Rewriting the Medical Textbooks: Why Clinical Research Matters

1. Rewriting the Medical Textbooks: Why Clinical Research Matters Designing Clinical Research 14 September 2010 Susan Desmond-Hellmann MD, MPH Chancellor

2. Agenda • Challenges & Opportunities • Lessons Learned • Academia’s Role • What’s Possible

3. Bringing Discoveries to the Clinic • My Perspective: Moving a discovery into clinical trials is a step in the journey, not the goal • Goals: FDA approval, product commercialization • #1 Challenge: Patient safety • During clinical trials, as the number of patients exposed increases • Proving long-term safety • Discoveries should reach the greatest number of patients and have the greatest good for society • Always be vigilant that innovation could be harmful as well

4. Developing First-in-Class TherapiesCase Studies Herceptin (trastuzumab) Avastin (bevacizumab)

5. …20 Years in the Making

6. Trastuzumab: Scientific Background • Nature 1981; 290:261-264. Shih, Padhy, Murray, Weinberg DNAs from multiple tumor lines can transform NIH3T3 cells on transfection • Nature 1984; 312:513-516. Schechter, Stern, Vaidyanathan, Decker, Drebin, Greene and Weinberg A series of rat neuro/glioblastomas all contain the same transforming gene (neu) which induces synthesis of a tumor antigen p185. Described homology between neu and erb-B oncogenes • Cell 1985; 41:695-706. Drebin, Link, Stern, Weinberg, Greene Down-modulation of oncogene protein product p185 and reversion of the transformed phenotype by monoclonal antibodies to the neu gene product

7. Shortened Median Survival* HER2 positive 3 years HER2 normal 6-7 years Scientific Rationale - Breast Cancer HER2 geneamplificationFISH HER2 positive protein overexpressionIHC (using rabbit antibody) * Combined metastatic and adjuvant patients. Slamon et al. Science. 1987;235:177. Pauletti et al. J Clin Oncol. 2000;18:3651. Trastuzumab

8. The Importance of a Predictive Biomarker First Line MBC (median survival ~ 22 months) 100% 50% 25% 1250 52 mos 3500 108 mos 11000 349 mos Required Sample Size And Study Duration Actual Benefit (All Patients) Expected Benefit Target Prevalence 5 months (22.7% ) 5 mos (22.7%) 2.5 mos (11.4%) 1.25 mos (5.7%) * Easy to miss a potentially active new therapy as target prevalence decreases

9. USE OF CHEMOTHERAPY PLUS A MONOCLONAL ANTIBODY AGAINST HER2 FOR METASTATIC BREAST CANCER THAT OVEREXPRESSES HER2 Dennis J Slamon et al New Engl J Med 2001;344 RR = 0.76 p = .025 25.4 mo (25% ) 20.3 mo

10. 2005: Trastuzumab results in the adjuvant setting Disease-Free Survival (DFS) Joint Analysis Results (NSABP-B31 and NCCTG-9881) AC  Paclitaxel + Trastuzumab DFS=87% DFS=85% AC  Paclitaxel DFS=75% Percentage (%) DFS=67% Years From Randomization Data presented by Romond EH et al. at ASCO May 2005

11. Trastuzumab and Cardiotoxicity • Most important safety issue for adjuvant tx • Overall experience (Chien, NEJM 2006) • ~1-4% cardiac failure • ~ 10% decline in cardiac function • Highest rates observed with concurrent anthracycline, adjuvant trials demonstrated higher than expected cardiac function decline following 4 cycles of AC • Mutant mouse models suggest a pivotal role of erbB2 in the embryonic and prenatal heart

12. “Clearly the results reported in this issue of the Journal are not evolutionary but revolutionary. The rational development of molecularly targeted therapies points the direction toward continued improvement in breast cancer therapy. Other targets and other agents will follow. However, trastuzumab and the two reports in this issue will completely alter our approach to the treatment of breast cancer.” Gabriel N. Hortobagyi, M.D., NEJM, October 20, 2005

13. …16 Years in the Making

14. Control Control mAb (200μg) Bevacizumab (10 μg) Bevacizumab (50μg) Bevacizumab (100μg) Bevacizumab (200μg) VEGF mAb Control mAb Avastin Pre-Clinical Activity • Neutralizing humanized anti-VEGF monoclonal antibody (derived from mouse mAb A4.6.1) • Broad activity in pre-clinical models 1600 1200 Tumor Volume (mm3) 800 400 0 0 7 14 21 Time (days) Regulation by Vascular Endothelial Growth Factor of Human Colon Cancer Tumorigenesis in a Mouse Model of Experimental Liver Metastasis. Warren et al, J Clin Invest, Vol 95, 1995, pp 1789-1797.

