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Forging a new standard in metastatic CRC

Forging a new standard in metastatic CRC. Eric Van Cutsem University Hospital Gasthuisberg Leuven, Belgium. Advances in the treatment of mCRC. 1980 1985 1990 1995 2000 2005 2010. Best supportive care. 5-FU.

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Forging a new standard in metastatic CRC

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  1. Forging a new standard in metastatic CRC Eric Van Cutsem University Hospital GasthuisbergLeuven, Belgium

  2. Advances in the treatment of mCRC 1980 1985 1990 1995 2000 2005 2010 Best supportive care 5-FU Irinotecan Capecitabine 35 30 25 20 15 10 5 0 Oxaliplatin Bevacizumab and EGFR inhibitors Months Median OS 1980 1985 1990 1995 2000 2005+ mCRC = metastatic colorectal cancer; 5-FU = 5-fluorouracil; MoAbs = monoclonal antibodies; OS = overall survival

  3. Capecitabine combinations are effective in the metastatic setting • CAPOX: capecitabine 1,000mg/m2 b.i.d. day 1–14 plus oxaliplatin 70mg/m2 day 1, 8 every 3 weeks • CAPIRI: capecitabine 1,000mg/m2 b.i.d. day 1–14 plus irinotecan 80–100mg/m2 day 1, 8 every 3 weeks ORR = overall response ratePFS = progression-free survivalb.i.d. = twice daily Grothey A, et al. J Clin Oncol 2004;22:254 (Abstract 3534)

  4. Efficacy of capecitabine versus 5-FU/LV:meta-analysis of survival in six clinical trials Capecitabine is therapeutically noninferior to 5-FU/LVin patients with colorectal or gastric cancer Cassidy J, et al. Presented at ASCO GI 2008 (Abstract 340) CI = confidence interval

  5. Bevacizumab adds strong benefit to all regimens 5-FU/LV PFS + bevacizumab OS IFL + bevacizumab FOLFOX + bevacizumab FOLFIRI + bevacizumab FOLFOX/FOLFIRI + bevacizumab 0 5 10 15 20 25 30 Months LV = leucovorin; IFL = irinotecan, 5-FU, leucovorin; FOLFOX = leucovorin, 5-FU, oxaliplatinFOLFIRI = leucovorin, 5-FU, irinotecan

  6. Linking the mechanism of action of bevacizumab with clinical benefit in mCRC EARLY EFFECTS CONTINUED EFFECTS Regression Normalisation Inhibition 1 2 3 Decrease tumour size Improve delivery of chemotherapy Suppress new vessel growth Suppress regrowth via vessel ‘scaffolds’ Enable metastasectomy Increase PFS Increase OS

  7. Irinotecan-containing regimens with bevacizumab and/or capecitabine

  8. AVF2107g: bevacizumab plus first-line IFL: superior PFS plus OS Median OS 15.6 vs 20.3 months HR=0.66 (p<0.001) Median PFS6.2 vs 10.6 monthsHR=0.54 (p<0.0001) 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 IFL + bevacizumab IFL + placebo IFL + bevacizumab IFL + placebo PFS estimate OS estimate 6.2 10.6 15.6 20.3 0 10 20 30 0 10 20 30 40 Months Months Hurwitz H, et al. N Engl J Med 2004;350:2335–42

  9. Bevacizumab plus FOLFIRI has been evaluated in several phase II trials 1Fuchs CS, et al. J Clin Oncol 2007;25:4779–862Samelis GF, et al. ASCO GI Cancers Symposium 2007 (Abstract 394) 3Kopetz S, et al. ASCO GI Cancers Symposium 2007 (Abstract 4089) mIFL = irinotecan, 5-FU, leucovorin

  10. Phase IV trial of bevacizumab plus FOLFIRI (AVIRI): study design • The largest trial of bevacizumab plus FOLFIRI • International multicentre trial: 31 centres • Primary endpoint: PFS • Secondary endpoints: OS, ORR and safety • Treatment until progression or unacceptable toxicity Patients with previously untreated, unresectable mCRC(n=209) Bevacizumab + FOLFIRI Ackland S, et al. Presented at ASCO GI 2008 (Abstract 463)

