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Johanna Bendell, MD Director, GI Oncology Research Associate Director, Drug Development Program

Discussion on Abstracts 362, 363, 364, 365, and 366 or…We still have a lot to learn about colorectal cancer. Johanna Bendell, MD Director, GI Oncology Research Associate Director, Drug Development Program Sarah Cannon Research Institute. Disclosures. I have no relevant disclosures.

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Johanna Bendell, MD Director, GI Oncology Research Associate Director, Drug Development Program

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  1. Discussion on Abstracts 362, 363, 364, 365, and 366or…We still have a lot to learn about colorectal cancer Johanna Bendell, MD Director, GI Oncology Research Associate Director, Drug Development Program Sarah Cannon Research Institute

  2. Disclosures • I have no relevant disclosures

  3. Adjuvant Studies • Abstract #362: AVANT, XELOX-bev vs. FOLFOX-bev vs. FOLFOX alone • Abstract #363: N0147, FOLFIRI +/- cetuximab • Abstract #364: Time to adjuvant chemotherapy

  4. AVANT • Eagerly anticipated given the results of NSABP C-08 • 3451 patients with high-risk stage II or stage III disease • Stage III patient results presented here, 3 year minimum follow up • Primary endpoint of DFS • Well-designed, well-balanced

  5. AVANT Results • DFS (3-year minimum follow-up) • HR FOLFOX-bev 1.17 (0.98,1.39) (73% 3y DFS) • NSABP 74 vs. 72% 3 y DFS for Stage III • HR XELOX-bev 1.07 (0.9,1.28) (75% 3y DFS) • No difference • HR for DFS at year 1, like NSABP C-08, was in favor of bev arms, but disappears after year 1 • Does the DFS at years 2, 2.5, and 3 suggest rebound effect off bev? • Sites of recurrence are similar between arms (no worse in bev arms) • What about survival after recurrence???

  6. AVANT Results • INTERIM OS • HR FOLFOX-bev 1.31 (1.03,1.67) • HR XELOX-bev 1.27 (0.99,1.62) • Are these results suggestive of rebound effect? • Results are not yet mature • Time from recurrence to death • No significant difference between the arms, but FOLFOX patients seem to do a bit better? • BUT – more patients in FOLFOX arm saw bevacizumab after recurrence (35% vs. 16% and 20%) – did this make a difference?

  7. N0147 – The FOLFIRI Arms • Irinotecan-based therapy does not improve survival in the adjuvant setting • PETACC-3, ACCORD2, CALGB 89803 • 3 yr DFS around 60% • CALGB 89803 analysis with no difference in K-ras WT vs. mut • Cetuximab plus FOLFOX does not improve survival in the adjuvant setting • Report on 146 stage III patients treated with FOLFIRI (106) or FOLFIRI-cetuximab (40) • Primary endpoint DFS • Well-balanced • Both arms 65% K-ras WT

  8. N0147 - Results • DFS • Overall (n=146) 3 yr DFS 86.6% vs. 66.7% • FOLFOX 72.3% vs. 75.8% • K-ras WT (n=95) 3 yr DFS 92.3% vs. 69.8% • FOLFOX 72.3% vs. 75.8% • K-ras mut (n=46) 3 yr DFS 82.5% vs. 56.3% • FOLFOX 64.2% vs. 67.2% • OS • Overall (n=146) 3 yr OS 91.8% vs. 84.4% • K-ras WT (n=95) 3 yr OS 92.0% vs. 85.2% • K-ras mut (n=46) 3 yr OS 90.9% vs. 80.6% • DFS data in the control arms look in line with previous irinotecan-based data • K-ras mut patients benefit too? • Small numbers • Is micrometastatic disease different? • Cetuximab-based treatment arms show very different results from previous studies with irinotecan or cetuximab – why???

  9. Irinotecan and Cetuximab – A Story of Synergy • Preclinical • Synergy of EGFR inhibition and DNA damaging agents • Cetuximab suppression of repair after DNA damaging agents1,2,3,4,5 • Cetuximab increases pro-apoptotic molecules and decreases anti-apoptotic molecules, rendering cells more sensitive to cytotoxic chemotherapy6 • Cellular stress increases EGFR pathway activation5 • MDR pathways • Certain MDR1 polymorphisms in the setting of EGFR inhibition decrease SN38 efflux7 • Clinical • Saltz, et al. and BOND 1 • Irinotecan-refractory cancers respond to irinotecan plus cetuximab • First line irinotecan vs. oxaliplatin cetuximab trials • Irinotecan –based therapies seem better • We’ll get to this in a moment… • Huang SM, Canc Res 1999, 2. Buchsbaum DJ, Int J Rad Oncol Biol Phys 2002, 3. Pery D, Cancer Res 1996 • 4. Huang SM, Clin Cancer Res 2000, 5. Koizumi F, Int J Cancer 2004, 6. Ellis LM, J Clin Oncol 2004, 7. Paule B, Med Oncol 2010

