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Chemotherapy for advanced disease  including biological therapies David Sebag-Montefiore Professor of Clinical Oncology St...
Disclosures <ul><li>Last 5 years </li></ul><ul><li>No advisory boards </li></ul><ul><li>No research funding from pharma </...
This lecture does NOT …… <ul><li>Present comprehensive data of all trials on a specific subject </li></ul><ul><li>Make rec...
Translating the acronyms! <ul><li>Monotherapy </li></ul><ul><ul><li>5FU/LV, Capecitabine, UFT/LV, S1 </li></ul></ul><ul><l...
Correlation between overall survival and exposure to three drugs  Grothey et al 2005 JCO Caveat – median age around 65 and...
Summary of the “three drugs” – broad generalisations <ul><li>Fluropyrimidine platform </li></ul><ul><ul><li>Infusional 5FU...
FOCUS trial – 2135 patients Seymour et al Lancet 2007 <ul><li>Adding a second drug to 5FU in first-line gives: </li></ul><...
FOCUS Trial Seymour et al Lancet 2007
FOCUS Trial – Overall Survival Seymour et al Lancet 2007 sequential single agents single agent then combination combinatio...
VEGF – Bevacizumab data Two key first line trials
IFL +/- Bevacizumab in first line Hurwitz et al 2004
XELOX/FOLFOX +/- Bev Saltz and Cassidy 2008 JCO
Bevacizumab <ul><li>Improves PFS and OS in first line </li></ul><ul><li>Relatively low toxicity </li></ul><ul><li>Not usef...
EGFR target -  Cetuximab and panitumimab data
EGFr pathway ras raf MEK ERK PI3K AKT PTE N Myc SMAD p53 Jun EGFr cetuximab panitumumab
<ul><li>1 st -line, IrFU ± Cetuximab  n=1217  Van Cutsem  </li></ul><ul><ul><li>Wild type PFS and OS advantage </li></ul><...
<ul><li>1 st -line, IrFU ± Cetuximab  n=1217  Van Cutsem  DATE </li></ul><ul><ul><li>Wild type PFS and OS advantage </li><...
<ul><li>1 st -line OxFU ±Cetuximab n=337 Bokemeyer 2007 </li></ul><ul><ul><li>Wild type PFS and RR benefit </li></ul></ul>...
<ul><li>1 st -line OxFU ±Cetuximab n=337 Bokemeyer 2007 </li></ul><ul><ul><li>Wild type PFS and RR benefit </li></ul></ul>...
Supportive Care +/- EGFr  KRAS -wt KRAS -mut KRAS -wt KRAS -mut Panitumumab +BSC BSC alone P’mab + BSC BSC alone KRAS -wt:...
Personalised medicine?
Predictive marker study: benefit from irinotecan or oxaliplatin <ul><li>Approach: </li></ul><ul><ul><li>Screen:  11 candid...
Candidate makers of benefit from irinotecan or oxaliplatin <ul><li>Tumour Immunohistochemistry: </li></ul><ul><ul><li>Topo...
Results: screen stage <ul><li>Topo1 </li></ul><ul><ul><li>no/low expression in 47% patients </li></ul></ul><ul><ul><ul><li...
Topo1:  second stage  DFS analysis  (n=1279) Topo1 score n Hazard Ratio for PFS (95% c.i.) p-value for interaction FU (ref...
Topo1:  second stage  OS analysis  (n=1279) Topo1 score n Hazard Ratio for survival (95% c.i.) p-value for interact n Sequ...
Topo1:  second stage  OS analysis  (n=1279) Sequential therapy starting with FU alone First-line combination with FU/Ir or...
Topo1 – hypotheses: <ul><li>Positive predictor: increased expression correlates with benefit from adding irinotecan/oxalip...
The next step: FOCUS-3 <ul><li>Hypotheses: </li></ul><ul><ul><li>Topo1 : predicts benefit from irinotecan and oxaliplatin ...
patient first approached about trial consent to send tumour block for testing FFPE block to Lab 1: rapid  KRAS  sequence r...
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: remo...
Conclusions <ul><li>All Fit patients with good performance status should be considered for three drugs </li></ul><ul><li>B...