  11. AVIRI: efficacy summary(ITT population) Median PFS and OS is comparable to that observed with bevacizumab plus IFL in the pivotal AVF2107g trial ITT = intent to treat Ackland S, et al. Presented at ASCO GI 2008 (Abstract 463)

  12. AVIRI: safety summary The safety profile of bevacizumab plus FOLFIRI is consistent with that reported for bevacizumab plus other standard chemotherapy regimens Ackland S, et al. Presented at ASCO GI 2008 (Abstract 463)

  13. BICC-C: bevacizumab plus irinotecan-based chemotherapy Initial design Amended design Bevacizumab + FOLFIRI (n=60) FOLFIRI(n=144) Bevacizumab + mIFL (n=57) mIFL(n=141) R R n=430 n=117 Protocol amended due to approval of bevacizumab CAPIRI(n=145) Primary endpoint: PFS Fuchs CS, et al. J Clin Oncol 2007;25:4779–86

  14. BICC-C: bevacizumab plus irinotecan-based chemotherapy – efficacy • Preliminary data suggest that FOLFIRI plus bevacizumab has superior efficacy to mIFL plus bevacizumab • results are comparable to those reported in AVF2107g Fuchs CS, et al. J Clin Oncol 2007;25:4779–86Fuchs CS, et al. J Clin Oncol 2007;26:689–90

  15. Bevacizumab plus FOLFIRI in first-line mCRC: impact on PFS FOLFIRI n=109 n=504 FOLFIRI + bevacizumab n=280 FOLFIRI + bevacizumab n=209 FOLFIRI + bevacizumab n=41 FOLFIRI + bevacizumab n=57 FOLFIRI + bevacizumab 0 2.5 5.0 7.5 10.0 12.5 15.0 Months Tournigand C, et al. J Clin Oncol 2004;22:229–37 Berry S, Van Cutsem E, et al. Eur J Cancer Suppl 2007;5:241 (Abstract P#3020) Kozloff M, et al. Presented at ASCO GI 2007 (Abstract 375) Sobrero A, et al. Eur J Cancer Suppl 2007;5:254 (Abstract P#3060)Kopetz S, et al. Presented at ASCO GI 2007 (Abstract 4089)Fuchs CS, et al. J Clin Oncol 2007;25:4779–86

  16. Oxaliplatin-containing regimens with bevacizumab and/or capecitabine

  17. E3200: bevacizumab second line: superior PFS plus OS with FOLFOX4 Median OS10.8 vs 12.9 months HR=0.75 (p=0.0011) Median PFS 4.7 vs 7.3 months HR=0.61 (p<0.0001) 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 FOLFOX4 + bevacizumab FOLFOX4 FOLFOX4 + bevacizumab FOLFOX4 PFS estimate OS estimate 4.7 7.3 10.8 12.9 0 3 6 9 12 15 18 21 24 27 30 33 36 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Months Months Giantonio BJ, et al. J Clin Oncol 2007;25:1539–44

  18. CAPOX is equivalent to FOLFOXin phase II/III studies ORR (%) PFS (months) OS (months) 1Porschen R, et al. J Clin Oncol 2007;25:4217–23; 2Díaz-Rubio E, et al. J Clin Oncol 2007;25:4224–30; 3Ducreux M, et al. J Clin Oncol 2007;25(Suppl. 18):170s (Abstract 4029)4Cassidy J, et al. ASCO GI 2007 (Abstract 270); 5Cassidy J, et al. J Clin Oncol 2007;25(Suppl. 18) (Abstract 4030); 6Rothenberg ML, et al. J Clin Oncol 2007;25(Suppl. 18):171s (Abstract 4031); 7Comella P, et al. Presented at ASCO GI 2008 (Abstract 344)