  10. Time to Adjuvant Therapy (TTAC)– an Issue in Trial Design and Overall Patient Treatment • Previous adjuvant trials have allowed for patients to start within either 8 weeks (more recent) or 12 weeks postop • Is there a difference in outcomes based on when a patient starts adjuvant therapy? • Review of 9 adjuvant studies that data on waiting time • 8 retrospective, 1 RCT • All 5-FU based chemotherapy only • Each 4 week delay from start of therapy results in a 12% increase in mortality • Implications: • Needs to be controlled in clinical trials • Needs to be encouraged in health systems – importance of coordinated care

  11. Where are we with adjuvant therapy? • Adjuvant bevacizumab: No improvement in DFS or OS • Prolonging bevacizumab therapy might hold down disease for some period of time, but at what cost? • Adjuvant FOLFIRI plus cetuximab may work • Treat patients as quickly as possible after surgery • Should be controlled in clinical trials • Common paradigms do not hold • What works in the metastatic setting does not hold true for the adjuvant setting • Is this a difference in tumor biology? • Where should we go from here? • Adjuvant bevacizumab development should stop for now • Metastatic adjuvant setting? Proof of concept as single agent maintenance rx? • FOLFIRI-cetuximab vs. FOLFOX? • We need new agents • We need biomarkers

  12. Metastatic Studies • Abstract #365: NORDIC VII Study • Abstract #366: AMG 102 or AMG 479 with panitumumab

  13. NORDIC VII • FLOX vs. FLOX-cetuximab vs. Intermittent FLOX with continuous cetuximab • First-line therapy • Primary endpoint PFS • Arms were well-balanced • Previous data of EGFR inhibitors with oxaliplatin-based regimens • In K-ras WT patients, only 2 studies have shown an improvement in PFS (OPUS and PRIME) • In K-ras mut patients, there are trends towards decreased survivals treating patients with anti-EGFR and oxaliplatin-based regimens • Irinotecan-based regimens show stronger data (CRYSTAL)

  14. EGFR Inhibitors in First-Line Therapy - Kras WT patients

  15. NORDIC VII • This trial shows no improvement in outcomes for patients with cetuximab plus oxaliplatin-based therapy • Is this an issue with the chemotherapy or an interaction with oxaliplatin and cetuximab? • Trend towards worse outcomes for cetuximab-treated patients, but numbers are small

  16. One possible reason for oxaliplatin and anti-EGFR negative outcomes Oxaliplatin R R Src activity Src Y Y Signal Transduction EGFR can be activated by Src in the absence of ligand binding EGFR resistance in vitro is mediated by Src Src is acutely and chronically activated by oxaliplatin Combination therapy is synergistic in vitro, in vivo Kopetz GI ESMO 2010 Kopetz, et al Cancer Res 2009, Liu et al Cancer Res 2007

  17. New agents for colorectal cancer patients • Combination therapies • Panitumumab plus AMG 479 (IGF-1R antibody) • Panitumumab plus AMG 102 (HGF antibody) • K-ras WT patients • Refractory to at least one previous chemotherapy and no prior anti-EGFR • Primary endpoint RR • RR better for AMG 102 plus pmab (31% vs. 21%) • IGF-1R plus EGFR inhibitor combinations show no clear signals • Median f/u 6.9 months (still early)

  18. C-met/Hepatocyte Growth Factor Pathway Abouander R, 2004

  19. c-met proof of concept in NSCLC - PFS and OS: Met High Population OS, HR=0.55 PFS, HR=0.56 • MetMAb+Erlotinib improves both PFS and OS in • Met High NSCLC patients Spigel, SCRI, ESMO 2010

  20. c-met proof of concept in NSCLC - PFS and OS: Met Low Population PFS, HR=2.01 OS, HR=3.02 • Met Low NSCLC Patients Do Worse with • MetMAb+Erlotinib Spigel, SCRI, ESMO 2010

  21. We have movement forward… • Targeting of the c-met/HGF pathway in combination with anti-EGFR therapy looks promising for colorectal cancer as well as NSCLC • We await further PFS data • Early look shows 5.2 mo vs. 3.7 mo • Other c-met inhibitors are currently in trial in colorectal cancer patients • Biomarker data will be important in assessing to see if c-met expression in colorectal cancers has same effect on outcomes as NSCLC

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