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A Report from ASCO 2007 First-Line Metastatic Colorectal Cancer

A Report from ASCO 2007 First-Line Metastatic Colorectal Cancer. Edward Chu, MD Professor, Medicine & Pharmacology Chief, Section of Medical Oncology Deputy Director, Yale Cancer Center Yale Cancer Center Yale University School of Medicine New Haven, CT. CRC Treatment Review.

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A Report from ASCO 2007 First-Line Metastatic Colorectal Cancer

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  1. A Report from ASCO 2007First-Line Metastatic Colorectal Cancer Edward Chu, MD Professor, Medicine & Pharmacology Chief, Section of Medical Oncology Deputy Director, Yale Cancer Center Yale Cancer Center Yale University School of Medicine New Haven, CT

  2. CRC Treatment Review • Chemotherapy for advanced disease • Oral vs. IV 5-FU • Sequential vs. combination • Continuous vs. intermittent • Targeted therapies • Anti-angiogenesis inhibitors • Bevacizumab • EGFR inhibitors • Cetuximab

  3. Chemotherapy for Advanced Disease

  4. Abstract 4029 Efficacy and Safety from a Phase III, Randomized Study of Capecitabine plus Oxaliplatin (XELOX) vs. Infusional 5-FU/LV plus Oxaliplatin (FOLFOX6) as First-Line Treatment for Metastatic Colorectal Cancer M. Ducreux, J. Bennouna, M. Hebbar, M. Ychou, G. Lledo, T. Conroy, A. Adenis, R. Faroux, C. Rebischung, J. Douillard

  5. XELOX 8 cycles (N = 156) R A N D O M I ZE Metastatic/advanced colorectal cancer, previously untreated by chemotherapy (N = 306) FOLFOX6 12 cycles (N = 150) Phase III Study of XELOX vs. FOLFOX6as First-Line Treatment of mCRC • Primary Endpoint: Non-inferiority of XELOX to FOLFOX on best RR • Secondary Endpoints: PFS; OS; Safety; QoL; Pharmacoeconomics Ducreux M, et al. ASCO 2007. Abstract #4029.

  6. Phase III Study of XELOX vs. FOLFOX6as First-Line Treatment of mCRCGrade 3/4 Hematologic Toxicity Ducreux M, et al. ASCO 2007. Abstract #4029.

  7. Phase III Study of XELOX vs. FOLFOX6as First-Line Treatment of mCRCClinical Activity Ducreux M, et al. ASCO 2007. Abstract #4029.

  8. Abstracts 4028 and 4030 Bevacizumab in Combination with XELOX or FOLFOX4: Updated Efficacy Results from XELOX-1/NO16966, a Randomized Phase III Trial in First-Line Metastatic Colorectal Cancer Abstract 4028: L. Saltz et al. Abstract 4030: J. Cassidy et al.

  9. Phase III NO16966 Trial: XELOX ± Bevacizumab vs. FOLFOX4 ± Bevacizumab RecruitmentJune 2003 – May 2004 RecruitmentFeb 2004 – Feb 2005 XELOX (N = 317) XELOX + Placebo (N = 350) XELOX + Bevacizumab (N = 350) FOLFOX4 (N = 317) FOLFOX4 + Placebo (N = 351) FOLFOX4 + Bevacizumab (N = 350) Initial 2-arm open-label study (N = 634) Protocol amended to 2x2 placebo-controlled design after bevacizumab phase III databecame available (N = 1,401)

  10. Phase III NO16966 Trial: XELOX ± Bevacizumab vs. FOLFOX4 ± BevacizumabStudy Objectives • Main endpoint: progression-free survival (PFS) • Two primary objectives • XELOX is non-inferior to FOLFOX • Bevacizumab + chemotherapy is superior to placebo + chemotherapy Saltz L, et al. ASCO 2007. Abstract #4028. Cassidy J, et al. ASCO 2007. Abstract #4030.

  11. 1.0 0.8 0.6 0.4 0.2 0 HR = 0.96 [97.5% CI: 0.80–1.16] (ITT) HR = 0.98 [97.5% CI: 0.81–1.18] (EPP) Survival FOLFOX N = 317; 294 events XELOX N = 317; 285 events 7.3 7.7 0 5 10 15 20 25 30 Months XELOX vs. FOLFOX: PFS 2-Arm Study Only (ITT) Saltz L, et al. ASCO 2007. Abstract #4028. Cassidy J, et al. ASCO 2007. Abstract #4030.

  12. 1.0 0.8 0.6 0.4 0.2 0 HR = 1.01 [97.5% CI: 0.83–1.23] (ITT) HR = 1.04 [97.5% CI: 0.84–1.27] (EPP) PFS Estimate 9.3 9.4 0 5 10 15 20 25 Months FOLFOX + bevacizumab N = 349; 255 events XELOX + bevacizumab N = 350; 258 events XELOX/BV vs. FOLFOX/BV: PFS(ITT) Saltz L, et al. ASCO 2007. Abstract #4028. Cassidy J, et al. ASCO 2007. Abstract #4030.