  19. Phase II trial of first-line bevacizumab plus CAPIRI or CAPOX (AIO): study design • Treatment (3-week cycle) • patients in arm A receive bevacizumab 7.5mg/kg (day 1) plus oxaliplatin 130mg/m2 (day 1) and capecitabine 1,000mg/m2 (b.i.d. day 1–14) • patients in arm B receive bevacizumab 7.5mg/kg (day 1) plus irinotecan 200mg/m2 (day 1) and capecitabine 800mg/m2 (b.i.d. day 1–14) CAPOX + bevacizumab 7.5mg/kg every 3 weeks PD or toxicity Previously untreated mCRC (n=255) CAPIRI + bevacizumab 7.5mg/kg every 3 weeks PD or toxicity Schmiegel WH, et al. J Clin Oncol 2007;25(Suppl. 18):172s (Abstract 4034) PD = progressive disease

  20. Phase II trial of first-line bevacizumab plus CAPIRI or CAPOX (AIO): efficacy Schmiegel WH, et al. J Clin Oncol 2007;25 (Suppl. 18):172s (Abstract 4034)

  21. Phase II trial of first-line bevacizumab plus CAPIRI or CAPOX (AIO): safety • CAPIRI and CAPOX have similar safety when combined with bevacizumab Schmiegel WH, et al. J Clin Oncol 2007;25 (Suppl. 18):172s (Abstract 4034)

  22. Phase III trial of CAPOX/FOLFOX4 ± bevacizumab (NO16966): study design RecruitmentJune 2003 – May 2004 RecruitmentFebruary 2004 – February 2005 • Primary endpoints • at least equivalent PFS with CAPOX versus FOLFOX4 • superior PFS with bevacizumab plus CAPOX/FOLFOX4 versus CAPOX/FOLFOX4 CAPOX (n=317) CAPOX +placebo (n=350) CAPOX + bevacizumab (n=350) FOLFOX4 (n=317) FOLFOX4 +placebo (n=351) FOLFOX4 + bevacizumab (n=349) Initial two-arm open-label study(n=1,000) Protocol amended to 2 x 2 placebo-controlled design after bevacizumab phase III data became available (n=1,400) Saltz L, et al. J Clin Oncol 2007;25 (Suppl. 18):170s (Abstract 4028)

  23. NO16966: PFS – chemotherapy plus bevacizumab (general and on-treatment populations) 1.0 0.8 0.6 0.4 0.2 0 FOLFOX4 or CAPOX + bevacizumab FOLFOX4 or CAPOX + placebo On treatment: HR=0.63 (97.5% CI: 0.52–0.75) p<0.0001 PFS estimate General: HR=0.83 (97.5% CI: 0.72–0.95) p=0.0023 0 5 10 15 20 PFS (months) • Bevacizumab-containing arm: separation occurs between the PFS for general versus on-treatment populations after 6 months (vertical arrow) Saltz L, et al. J Clin Oncol 2007;25(Suppl. 18):170s (Abstract 4028)

  24. NO16966: bevacizumab first-line – PFS plus OS with CAPOX/FOLFOX4 Median PFS8.0 vs 9.4 months HR=0.83 (p=0.023) Median OS 19.9 vs 21.2 months HR=0.89 (p=0.0769) 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 CAPOX/FOLFOX4 + bevacizumab CAPOX/FOLFOX4 + placebo CAPOX/FOLFOX4 + bevacizumab CAPOX/FOLFOX4 + placebo PFS estimate OS estimate 8.0 9.4 19.9 21.2 0 5 10 15 20 25 0 6 12 18 24 30 36 Months Months Saltz L, et al. Proc World Congress on Gastrointestinal Cancer 2007 (Abstract O-0032)

  25. NO16966: efficacy results for superiority – major points • Bevacizumab provides significant/superior PFS when added to oxaliplatin-based chemotherapy regimens • Treatment until progression is crucial to demonstrate full potential of bevacizumab • Analyses of withdrawal data and PFS on treatment show excellent efficacy for bevacizumab • IRC analysis clearly demonstrates superior PFS for bevacizumab in all treatment groups IRC = independent review committee

  26. NO16966: bevacizumab is well toleratedwhen combined with oxaliplatin- or capecitabine-based regimens Saltz L, et al. J Clin Oncol 2007;25 (Suppl. 18):170s (Abstract 4028)