15. Considerations in Trial Design Prostate Cancer Phase II Refractory Single Agent • Avastin Phase II Development Concept Breast Cancer Renal Cell Carcinoma • Endpoints: • Time-to-progression • Response Rate • Survival Phase I Program Non-Small Cell Lung Cancer Phase II Metastatic with Chemotherapy Colorectal Cancer

16. First Phase III Clinical Validation and First Demonstration of Survival of the Long-pursued 'Anti-angiogenic' Hypothesis (ASCO 2003): • Avastin first-line metastatic colorectal cancer Phase III 2107 trial results: The median duration of survival (indicated by the dotted lines) was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo. HR = 0.66 P=<0.001 Hurwitz et al, New England Journal of Medicine, Vol. 350, June 3, 2004, pp 2335-2342.

17. Avastin Phase III Advanced Non-Squamous Non-Small Cell Lung Cancer Study (ECOG 4599) • Survival Results Probability Survival (in months) Data presented by Sandler AB et al. at ASCO May 2005 *Eligible patients.

18. Avastin Phase III Non-Squamous Non-Small Cell Lung Cancer Study: Safety Data Data presented by Sandler, AB et al at ASCO May 2005 *Includes one death on each arm due to neutropenic fever

19. Avastin + Taxol 11.4 months 1.0 Taxol Alone 6.11 months 0.8 0.6 PFS Probability 0.4 0.2 0.0 0 6 12 18 24 30 Months Avastin for Breast Cancer (E2100 results) Progression Free Survival HR = 0.51 (0.43-0.62) Log Rank Test p<0.0001 484 events reported Data presented by Miller KD et al. at SABCS Dec 2005

20. Avastin Phase III First-line Metastatic Breast Cancer Study: Safety Data Data presented by Miller KD et al. at SA BCS Dec 2005 *p<0.0001; **p=0.02; ***p= 0.002 ^p=0.05

21. Avastin Summary and Open Questions • Anti-angiogenesis can slow tumor growth and extend survival • Differential patient benefit by tumor type but no biomarker yet available • Key Questions • Duration of therapy • Best dose • Long term safety

22. How Can We Improve Our Ability to Translate Discoveries into Benefits?

23. Reverse Translation 23

24. Improved Translation 24

25. More Effective Clinical Trials 25

26. Translational Research in Academia • Universities: stimulate curiosity and create knowledge • Companies: develop and commercialize products • Academia’s value added: the scholarly pursuit of technical excellence • Translational programs emerging at UCSF: • Clinical and Translational Sciences Institute (CTSI) • Quantitative Biology Institute (QB3) • Bioengineering and Therapeutic Sciences (BTS)

27. What I’ve Learned • Always ask: does this approach offer the highest likelihood of (and fastest route to) relieving human suffering? • Ensure that you learn something from: • Each and every trial carried out (the answer may be yes or no, but the tragedy is when the answer is “maybe”) • Every patient who enters any of your trials – both short- and long-term • Ask: what can you do to make the approach as simple and as inexpensive as possible? • Therapy should be scalable and accessible

28. UCSF should contribute to change • Prevention • Moving from a disease-based to a health-based approach • Will require new approaches (more reliable surrogate markers ,biomarkers) to advance more quickly • Healthcare reform • Can we utilize electronic health record instead of case report forms? • What will be the impact of cost containment on the pace of innovation? • Why can’t Medical Innovations drive down cost?

29. What’s Possible Turning biomedical discoveries into products that benefit patients

30. Thank you! Questions?