  13. FOLFOX vs. XELOX: Safety Profile Saltz L, et al. ASCO 2007. Abstract #4028. Cassidy J, et al. ASCO 2007. Abstract #4030.

  14. XELOX vs. FOLFOX: Conclusions • XELOX and FOLFOX are equivalent in terms of clinical efficacy (RR, PFS, and OS) • Safety profiles of XELOX and FOLFOX are similar • Increased grade 3/4 myelosuppression and neutropenic fever with FOLFOX • Increased incidence of hand-foot syndrome with XELOX • XELOX should be considered a standard treatment option in first-line setting Saltz L, et al. ASCO 2007. Abstract #4028. Cassidy J, et al. ASCO 2007. Abstract #4030.

  15. Capecitabine-Based RegimensIssues to Consider • What is the optimal dose of capecitabine when used in combination with oxaliplatin? • 1,000 mg/m2 bid 2 weeks on / 1 week off • Lower doses, 750-850 mg/m2 bid • Fixed dose • What is the optimal schedule for capecitabine-based regimens? • 2 weeks on / 1 week off (every 3 weeks) • 1 week on / 1 week off (every 2 weeks)

  16. Capecitabine DosingU.S. vs Europe • European trials • Capecitabine 1,000-1,250 mg/m2 bid (d1-14, q3w) • United States trials • Capecitabine 1,250 mg/m2 bid dose too toxic (d1-14, q3w) • 1,000 mg/m2 bid more tolerable, but still toxic • Lower doses more tolerable in U.S. (850 mg/m2 bid) • Reasons for discrepancy? • United States diet fortified with folic acid • Vitamin/nutritional supplements • Folic acid exacerbates capecitabine toxicity • Pharmacogenetic differences in folate metabolism, DPD? • Other?

  17. Abstract 4012 Sequential Compared to Combination Chemotherapy with Capecitabine, Irinotecan, and Oxaliplatin in Advanced Colorectal Cancer: A Dutch Colorectal Caner Group (DCCG) Phase III Study C. J. Punt, M. Koopman, J. Douma, J. Wals, A. H. Honkoop, F. L. Erdkamp, R. S. de Jong, C. J. Rodenburg, L. Mol, N. F. Antonini

  18. CAPIRI (N = 378) CAPOX (N = 213) mCRC No prior therapy (N = 820) Capecitabine (N = 397) Irinotecan (N = 251) CAPOX (N = 143) CAIRO Study Design • Primary Endpoint: Survival • Secondary Endpoints: PFS, RR, Safety, QoL • Sample Size: 1,298 patients in 221 centers Punt CJ, et al. ASCO 2007. Abstract #4012.

  19. CAIRO StudyClinical Efficacy Punt CJ, et al. ASCO 2007. Abstract #4012.

  20. CAIRO StudyConclusions • Median OS equivalent between sequential and combination strategies • Highlights the role of effective salvage treatments in mCRC • Sequential therapy is a reasonable treatment option for patients with mCRC • Consider in good risk patients • Role of biologics in improving clinical efficacy and maintaining safety profile Punt CJ, et al. ASCO 2007. Abstract #4012.

  21. Abstract 4013 Final Results of OPTIMOX2, a Randomized Phase II Study of Maintenance Therapy of Chemotherapy-Free Intervals (CFI) after FOLFOX in Patients with Metastatic Colorectal Cancer F. Maindrault-Goebel, G. Lledo, B. Chibaudel, L. Mineur, T. Andre, M. Bennamoun, M. Mabro, P. Artru, C. Louvet, A. de Gramont

  22. FOLFOX4 R 6x FOLFOX7 → 12x sLV5FU2 → 6xFOLFOX7 620 pts Cum. Oxaliplatin 780 1,560 (%)FOLFOX4FOLFOX7 RR 58.5 58.3 PFS 9.0 8.7 DDC 9.0 10.6 OS 19.3 21.2 G3/4 N-Tox 17.9 13.3 Primary endpoint OPTIMOX1 Study Tournigand et al, JCO 2006.

  23. FOLFOX 4 until TF OPTIMOX1 FOLFOX7 FOLFOX7 sLV5FU2 mFOLFOX7 mFOLFOX7 sLV5FU2 OPTIMOX2 mFOLFOX7 mFOLFOX7 CFI OPTIMOX Studies CFI: Chemotherapy-Free Interval

  24. OPTIMOX2 StudyContinuous vs. Intermittent Chemotherapy • mFOLFOX7: no bolus 5-FU, 100 mg/m2 oxaliplatin • Comparison: maintenance therapy vs. chemotherapy-free intervals (CFI) • Primary endpoint: Duration of disease control (DDC) • Planned trial size, N = 600 • After bevacizumab approved downsized to a randomized phase II trial (N = 200) Maindrault-Goebel F, et al. ASCO 2007. Abstract #4013.

