1. 1 Trends in drug development programs in the era of Personalized Medicine Gunnar Saeter, M.D., Ph.D. Head, Institute for Cancer Research Oslo University Hospital Institute for Cancer Research

2. Disclosures Global Director of Scientific Affairs, Merck (MSD) Oncology 2009 - 2013 Institute for Cancer Research

3. Drugs in clinical development

4. Institute for Cancer Research Industry Cost of a Successfully Developed New Molecule $137 $319 $445 $802 $1,300 $0 $200 $400 $600 $800 $1,000 $1,200 $1,400 19761988199220002010 Millions of $ Includes cost of 90% failures…

5. Institute for Cancer Research Historically: Statistical significance but marginal clinical benefit Years of enrollment...

6. Institute for Cancer Research Main Challenges in Drug Development 1.Insufficient patient benefit 2.Long time line until patient access 3.High failure rate 4.Unsustainable cost Major Opportunities & Changes in the ”Era of Personalized Medicine”

7. Institute for Cancer Research Main Challenges 1.Insufficient patient benefit 2.High failure rate 3.Long time line 4.Unsustainable cost Responses 1. Targeted attack on tumour driving abnormalities

9. PI3K Targeted attack on key cell signalling abnormalities in the tumour at hand…. 1. Single drug and combinations EGFR Institute for Cancer Research

10. PI3K Sosman et al., N Engl J Med 2012; 366:707-714 Institute for Cancer Research

11. Selectively attacking the sustained driving abnormality: The imatinib - KIT example in GIST Survival

12. Institute for Cancer Research Main Challenges 1.Insufficient patient benefit 2.High failure rate 3.Long time line 4.Unsustainable cost Responses 1. Targeted attack on tumour driving abnormalities 2. Biologically based approach with ↑ efficacy and ↓ toxicity 3. 4. Survival

13. Institute for Cancer Research Paradigm shift away from general mechanisms of action: Narrow therapeutic window with effects on tumour and normal tissues..

14. Institute for Cancer Research Main Challenges 1.Insufficient patient benefit 2.High failure rate 3.Long time line 4.Unsustainable cost Responses 1. Targeted attack on tumour driving abnormalities 2. Biologically based approach 3. Novel study designs with need for fewer patients 4.

15. Institute for Cancer Research From: Phase I Safety No efficacy Phase II Single arm Efficacy Phase III Large random. Benchmark Registration Phase IV Pharmaco-vigilance Cost benefit Optional To: Approval (high failure rate) (Conditional) Approval (Approval re-assessment) (Approval re-assessment) (Conditional) Approval Phase I Safety Efficacy signal Biomarker research Randomized Phase II Low patient number Efficacy verification Biomarker verification Phase III Low patient no. Confirmatory Phase IV Long term safety May be conditional Phase I expansion Dose/schedule refinement Efficacy Biomarker refinement Changes in Study Design & Conduct

16. Institute for Cancer Research Hamid et al., N Eng J Med 2013 Accelerated FDA approval on expanded Phase I: Pembrolizumab in advanced melanoma Sept. 2014 Keynote 001 Ph. I study activated Feb. 2011

17. BATTLE 2: Adaptive randomized design for NSCLC who have failed at least one front-line chemotherapy regimen Primary Endpoint: 8-week Disease Control Continue on study if stable or response.. If progression, subject has option of re- enrolling into BATTLE-2 program * EGFR Mut + EML4-ALK + Excluded Biopsy performed. Biomarker profile obtained Adaptive Randomization (AR) Subject assigned to one of the treatment arms based on K-Ras mutational status Statistical Modeling and Biomarker Selection Refined AR based on CLIA certified markers (n=4-6) STAGE 1 N=200 STAGE 2 N=200 ErlotinibErlotinib + AKTi MEKi + AKTI SORAFENIB ErlotinibErlotinib + AKTi MEKi + AKTI SORAFENIB

18. Institute for Cancer Research Some other traits in drug development...

19. PARP mTOR BRAF

20. Need for combinations: Pharma-Pharma collaboration PI3K Institute for Cancer Research EGFR

21. Institute for Cancer Research Big Pharma Pharma downscaling discovery and early research Essential need for aquisitions & joint ventures with Biotech Happens later in development path to reduce risk Drug development path more dependent on venture capital Higher dependence on academic input & collaboration

22. Institute for Cancer Research “Preferred Academic Partners”

23. Institute for Cancer Research

24. Main Challenges 1.Insufficient patient benefit 2.High failure rate 3.Long time line 4.Unsustainable cost Responses 1. Targeted attack on tumour driving abnormalities 2. Biologically based approach 3. Novel study designs with fewer patients 4. All of the above

25. Leonard Saltz, 2015 ASCO ? Courtesy of S. Aamdal