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MCC 2011 - Slide 29

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Transcript of "MCC 2011 - Slide 29"

  1. 1. Chemotherapy for advanced disease including biological therapies David Sebag-Montefiore Professor of Clinical Oncology St James’s Institute of Oncology, Leeds
  2. 2. Disclosures <ul><li>Last 5 years </li></ul><ul><li>No advisory boards </li></ul><ul><li>No research funding from pharma </li></ul><ul><li>Conference travel funding </li></ul><ul><ul><li>Pfizer </li></ul></ul><ul><ul><li>Roche </li></ul></ul>
  3. 3. This lecture does NOT …… <ul><li>Present comprehensive data of all trials on a specific subject </li></ul><ul><li>Make recommendations for a specific treatment strategy </li></ul><ul><li>Avoid some bias in presenting some UK data </li></ul>
  4. 4. Translating the acronyms! <ul><li>Monotherapy </li></ul><ul><ul><li>5FU/LV, Capecitabine, UFT/LV, S1 </li></ul></ul><ul><li>Oxaliplatin based regmens (doublet) </li></ul><ul><ul><li>FOLFOX and OxMdG(inf FU/LV+Ox); XELOX (Cape+Ox) </li></ul></ul><ul><li>Irinotecan based regimens (doublet) </li></ul><ul><ul><li>FOLFIRI and Ir MdG (inf 5FU/LV+Ir); Irinotecan alone; (XELIRI) </li></ul></ul><ul><li>Triplet regimens </li></ul><ul><ul><li>FOLFOXIRI (5FU/LV + Ox + Ir) </li></ul></ul><ul><li>Biological therapy </li></ul><ul><ul><li>VEGF target – Bevacizumab </li></ul></ul><ul><ul><li>EGFR – Cetuximab, Panitumimab </li></ul></ul>
  5. 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. 6. Summary of the “three drugs” – broad generalisations <ul><li>Fluropyrimidine platform </li></ul><ul><ul><li>Infusional 5FU / Leucovorin or oral fluoropyrimidine </li></ul></ul><ul><ul><li>Oral vs intravenous – patient choice, toxicity, geography </li></ul></ul><ul><ul><li>Monotherapy suitable choice for some patients </li></ul></ul><ul><li>Oxaliplatin doublet and Irinotecan doublet </li></ul><ul><ul><li>Evidence that supports either sequence </li></ul></ul><ul><li>Triplet (FOLFOXIRI) </li></ul><ul><ul><li>Further evaluation (ph II high response; more toxicity) </li></ul></ul>
  7. 7. FOCUS trial – 2135 patients Seymour et al Lancet 2007 <ul><li>Adding a second drug to 5FU in first-line gives: </li></ul><ul><ul><li>Better response rate and PFS </li></ul></ul><ul><ul><li>More toxicity </li></ul></ul><ul><ul><li>Minimal/no effect on overall survival </li></ul></ul>
  8. 8. FOCUS Trial Seymour et al Lancet 2007
  9. 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. 10. VEGF – Bevacizumab data Two key first line trials
  11. 11. IFL +/- Bevacizumab in first line Hurwitz et al 2004
  12. 12. XELOX/FOLFOX +/- Bev Saltz and Cassidy 2008 JCO
  13. 13. Bevacizumab <ul><li>Improves PFS and OS in first line </li></ul><ul><li>Relatively low toxicity </li></ul><ul><li>Not useful as a single agent </li></ul><ul><li>Duration of therapy? </li></ul><ul><li>Lack of predictive marker </li></ul><ul><li>Expensive – variable funding within healthcare </li></ul>
  14. 14. EGFR target - Cetuximab and panitumimab data
  15. 15. EGFr pathway ras raf MEK ERK PI3K AKT PTE N Myc SMAD p53 Jun EGFr cetuximab panitumumab