  25. B 400 B 400 600 600 200 200 FOLFOX4 85 B 400 FOLFOX6 2,400-3,000 400 100 FOLFOX7 2,400 400 130 3,000 mFOLFOX7 400 100 FOLFOX Regimens Maindrault-Goebel F, et al. ASCO 2007. Abstract #4013.

  26. OPTIMOX2Clinical Efficacy Maindrault-Goebel F, et al. ASCO 2007. Abstract #4013.

  27. OPTIMOX2Conclusions • Stop-and-go with maintenance is associated with prolonged OS and DDC vs. chemotherapy-free interval • Incidence of grade 3 neurotoxicity similar between 2 arms • Break in chemotherapy not recommended • May consider for patients with “good” tumor biology • Role of biologics in maintenance strategy needs to be explored in phase III trials (Dream Study) Maindrault-Goebel F, et al. ASCO 2007. Abstract #4013.

  28. Targeted TherapyVEGF Inhibitors

  29. Abstracts 4028 and 4030 Bevacizumab in Combination with XELOX or FOLFOX4: Updated Efficacy Results from XELOX-1/NO16966, a Randomized Phase III Trial in First-Line Metastatic Colorectal Cancer Abstract 4028: L. Saltz et al. Abstract 4030: J. Cassidy et al.

  30. Phase III NO16966 Trial: XELOX ± Bevacizumab vs. FOLFOX4 ± Bevacizumab RecruitmentJune 2003 – May 2004 RecruitmentFeb 2004 – Feb 2005 XELOX (N = 317) XELOX + Placebo (N = 350) XELOX + Bevacizumab (N = 350) FOLFOX4 (N = 317) FOLFOX4 + Placebo (N = 351) FOLFOX4 + Bevacizumab (N = 350) Initial 2-arm open-label study (N = 634) Protocol amended to 2x2 placebo-controlled design after bevacizumab phase III databecame available (N=1,401)

  31. 1.0 0.8 0.6 0.4 0.2 0 HR = 1.01 [97.5% CI: 0.83–1.23] (ITT) HR = 1.04 [97.5% CI: 0.84–1.27] (EPP) PFS Estimate 9.3 9.4 0 5 10 15 20 25 Months FOLFOX + bevacizumab N = 349; 255 events XELOX + bevacizumab N = 350; 258 events XELOX/BV vs. FOLFOX/BV: PFS(ITT) Saltz L, et al. ASCO 2007. Abstract #4028. Cassidy J, et al. ASCO 2007. Abstract #4030.

  32. XELOX vs. FOLFOX4 ± Bevacizumab Safety Profile Saltz L, et al. ASCO 2007. Abstract #4028. Cassidy J, et al. ASCO 2007. Abstract #4030.

  33. 1.0 0.8 0.6 0.4 0.2 0 HR = 0.83 [97.5% CI 0.72–0.95] P = 0.0023 PFS Estimate 8.0 9.4 0 3 6 9 12 15 18 21 Months XELOX + Placebo(X+P) XELOX + Bevacizumab(X+A) VS. FOLFOX-4 + Bevacizumab(F+A) FOLFOX-4 + Placebo(F+P) Effect of Bevacizumab on PFS

  34. 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 PFS Estimate 7.4 9.3 8.6 9.4 0 5 10 15 20 25 Months Months FOLFOX + Placebo N = 351; 277 events FOLFOX + Bevacizumab N = 349; 255 events XELOX + Placebo N = 350; 270 events XELOX + Bevacizumab N = 350; 258 events FOLFOX subgroupHR = 0.89 [97.5% CI 0.73–1.08] (ITT) P = 0.1871 XELOX subgroupHR = 0.77 [97.5% CI 0.63–0.94] (ITT) P = 0.0026 Effect of Bevacizumab on PFS XELOX and FOLFOX Subgroups 0 5 10 15 20 25

  35. Phase III NO16966 TrialConclusions • First study to show that XELOX and FOLFOX regimen are clinically equivalent • Provides first evidence that bevacizumab confers clinical benefit to FOLFOX chemotherapy • Safety profile in line with previous trial results in CRC • Supports the use of bevacizumab in combination with standard first-line chemotherapy Saltz L, et al. ASCO 2007. Abstract #4028. Cassidy J, et al. ASCO 2007. Abstract #4030.

