1. European Statistical meeting on Oncology Thursday 24 th, June 2010 Introduction - Challenges in development in Oncology H.U. Burger, Hoffmann-La Roche

2. Some challenges in Oncology Early developments: –Dose determination for safety and/or efficacy –Proof of concept study designs Late development: –PFS versus OS as endpoint –Go-No Go decisions for phase III –Personalized health care strategies

3. Early Developments in Oncology Since about 10 years the paradigm of developing oncology drugs has changed –More and more biological treatments are developed for oncology indications –Targeted therapies play a larger role (pathway and mechanism of actions) –Balance between safety and efficacy more important with more effective treatments available Therefore, aspects which have not been so important in the past become more dominant. This concerns –Proof of concept for biologics or combination regimen –Dose finding using alternative approaches (e.g. model-based approaches)

4. The Classical development paradigm in Oncology Phase I: Dose escalation to define the dose for development as the highest tolerable dose (MTD, 3+3 design classically based on ~ 20 to 40 patients) Phase II: Proof of concept: “One” responder is sufficient to prove anti tumor activity and to move into phase III (based on ~ 40 patients) Phase III: Large randomized clinical trial to confirm efficacy versus standard or in combination with standard versus standard

5. Challenge: Proof of concept Classically, proof of concept for a cytotoxic therapy was based on a single arm monotherapy study in phase II where some tumor responses were sufficient to warrant the compound to go into phase III What triggers today proof of concept ? –For biologics, responses not necessarily expected –For combination therapies, responses can originate from the combination partner => Proof of concept more and more based on randomized studies including time to event endpoints; increasing role of the biomarker data

6. Challenge: Dose finding Dose finding originally based on MTD trials for safety CRM methods introduced with the potential to improve the precision of such studies to determine a dose with a certain toxicity threshold More flexible two-parameter Bayesian logistic models developed to better characterize the dose-toxicity relationship For most of biologic therapies in oncology, maximal tolerated doses become irrelevant as therapeutic effects are already achieved at lower doses  Optimal biologic dose or dose range leading to phase II dose finding studies

7. Late Developments in Oncology Go-No Go decisions become more complex –More sophisticated methods used in early development. Efficacy assessment not based on single responses observed anymore –More competitive environment requiring new risk-benefit assessments Discussion around phase III endpoints never ending story –Overall survival (OS) clinically most relevant but sometimes difficult to observe and frequently leads to long studies –What are suitable surrogate endpoints for OS Response rates ? MRD (minimal residual disease) ? Progression-free survival ?

8. Late Developments in Oncology Targeted therapies: Personalized health care major development challenge in the future Three types of development scenarios –New treatment for all comers –New treatment only for a subset of patient (defined by biomarker) –Right population unknown upfront For last case challenges in development potentially huge

9. Today's Session 08:45-09:15 Registration Chair: Hans-Ulrich Burger (Hoffmann-La Roche) 09:15-09:30Introduction – Challenges in early phase development of Oncology, Hans-Ulrich Burger (Hoffmann-La Roche) 09:30-10:10Understanding Progression-free Survival, Bertil Jonsson, MD (Medical Products Agency) 10:10-10:50IRESSA: A Journey of Experience from Broad to Biomarker Populations, Claire Watkins (AstraZeneca) 10:50-11:15Coffee Chair: Pierre Verweij (Merck and EFSPI) 11:15-11:55Adaptive Bayesian Designs for Phase I Oncology Trials, Stuart Bailey (Novartis) 11:55-12:35Oncology Dose Finding – A Case Study, Jonas Wiedemann (Hoffmann-La Roche)

10. Today's Session 12:35-13:35 Lunch Chair: Nigel Howitt (PRA International and EFSPI) 13:35-14:15Bayesian Hierarchical Modelling of Clinical Response in NSCLC Subpopulations, Simon Wandel (Novartis) 14:15-14:55The Time to Progression Ratio for Phase II Trials of Personalized Medicine, Marc Buyse (IDDI and University of Hasselt) 14:55-15:20Coffee Chair: Hans-Ulrich Burger (Hoffmann-La Roche) 15:20-16:00Optimal Cost-Effective Go-No Go Decisions in Late-Stage Oncology Drug Development, Cong Chen (Merck) 16:00-16:40Panel Discussion