  16. 16. <ul><li>1 st -line, IrFU ± Cetuximab n=1217 Van Cutsem </li></ul><ul><ul><li>Wild type PFS and OS advantage </li></ul></ul><ul><ul><li>Mutant no benefit </li></ul></ul><ul><li>1 st -line, IrFU/bev ±Panitumimab n=230 Hecht 2009 </li></ul><ul><ul><li>Wild type worse </li></ul></ul><ul><ul><li>Mutant worse </li></ul></ul><ul><ul><li>Stopped early small numbers no stats </li></ul></ul><ul><li>2 nd -line, IrFU ±Panitumimab n=1186 </li></ul><ul><ul><li>Wild type PFS benefit Peeters 2009 </li></ul></ul><ul><ul><li>Mutant no benefit – definitely not worse </li></ul></ul><ul><li>2 nd -line, irinotecan alone ±Cetuximab Sobrero 2008 </li></ul><ul><ul><li>No Kras analysis Impoved PFS </li></ul></ul>Studies involving irinotecan n=3931 (2347 with KRAS data)
  17. 17. <ul><li>1 st -line, IrFU ± Cetuximab n=1217 Van Cutsem DATE </li></ul><ul><ul><li>Wild type PFS and OS advantage </li></ul></ul><ul><ul><li>Mutant no benefit </li></ul></ul><ul><li>1 st -line, IrFU/bev ±Panitumimab n=230 Hecht 2009 </li></ul><ul><ul><li>Wild type worse </li></ul></ul><ul><ul><li>Mutant worse </li></ul></ul><ul><ul><li>Stopped early small numbers no stats </li></ul></ul><ul><li>2 nd -line, IrFU ±Panitumimab n=1186 </li></ul><ul><ul><li>Wild type PFS benefit Peeters 2009 </li></ul></ul><ul><ul><li>Mutant no benefit – definitely not worse </li></ul></ul><ul><li>2 nd -line, irinotecan alone ±Cetuximab Sobrero 2008 </li></ul><ul><ul><li>No Kras analysis Impoved PFS </li></ul></ul>Studies involving irinotecan n=3931 (2347 with KRAS data)
  18. 18. <ul><li>1 st -line OxFU ±Cetuximab n=337 Bokemeyer 2007 </li></ul><ul><ul><li>Wild type PFS and RR benefit </li></ul></ul><ul><ul><li>Mutant PFS worse </li></ul></ul><ul><li>1 st -line OxFU ±Panitumimab Cassidy 2009 </li></ul><ul><ul><li>Wild type PFS benefit </li></ul></ul><ul><ul><li>Mutant PFS and OS worse </li></ul></ul><ul><li>1 st -line OxCap or OxFU ±Cetuximab Maughan 2009 </li></ul><ul><ul><li>Wild type RR better </li></ul></ul><ul><ul><li>Mutant PFS and OS definitely not worse </li></ul></ul><ul><li>1 st -line, OxFU/bev ± Panitumumab n=823 Hecht 2009 </li></ul><ul><ul><li>Wild type Worse </li></ul></ul><ul><ul><li>Mutant No benefit </li></ul></ul><ul><ul><li>Trial stopped early </li></ul></ul><ul><li>1 st -line, OxCap/bev ± Cetuximab n=755 Tol 2009 </li></ul><ul><ul><li>Wild type Worse </li></ul></ul><ul><ul><li>Mutant Worse </li></ul></ul>Studies involving oxaliplatin n=4717 (3815 with KRAS data)
  19. 19. <ul><li>1 st -line OxFU ±Cetuximab n=337 Bokemeyer 2007 </li></ul><ul><ul><li>Wild type PFS and RR benefit </li></ul></ul><ul><ul><li>Mutant PFS worse </li></ul></ul><ul><li>1 st -line OxFU ±Panitumimab Cassidy 2009 </li></ul><ul><ul><li>Wild type PFS benefit </li></ul></ul><ul><ul><li>Mutant PFS and OS worse </li></ul></ul><ul><li>1 st -line OxCap or OxFU ±Cetuximab Maughan 2009 </li></ul><ul><ul><li>Wild type RR better </li></ul></ul><ul><ul><li>Mutant PFS and OS definitely not worse </li></ul></ul><ul><li>1 st -line, OxFU/bev ± Panitumumab n=823 Hecht 2009 </li></ul><ul><ul><li>Wild type Worse </li></ul></ul><ul><ul><li>Mutant No benefit </li></ul></ul><ul><ul><li>Trial stopped early </li></ul></ul><ul><li>1 st -line, OxCap/bev ± Cetuximab n=755 Tol 2009 </li></ul><ul><ul><li>Wild type Worse </li></ul></ul><ul><ul><li>Mutant Worse </li></ul></ul>Studies involving oxaliplatin n=4717 (3815 with KRAS data)
  20. 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. 21. Personalised medicine?