  36. Abstract 4027 Updated Results of BICC-C Study Comparing First-Line Irinotecan/Fluoropymidine Combinations with or without Celecoxib in mCRC C. Fuchs, J. Marshall, E. Mitchell, R. Wierzbicki, V. Ganju, M. Jeffery, J. Schultz, D. A. Richards, R. Soufi-Mahjoubi, J. Barrueco

  37. Original Design (Period 1: 2/03-4/04) ± Celecoxib 400 mg bid ARM A: FOLFIRI RANDOMI ZAT ION Irinotecan 180 mg/m2 D 1 q 2wk 5-FU 400 mg/m2 (bolus) D1 q 2 wk LV 400 mg/m2 D 1 q 2 wk 5-FU 400 mg/m2 bolus/2.4 g/m2 (46 hr infusion) D 1 q 2 wk ± Celecoxib 400 mg bid ARM B: Modified Saltz Irinotecan: 125 mg/m2 5-FU: 500 mg/m2 LV: 20 mg/m2 D 1, 8, q 3 wks ARM C: XELIRI ± Celecoxib 400 mg bid Irinotecan: 250 mg/m2 d1 q 3 wks Capecitabine: 1,000 mg/m2 bid d1-14 q 3 wks N = 1,000 (430) 3 x 2 design Phase III Study of Three Irinotecan Regimens in First-Line mCRC (BICC-C) Fuchs C, et al. ASCO 2007. Abstract #4027.

  38. Amended Design (Period 2: 5/04-12/04) ± Celecoxib 400 mg bid ARM A: FOLFIRI + BV RANDOMI ZAT ION ARM B: Modified Saltz IFL + BV ± Celecoxib 400 mg bid ARM C: XELIRI This arm was discontinued Phase III Study of Three Irinotecan Regimens in First-Line mCRC (BICC-C) N = 1172 x 2 design Fuchs C, et al. ASCO 2007. Abstract #4027.

  39. BICC-C StudyClinical Efficacy Fuchs C, et al. ASCO 2007. Abstract #4027.

  40. BICC StudyUpdate on Clinical Efficacy Barrueco J, et al, ASCO 2007, Abstract #4076.

  41. FOLFIRI + BV vs. FOLFOX + BVClinical Efficacy NO16966 / TREE-2 Trials BICC-C Trial

  42. Bevacizumab TherapyConclusions • Bevacizumab can be safely and effectively used in combination with 5-FU-, irinotecan-, and oxaliplatin-based chemotherapy for the first-line treatment of mCRC • VEGF and the VEGF-signaling pathway are rational targets for anticancer therapy • Agents in clinical development target the VEGF ligand, VEGF receptors, and VEGFR-TK

  43. Bevacizumab Therapy Arterial Thromboembolic Events • Risk factors for arterial thromboembolic events* included: • History of prior arterial thromboembolic events such as stroke or heart attack • Age of 65 years or older *Pooled analysis of 5 randomized trials

  44. BevacizumabRecommendations • Recommended dose is 5 mg/kg every 14 days as an IV infusion until disease progression • Bevacizumab therapy should not be initiated for at least 28 days following surgery • Bevacizumab should be permanently discontinued in patients who develop: • Gastrointestinal perforation • Wound dehiscence requiring medical intervention • Serious bleeding • Nephrotic syndrome • Hypertensive crisis

  45. Bevacizumab TherapyIssues • Should bevacizumab be continued at time of disease progression? • What dose of bevacizumab should be used in second-line and disease refractory setting? • What are the biomarkers of response to bevacizumab therapy?

  46. Targeted TherapyEGFR Inhibitors

  47. Abstract 4000 Randomized Phase III Study of Irinotecan and 5-FU/FA with or without Cetuximab in the First-Line Treatment of Patients with Metastatic Colorectal Cancer (mCRC): The CRYSTAL Trial E. Van Cutsem, M. Nowacki, I. Lang, S. Cascinu, I. Shchepotin, J. Maurel, P. Rougier, D. Cunningham, J. Nippgen, C. Köhne

  48. CRYSTAL TrialStudy Design FOLFIRI q2w mCRC EGFR positive (N = 1,217) PFS FOLFIRI q2w + Cetuximab Primary Endpoint: PFS Secondary Endpoints: ORR, OS, QoL, Safety Van Cutsem E, et al. ASCO 2007. Abstract #4000.

  49. CRYSTAL TrialGrade 3/4 Toxicity Van Cutsem E, et al. ASCO 2007. Abstract #4000.

  50. 1.0 0.9 Cetuximab + FOLFIRI (N = 609) 0.8 FOLFIRI (N = 608) 0.7 HR = 0.851; 95% CI = [0.726-0.998] Log-rank P-value = 0.0479 0.6 0.5 8.9 mos. PFS Estimate 0.4 1-year PFS rate 34% vs. 23% 8.0 mos. 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 Progression-Free Survival (months) CRYSTAL TrialProgression-Free Survival Van Cutsem E, et al. ASCO 2007. Abstract #4000.

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