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

Disclosures Global Director of Scientific Affairs, Merck (MSD) Oncology Institute for Cancer Research

Drugs in clinical development

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, Millions of $ Includes cost of 90% failures…

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

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”

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

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

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

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

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 Survival

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

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.

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

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

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

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

PARP mTOR BRAF

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

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

Institute for Cancer Research “Preferred Academic Partners”

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 fewer patients 4. All of the above

Leonard Saltz, 2015 ASCO ? Courtesy of S. Aamdal