  22. 22. Predictive marker study: benefit from irinotecan or oxaliplatin <ul><li>Approach: </li></ul><ul><ul><li>Screen: 11 candidates, 750 pts; select if interaction p<0.05 </li></ul></ul><ul><ul><li>Re-test: screen-selected markers, all available samples, p<0.01 </li></ul></ul><ul><ul><li>Survival: evaluated if significant interaction for PFS </li></ul></ul><ul><ul><li>Validation: independently, required if positive interaction seen </li></ul></ul>
  23. 23. Candidate makers of benefit from irinotecan or oxaliplatin <ul><li>Tumour Immunohistochemistry: </li></ul><ul><ul><li>Topo1 (molecular target of irinotecan) </li></ul></ul><ul><ul><li>ERCC1 (nucleotide excision DNA repair) </li></ul></ul><ul><ul><li>MLH1/MSH2 (markers of mismatch repair deficiency) </li></ul></ul><ul><ul><li>COX2 (anti-apoptotic signalling) </li></ul></ul><ul><ul><li>MGMT (involved in repairing alkylated DNA) </li></ul></ul><ul><ul><li>P53 (signalling DNA damage and apoptosis) </li></ul></ul><ul><li>Normal tissue DNA polymorphisms </li></ul><ul><ul><li>UGT1A1 (irinotecan detoxification/clearance) </li></ul></ul><ul><ul><li>ABCB1 (irinotecan biliary clearance) </li></ul></ul><ul><ul><li>XRCC1 (scaffold for base excision repair) </li></ul></ul><ul><ul><li>ERCC2 (nucleotide excision repair) </li></ul></ul><ul><ul><li>GST-P1 (xenobiotic drug detoxification) </li></ul></ul>
  24. 24. Results: screen stage <ul><li>Topo1 </li></ul><ul><ul><li>no/low expression in 47% patients </li></ul></ul><ul><ul><ul><li>better prognosis with 5FU alone </li></ul></ul></ul><ul><ul><ul><li>no benefit from addition of irinotecan or oxaliplatin </li></ul></ul></ul><ul><ul><li>mod/high expression in 53% patients </li></ul></ul><ul><ul><ul><li>worse prognosis with 5FU alone </li></ul></ul></ul><ul><ul><ul><li>major benefit from addition of irinotecan or oxaliplatin </li></ul></ul></ul><ul><ul><li>statistically significant interactions: </li></ul></ul><ul><ul><ul><li>p=0.03 (TTF) </li></ul></ul></ul><ul><ul><ul><li>p=0.0002 (PFS) </li></ul></ul></ul>
  25. 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. 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. 27. Topo1: second stage OS analysis (n=1279) Sequential therapy starting with FU alone First-line combination with FU/Ir or FU/Ox
  28. 28. Topo1 – hypotheses: <ul><li>Positive predictor: increased expression correlates with benefit from adding irinotecan/oxaliplatin to FU </li></ul><ul><li>or alternatively… </li></ul><ul><li>Negative predictor: increased expression correlates with resistance to FU </li></ul>
  29. 29. The next step: FOCUS-3 <ul><li>Hypotheses: </li></ul><ul><ul><li>Topo1 : predicts benefit from irinotecan and oxaliplatin </li></ul></ul><ul><ul><li>KRAS : predicts benefit from anti-EGFR mAbs </li></ul></ul><ul><li>Can patients with low-Topo1 tumours do better if treated without them? </li></ul><ul><li>Can patients with high-Topo1 tumours do better if treated with both? </li></ul><ul><li>Can patients with KRAS-mutated tumours benefit from anti-VEGF mAb? </li></ul><ul><li>Which of the patients with KRAS-w.t. tumours do/do not benefit? </li></ul>
  30. 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. 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. 32. Conclusions <ul><li>All Fit patients with good performance status should be considered for three drugs </li></ul><ul><li>Bevacizumab benefit in first line </li></ul><ul><ul><li>Variation in funding between countries </li></ul></ul><ul><li>Cetuximab and Panitumimab benefit in combination with chemo and monotherapy </li></ul><ul><li>Predictive markers </li></ul><ul><ul><li>Incomplete picture </li></ul></ul><ul><ul><li>Opportunities for marker driven trials </li></ul></ul>

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