. Chirag Desai, MD, DM (Oncology) Hemato-oncology Clinic, Vedanta, Ahmedabad Chiragdesai.oncology@gmail.com

2. Metastatic colon cancer (unresectable) 1970s – Only 5-FU – survival of 6 mths Survival Increased 4 folds In 30 years 1980s – Leucovorin/5-FU – survival of 9 mths 1990s – Only 5-FU – Addition of oxaliplatin/ Irinotecan/capecitabine - – survival of 18 mths 2000s – Avastin - – survival of 21 mths Now – Erbitux – survival of 25 mths

3. Breast Cancer – stage II 1960s – Only surgery - 40% cured Cure Rate Doubled In 40 years 1970s – CMF - 50% cured 1980s – CMF and Tamoxifen - 60% cured 1990s – Anthracyclines and taxanes - 67% cured 2000s – Aromatase inhibitors - 73% cured Now – Herceptin - 80% cured ??

4. Biotechnology in Cancer: Translational Research Bench to bedside

5. The biological revolution of 20th century totally reshaped all fields of biomedical study -- cancer research being only one of them.

6. Biotechnology helps in elucidating the normal cellular functioning And the derangements thereof resulting in disease Including cancer…….and The ways to tackle these derangements

7. Chronic Myeloid Leukemia One cancer One chromosome One gene One Treatment

8. Most Cancers Each cancer Multiple chromosomes Multiplegenes Multiple Treatments

9. Initiation Normal Cell Promotion Pre-Cancerous Cell Cancer Cell Immune Surveillance Signal transduction Invasion Angiogenesis Migration Metastases Seed/Soil

10. Prevention/early detection Diagnosis/ prognosis Treatment

11. Biotechnology techniques and processes (Evans, P. R. Biotechnology and Biological Preparations in Encyclopaedia of PT vol. 1, 3rd edn.)

12. Growth Factor Growth Factor receptor Signal Transduction

13. Research and development network

14. Examples of Biologicals: • Growth Factors: • EGF • VEGF • FGF • IGF • PDGF • Receptors: • EGFR • Her-2 • VEGFR • PDGFR • ER/PR • STIs: • TKIs • mTORI • CDKI • FTIs • Others • Mabs: • Rituximab • Avastin • Herceptin • Erbitux • Biomab

15. Evolution From Empiric to Personalized Therapy in NSCLC Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:148-150.

16. Patient Selection Improves Treatment Results in NSCLC Molecular selection…. No selection Clinical selection 28 24 20 16 12 8 4 0 Erlotinib alone >27 months Median survival (months) Bevacizumab + platinum: >14 months Pemetrexed + platinum: >12 months Bevacizumab + platinum-based doublet: >12 months Platinum-based doublets (3rd gen):8–10 months Cisplatin-based regimens:6–8 months Non- squamous Adeno- only Adeno- only EGFR- mut+ BSC: 2–4 months 2008 1970s 1980s 1990–2005 2005 2008 2009/10

17. VEGF in clinic • Antibody – Bevacezumab (Avastin) • Lung Cancer, Colon Cancer, Ovarian Cancer, Renal Cell Carcinoma, Brain Tumors, Breast Cancer • Tyrosine kinase Inhibitors: • Sunitinib, Sorafenib, Pazopinib, Axitinib, Dovitinib, others • Renal Cell Cancer, Neuro-endocrine tumors, Liver cancers, GIST, Sarcoma

21. Biologicals help in the treatment of >80% of cancers either curatively or in advanced cancers • Biologicals are effective in: • Lung cancer • Colon cancer • Breast cancer • Head and neck cancer • Leukemias/Lymphomas • Renal/Liver cancers • Others

22. Challenges in the development of biologicals

23. RBF Symposium Feb 2011 A Nobel Prize by Chance

24. Start at the top Generate Hypothesis Design study Develop new theory Collect information Analyse and interprete finding • Formulate testable hypothesis • Make the plan / design the study

25. New Therapeutic Agent: Development Phases Biomarker Integration Drug Approval N = 1600 N = 300 N = 30 Total Time ~ 90 mos or 7.5 yrs Preclinical (~ 18 mos) Phase I (~ 18 mos) Phase II (~ 18 mos) Phase III (~ 36 mos) Phases of Development of New Biomarker linked to New Drug Confirm target Assay development Integrate biomarker Assay performance Biomarker informative? Assay performance Clinical validation Coprimary endpoint Clinical application of biomarker Gandara D, et al. NCI CAPR Workshop. 2011. Printed with permission.

26. A large number of biologically/molecularly acting drugs are under development • Traditional end points are less relevant • New end points required • OS still is a gold standard end point • Surrogate end points need to be re-defined • Even though response rate is less important, exact definition of response is critical • Ongoing analysis of tissue/blood based biomarkers is critical

27. Surrogate End points with targeted Therapies: • Traditional • PFS • QoL • OS • Pharmacoeconomics • Others • Exploratory • Target inhibition • Tissue level • Blood level • Pharmacogenetic • Tissue based • Blood based

28. BATTLE: Phase II NSCLC Biomarker Study Umbrella protocol Core biopsy Biomarkerprofile EGFR KRAS/BRAFVEGF RXR/CyclinD1 Randomization:Equal ® Adaptive ErlotinibEqual (n = 25)Adaptive (n = 33) VandetanibEqual (n = 23)Adaptive (n = 29) Erlotinib + BexaroteneEqual (n = 21)Adaptive (n = 15) SorafenibEqual (n = 26)Adaptive (n = 72) Primary endpoint: 8-wk disease control rate; 30% assumed Kim ES, et al. AACR 2010. Abstract LBA1. Reprinted with permission.

29. BATTLE: Phase II NSCLC Biomarker Study—Discovery Platform Kim ES, et al. AACR 2010. Abstract LBA1. Reprinted with permission.

30. Who should do this? Generate Hypothesis • Academic institutions • Corporate hospitals • Individual practitioners • Medical associations • Collaborative effort Design study Develop new theory Collect information Analyse and interprete finding

31. Who should do this? Generate Hypothesis Design study Develop new theory Collect information Analyse and interprete finding

32. Innovations chiragdesai.oncology@gmail.com

33. Future: Making cancer a chronic Disease Tests like Oncotype Dx21 in breast cancer Drugs like Imatinib in CML Outcome like sequential use of chemo and targeted drugs in myeloma