  27. Bevacizumab in the clinical setting Data from BEAT and BRiTE

  28. Bevacizumab plus first-line chemotherapy in clinical practice: BEAT and BRiTE BEAT1 Patients with previously untreated, unresectable mCRC (n=1,914) Bevacizumab + chemotherapy PD BRiTE2 Patients with previously untreated, unresectable mCRC (n=1,953) Bevacizumab + chemotherapy PD 1Berry S, Van Cutsem E, et al. Eur J Cancer Suppl 2007;5:241 (Abstract P#3020)2Grothey A, et al. J Clin Oncol 2007;25(Suppl. 18):172s (Abstract 4036)

  29. BEAT BRiTE Bevacizumab adds clinical benefit when combined with chemotherapy: BEAT and BRiTE n=1,914 n=1,953 n=503 n=280 n=552 n=1,092 n=346 n=94 0 2.5 5.0 7.5 10.0 PFS (months) Berry S, Van Cutsem E, et al. Presented at ASCO GI 2008 (Abstract 350) Kozloff M, et al. Presented at ASCO GI 2007 (Abstract 375)

  30. BRiTE and BEAT: serious AEs of special interest to bevacizumab *Grade 3/4 • No new safety concerns for bevacizumab therapyhave been identified 1Grothey A, et al. J Clin Oncol 2007;25(Suppl. 18):172s (Abstract 4036) 2Kretzschmar A, Van Cutsem E, et al. J Clin Oncol 2007;25(Suppl. 18): 181s (Abstract 4072) NR = no response

  31. BRiTE: bevacizumab increases survival post first progression Post-progression therapy: 1.0 0.8 0.6 0.4 0.2 0 Bevacizumab post PD (n=642) No bevacizumab post PD (n=531) No treatment (n=253) OS estimate Post-progressionbevacizumabHR=0.48 (0.41–0.57) p<0.001 12.6 19.9 31.8 0 5 10 15 20 25 30 35 Months Grothey A, et al. J Clin Oncol 2007;25(Suppl. 18):172s (Abstract 4036)

  32. Withdrawal of anti-VEGF therapyresults in vessel regrowth CD31 Untreated AG-013736, 7 days Withdrawal, 2 d Withdrawal, 7 d RIP-Tag2 Continue anti-angiogenic therapy to avoid vessel regrowth Mancuso MR, et al. J Clin Invest 2006;116:2610–21 VEGF = vascular endothelial growth factor

  33. Bevacizumab in the neoadjuvant setting

  34. Potential use of neoadjuvant bevacizumab Bevacizumab improves outcomes and has potential to increase metastasectomy rates Studies includingselected patients(liver metastases only, no extrahepatic disease) (r=0.96, p=0.002) 0.6 0.5 0.4 0.3 0.2 0.1 0 Studies including all patients with mCRC (solid line) (r=0.74, p<0.001) Resection rate Phase III studies including all patients in mCRC (dashed line) (r=0.67, p=0.024) 0.3 0.4 0.5 0.6 0.7 0.8 0.9 Response rate Folprecht G, et al. Ann Oncol 2005;16:1311–9

  35. Potential use of neoadjuvant bevacizumab (cont’d) • Impaired wound healing and liver regeneration have been associated with anti-VEGF therapies • Using bevacizumab in patients who may become eligible for surgery raises the question of scheduling/best practice

  36. Retrospective analysis of 1,186 patients with mCRC Bevacizumab in mCRC patients undergoing metastasectomy: retrospective analysis Bevacizumab does not increase the risk of postoperative complications in patients undergoing metastasectomy with curative intent Kesmodel SV, et al. Presented at ASCO GI 2007 (Abstract 234)

