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  • 1. Chemotherapy for advanced disease including biological therapies David Sebag-Montefiore Professor of Clinical Oncology St James’s Institute of Oncology, Leeds
  • 2. Disclosures
    • Last 5 years
    • No advisory boards
    • No research funding from pharma
    • Conference travel funding
      • Pfizer
      • Roche
  • 3. This lecture does NOT ……
    • Present comprehensive data of all trials on a specific subject
    • Make recommendations for a specific treatment strategy
    • Avoid some bias in presenting some UK data
  • 4. Translating the acronyms!
    • Monotherapy
      • 5FU/LV, Capecitabine, UFT/LV, S1
    • Oxaliplatin based regmens (doublet)
      • FOLFOX and OxMdG(inf FU/LV+Ox); XELOX (Cape+Ox)
    • Irinotecan based regimens (doublet)
      • FOLFIRI and Ir MdG (inf 5FU/LV+Ir); Irinotecan alone; (XELIRI)
    • Triplet regimens
      • FOLFOXIRI (5FU/LV + Ox + Ir)
    • Biological therapy
      • VEGF target – Bevacizumab
      • EGFR – Cetuximab, Panitumimab
  • 5. Correlation between overall survival and exposure to three drugs Grothey et al 2005 JCO Caveat – median age around 65 and good performance status
  • 6. Summary of the “three drugs” – broad generalisations
    • Fluropyrimidine platform
      • Infusional 5FU / Leucovorin or oral fluoropyrimidine
      • Oral vs intravenous – patient choice, toxicity, geography
      • Monotherapy suitable choice for some patients
    • Oxaliplatin doublet and Irinotecan doublet
      • Evidence that supports either sequence
    • Triplet (FOLFOXIRI)
      • Further evaluation (ph II high response; more toxicity)
  • 7. FOCUS trial – 2135 patients Seymour et al Lancet 2007
    • Adding a second drug to 5FU in first-line gives:
      • Better response rate and PFS
      • More toxicity
      • Minimal/no effect on overall survival
  • 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
  • 13. Bevacizumab
    • Improves PFS and OS in first line
    • Relatively low toxicity
    • Not useful as a single agent
    • Duration of therapy?
    • Lack of predictive marker
    • Expensive – variable funding within healthcare
  • 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
  • 16.
    • 1 st -line, IrFU ± Cetuximab n=1217 Van Cutsem
      • Wild type PFS and OS advantage
      • Mutant no benefit
    • 1 st -line, IrFU/bev ±Panitumimab n=230 Hecht 2009
      • Wild type worse
      • Mutant worse
      • Stopped early small numbers no stats
    • 2 nd -line, IrFU ±Panitumimab n=1186
      • Wild type PFS benefit Peeters 2009
      • Mutant no benefit – definitely not worse
    • 2 nd -line, irinotecan alone ±Cetuximab Sobrero 2008
      • No Kras analysis Impoved PFS
    Studies involving irinotecan n=3931 (2347 with KRAS data)
  • 17.
    • 1 st -line, IrFU ± Cetuximab n=1217 Van Cutsem DATE
      • Wild type PFS and OS advantage
      • Mutant no benefit
    • 1 st -line, IrFU/bev ±Panitumimab n=230 Hecht 2009
      • Wild type worse
      • Mutant worse
      • Stopped early small numbers no stats
    • 2 nd -line, IrFU ±Panitumimab n=1186
      • Wild type PFS benefit Peeters 2009
      • Mutant no benefit – definitely not worse
    • 2 nd -line, irinotecan alone ±Cetuximab Sobrero 2008
      • No Kras analysis Impoved PFS
    Studies involving irinotecan n=3931 (2347 with KRAS data)
  • 18.
