1. Chemotherapy for advanced disease including biological therapies David Sebag-Montefiore Professor of Clinical Oncology St James’s Institute of Oncology, Leeds

5. Correlation between overall survival and exposure to three drugs Grothey et al 2005 JCO Caveat – median age around 65 and good performance status

8. FOCUS Trial Seymour et al Lancet 2007

9. FOCUS Trial – Overall Survival Seymour et al Lancet 2007 sequential single agents single agent then combination combination from the start overall survival HR 1.06 (90%CI 0.97-1.17)

10. VEGF – Bevacizumab data Two key first line trials

11. IFL +/- Bevacizumab in first line Hurwitz et al 2004

12. XELOX/FOLFOX +/- Bev Saltz and Cassidy 2008 JCO

14. EGFR target - Cetuximab and panitumimab data

15. EGFr pathway ras raf MEK ERK PI3K AKT PTE N Myc SMAD p53 Jun EGFr cetuximab panitumumab

20. Supportive Care +/- EGFr KRAS -wt KRAS -mut KRAS -wt KRAS -mut Panitumumab +BSC BSC alone P’mab + BSC BSC alone KRAS -wt: benefit KRAS -mut: no benefit

21. Personalised medicine?

25. Topo1: second stage DFS analysis (n=1279) Topo1 score n Hazard Ratio for PFS (95% c.i.) p-value for interaction FU (reference) irinotecan+FU oxaliplatin+FU 1 602 1.0 0.98 (0.78, 1.22) 0.85 (0.68, 1.07) 0.005 (4df) 2 460 1.0 0.64 (0.50, 0.82) 0.70 (0.55, 0.90) 3 217 1.0 0.48 (0.32, 0.72) 0.49 (0.34, 0.71)

26. Topo1: second stage OS analysis (n=1279) Topo1 score n Hazard Ratio for survival (95% c.i.) p-value for interact n Sequential (reference) 1 st -line combination 1 606 1.0 1.1 (0.9-1.3) 0.005 (2df) 2 463 1.0 0.9 (0.8-1.1) 3 219 1.0 0.6 (0.4-0.8)

27. Topo1: second stage OS analysis (n=1279) Sequential therapy starting with FU alone First-line combination with FU/Ir or FU/Ox

30. patient first approached about trial consent to send tumour block for testing FFPE block to Lab 1: rapid KRAS sequence rapid Topo1 immuno Trials Unit randomisation patient gives consent for randomisation Exchange material with sister lab for QC next-level projects: candidate predictive markers; marker discovery; pharmacogenomics, etc clinical outcomes analysis

31. FOCUS-3 randomisation: 1:1:1 Control arm: FU/Ir FU alone FU/Ir + Ox FU/Ir + cetux’mb FU/Ir + bevaciz’mb Topo1 low: remove Ir Topo1 high: add Ox KRAS w.t.: anti-EGFR KRAS mut: anti-VEGF