  37. Hepatic metastectomy* Hepatic metastectomy withno residual disease (R0)** BEAT: surgery with curative intent Overall population: rates of potentiallycurative hepatic metastectomy Patients with liver metastases only: rates of potentially curative hepatic metastectomy 20.3 10 5 0 20 15 10 5 0 9.6 15.4 15.2 7.3 14.3 7.0 6.2 12.1 11.7 5.6 5.3 Patients (%) Patients (%) n=107 n=99 n=145 n=76 n=114 n=33 n=54 n=85 n=71 n=34 n=43 n=27 Bevacizumab + chemo. (all) Bevacizumab + chemo. including oxaliplatin Bevacizumab + chemo. including irinotecan Bevacizumab + chemo. (all) Bevacizumab + chemo. including oxaliplatin Bevacizumab + chemo. including irinotecan (n=1,914) (n=704) (n=946) (n=662) (n=349) (n=230) *Secondary endpoint; **Prospectively assessedUpdated data will be presented at the meeting Berry S, Van Cutsem E, et al. Eur J Cancer Suppl. 2007;5:241 (Abstract P#3020)

  38. NO16966: surgery with curative intent CAPOX/FOLFOX4 + placebo CAPOX/FOLFOX4 + bevacizumab ITT population Patients with liver metastases only 19.2 10 5 0 20 15 10 5 0 8.4 12.9 6.1 Patients (%) Patients (%) Placebo Bevacizumab (n=701) (n=699) Placebo Bevacizumab (n=178) (n=177) Saltz L, et al. Proc World Congress on Gastrointestinal Cancer 2007 (Abstract O-0032)

  39. Neoadjuvant bevacizumab in patients with CRC: single-centre, non-randomised trial – postoperative liver function and regeneration Initial resection site Full transverse image Postoperative liver function and regeneration, assessed 3 months after surgery by chemotherapy, normal in all but one patient Gruenberger T, et al. Ann Oncol 2006;17(Suppl. 9)ix128 (Abstract 374P) Gruenberger T, et al. Eur J Cancer Supp. 2007;5:255 (Abstract P#3064)

  40. Surgery with curative intent in patients receiving bevacizumab is feasible • With appropriate management, bevacizumab can be usedin combination with chemotherapy with minimal risk of bleeding/wound-healing complications in patients with mCRC undergoing resection of metastases • Data suggest that bevacizumab can be administered until5 weeks prior to liver resection without any wound healing/bleeding complications • Liver generation following resection does not appear to be affected in patients receiving bevacizumab in combination with chemotherapy

  41. EORTC GI Group Guidelines FOLFOX/CAPOX + bevacizumab* FOLFIRI Irinotecan + cetuximab Irinotecan + cetuximab FOLFOX/CAPOX FOLFIRI + bevacizumab* mCRC Irinotecan + cetuximab FOLFOX/CAPOX Capecitabine (5-FU/LV) ± bevacizumab* FOLFOX/CAPOX FOLFIRI *If no cardiovascular contraindicationsEORTC = European Organisation for Research and Treatment of Cancer

  42. Key bevacizumab trials in mCRC 1Sobrero A, et al. Eur J Cancer Suppl 2007;5:254 (Abstract P#3060)2Saltz L, et al. J Clin Oncol 2007;25(Suppl. 18):170s (Abstract 4028) 3Berry S, Van Cutsem E, et al. Eur J Cancer Suppl 2007;5:241 (Abstract P#3020) 4Grothey A, et al. J Clin Oncol 2007;25(Suppl. 18):172s (Abstract 4036)

  43. Key capecitabine trials in mCRC 1 Saltz L, et al. J Clin Oncol 2007;25(Suppl. 18):170s (Abstract 4028) 2Rothenberg ML, et al.J Clin Oncol 2007;25(Suppl. 18):171s (Abstract 4031) 3Ducreux M, et al. J Clin Oncol 2007;25(Suppl. 18):170s (Abstract 4029)4Comella P, et al. Eur J Cancer Suppl 5:248 (Abstract P#3044)

  44. Conclusions • Bevacizumab combined with standard therapies is an effective first-line treatment strategy for mCRC • Bevacizumab is generally well tolerated • Efficacy and safety outcomes in clinical evaluation studies are similar to those reported in clinical trials • Capecitabine is effectively replacing 5-FU in mCRC • Data suggest that metastasectomy is feasible in patients with mCRC treated with bevacizumab plus chemotherapy

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