    • 1 st -line OxFU ±Cetuximab n=337 Bokemeyer 2007
      • Wild type PFS and RR benefit
      • Mutant PFS worse
    • 1 st -line OxFU ±Panitumimab Cassidy 2009
      • Wild type PFS benefit
      • Mutant PFS and OS worse
    • 1 st -line OxCap or OxFU ±Cetuximab Maughan 2009
      • Wild type RR better
      • Mutant PFS and OS definitely not worse
    • 1 st -line, OxFU/bev ± Panitumumab n=823 Hecht 2009
      • Wild type Worse
      • Mutant No benefit
      • Trial stopped early
    • 1 st -line, OxCap/bev ± Cetuximab n=755 Tol 2009
      • Wild type Worse
      • Mutant Worse
    Studies involving oxaliplatin n=4717 (3815 with KRAS data)
  • 19.
    • 1 st -line OxFU ±Cetuximab n=337 Bokemeyer 2007
      • Wild type PFS and RR benefit
      • Mutant PFS worse
    • 1 st -line OxFU ±Panitumimab Cassidy 2009
      • Wild type PFS benefit
      • Mutant PFS and OS worse
    • 1 st -line OxCap or OxFU ±Cetuximab Maughan 2009
      • Wild type RR better
      • Mutant PFS and OS definitely not worse
    • 1 st -line, OxFU/bev ± Panitumumab n=823 Hecht 2009
      • Wild type Worse
      • Mutant No benefit
      • Trial stopped early
    • 1 st -line, OxCap/bev ± Cetuximab n=755 Tol 2009
      • Wild type Worse
      • Mutant Worse
    Studies involving oxaliplatin n=4717 (3815 with KRAS data)
  • 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?
  • 22. Predictive marker study: benefit from irinotecan or oxaliplatin
    • Approach:
      • Screen: 11 candidates, 750 pts; select if interaction p<0.05
      • Re-test: screen-selected markers, all available samples, p<0.01
      • Survival: evaluated if significant interaction for PFS
      • Validation: independently, required if positive interaction seen
  • 23. Candidate makers of benefit from irinotecan or oxaliplatin
    • Tumour Immunohistochemistry:
      • Topo1 (molecular target of irinotecan)
      • ERCC1 (nucleotide excision DNA repair)
      • MLH1/MSH2 (markers of mismatch repair deficiency)
      • COX2 (anti-apoptotic signalling)
      • MGMT (involved in repairing alkylated DNA)
      • P53 (signalling DNA damage and apoptosis)
    • Normal tissue DNA polymorphisms
      • UGT1A1 (irinotecan detoxification/clearance)
      • ABCB1 (irinotecan biliary clearance)
      • XRCC1 (scaffold for base excision repair)
      • ERCC2 (nucleotide excision repair)
      • GST-P1 (xenobiotic drug detoxification)
  • 24. Results: screen stage
    • Topo1
      • no/low expression in 47% patients
        • better prognosis with 5FU alone
        • no benefit from addition of irinotecan or oxaliplatin
      • mod/high expression in 53% patients
        • worse prognosis with 5FU alone
        • major benefit from addition of irinotecan or oxaliplatin
      • statistically significant interactions:
        • p=0.03 (TTF)
        • p=0.0002 (PFS)
  • 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
  • 28. Topo1 – hypotheses:
    • Positive predictor: increased expression correlates with benefit from adding irinotecan/oxaliplatin to FU
    • or alternatively…
    • Negative predictor: increased expression correlates with resistance to FU
  • 29. The next step: FOCUS-3
    • Hypotheses:
      • Topo1 : predicts benefit from irinotecan and oxaliplatin
      • KRAS : predicts benefit from anti-EGFR mAbs
    • Can patients with low-Topo1 tumours do better if treated without them?
    • Can patients with high-Topo1 tumours do better if treated with both?
    • Can patients with KRAS-mutated tumours benefit from anti-VEGF mAb?
    • Which of the patients with KRAS-w.t. tumours do/do not benefit?
  • 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
  • 32. Conclusions
    • All Fit patients with good performance status should be considered for three drugs
    • Bevacizumab benefit in first line
      • Variation in funding between countries
    • Cetuximab and Panitumimab benefit in combination with chemo and monotherapy
    • Predictive markers
      • Incomplete picture
      • Opportunities for marker driven trials