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For a brighter future: new Xeloda combinations

For a brighter future: new Xeloda combinations. Hans-Joachim Schmoll Martin Luther Universität Halle, Germany. Xeloda: rational partner for novel biological agents in colorectal cancer (CRC). Treatment regimens are becoming increasingly complex

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For a brighter future: new Xeloda combinations

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  1. For a brighter future: new Xeloda combinations Hans-Joachim Schmoll Martin Luther UniversitätHalle, Germany

  2. Xeloda: rational partner for novel biological agents in colorectal cancer (CRC) • Treatment regimens are becoming increasingly complex • including up to three cytotoxic agents and one or more biological agents • Simplified administration of fluoropyrimidines will be important • Xeloda is about to replace i.v. 5-FU/LV as backbone of chemotherapy • at least as effective and safe as i.v. 5-FU/LV • convenient oral agent • simplifies infused fluoropyrimidine-based combination treatment • Preclinical data have shown synergy with Avastin and EGFR inhibitors

  3. Synergistic or additive activity with Xeloda in different preclinical models 1Sawada N et al. Clin Cancer Res 1999;5:2948–53; 2Cassidy J et al. J Clin Oncol 2004;22:2084–91 3Raymond E et al. Anticancer Drugs 1997;8:876–854Tewes M et al. Ann Oncol 2003;14:1442-8; 5Azrak RG et al. Clin Cancer Res 2004;10:1121–36Tanaka Y et al. Proc Am Assoc Cancer Res 2003;44 (Abst 4678) 7Budman DR et al. Breast Cancer Res Treat 2002;76(Suppl. 1):S131 (Abst 521) 8Shen B-Q et al. Proc Am Assoc Cancer Res 2004;45 (Abst 2203); 9Hurwitz H et al. N Engl J Med 2004;350:2335–42

  4. Control Avastin* Xeloda* Avastin* plus Xeloda* Xeloda and Avastin are synergistic in human colon cancer Colo205 xenografts Mean tumor volume (mm3) 2000 1750 1500 1250 1000 750 500 250 0 0 7 14 21 28 35 42 49 56 63 Day *Sub-maximum effective dosesof Xeloda and Avastin used Shen B-Q et al. Proc Am Assoc Cancer Res 2004;45 (Abst 2203)

  5. Xeloda/Avastin: minimal added toxicity in metastatic breast cancer Miller K et al. J Clin Oncol 2005;23:792–9

  6. 30–90 185–395 180–240 Replacing infused 5-FU/LV with Xeloda: less chair time per patient ~3–6 x less 1Köhne CH et al. J Clin Oncol 2003;21:3721–8 2de Gramont A et al. J Clin Oncol 1997;15:808–15 3Van Cutsem E et al. Br J Cancer 2004;90:1190–7 4Kabbinavar F et al. J Clin Oncol 2003;21:60–5

  7. Xeloda plus biological agents in metastatic CRC: randomized trials *Roche registration study

  8. Xeloda plus biological agents in adjuvant CRC: randomized trials *Roche registration study

  9. FOLFOX-Avastin (infusional 5-FU/LV + oxaliplatin + Avastin) RAN D O M I Z A T I O N n=73 bFOL-Avastin(bolus 5-FU/LV + oxaliplatin + Avastin) n=74 n=74 XELOX-Avastin(Xeloda + oxaliplatin + Avastin) TREE-2 randomized phase II study: first-line XELOX + Avastin (n=223) Hochster HS et al. Proc 2005 GI Cancers Symposium 2005;204 (Abst 241)

  10. XELOX-Avastin (n=72) FOLFOX-Avastin (n=71) bFOL-Avastin (n=70) TREE-2: promising response rates with XELOX + Avastin Patients (%) 100 80 60 40 20 0 62 57 43 ORR Hochster HS et al. Proc 2005 GI Cancers Symposium 2005;204 (Abst 241)

  11. XELOX-Avastin (n=72) FOLFOX-Avastin (n=71) bFOL-Avastin (n=70) XELOX (n=48) FOLFOX (n=49) bFOL (n=50) TREE-1/2: limited added toxicity with Avastin (grade 3/4 adverse events*) Patients (%) TREE-1 TREE-2 Hand-foot syndrome Diarrhea Neutropenia Neuro-toxicity Bleeding Venousthromboembolism Hypertension *First 12 weeks Hochster HS et al. Proc 2005 GI Cancers Symposium 2005;204 (Abst 241)

  12. TREE-2: XELOX-Avastin is highly effective and well tolerated • XELOX-Avastin is a highly effective and well-tolerated first-line treatment for metastatic CRC (MCRC) similar to FOLFOX-Avastin • bFOL-Avastin appears to be less active than FOLFOX-Avastin (p=0.03 for response rates) • Updated efficacy data to be reported at ASCO 2005 Hochster HS et al. Proc 2005 GI Cancers Symposium 2005;204 (Abst 241)

  13. Repeat cycle at day 15 Xeloda starting dose reduced to 825mg/m2 due to toxicity in 40% of patients US phase II trial: MCRC first-lineXeloda/oxaliplatin + Avastin Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Oxaliplatin85mg/m2 Avastin10mg/m2 Xeloda1000mg/m2twice daily Days 1–5 Days 8–12 Fernando NH et al. Proc 2005 GI Cancers Symposium 2005;228 (Abst 289)

  14. Xeloda/oxaliplatin + Avastin schedule achieves interesting first-line efficacy in MCRC • Median TTP amongst the highest reported in this setting Fernando NH et al. Proc 2005 GI Cancers Symposium 2005;228 (Abst 289)

  15. At reduced dose no patient experienced >grade 1 diarrhea Enrollment is continuing with Xeloda 825mg/m2 (target n=50) Safety of Xeloda/oxaliplatin + Avastinin MCRC (n=30) Fernando NH et al. Proc 2005 GI Cancers Symposium 2005;228 (Abst 289)

  16. Phase III trial: XELOX ± Avastin vs FOLFOX4 ± Avastin (XELOX1*) • 2 x 2 factorial, randomised phase III trial Avastin 5mg/kg every 2 weeks (n=330) PD FOLFOX4 (n=300) Previously untreated patients with metastatic CRC(n=1920) PD Placebo (n=330) Avastin 7.5mg/kg every 3 weeks (n=330) PD XELOX (n=300) Placebo (n=330) PD • Primary objectives • at least equivalent time to progression with XELOX (± Avastin) versus FOLFOX4 (± Avastin) • improved time to progression with the addition of Avastin *Roche registration study

  17. French GERCOR: randomized phase III trial in MCRC XELOX4 + Avastin Oxaliplatin 100mg/m2 day 1, Xeloda 1500–1750mg/m2 twice daily, days 1–7, q14d RANDO MIZATION Tarceva nil Estimated n=604 First-line MCRC FOLFOX7 + Avastin Oxaliplatin 130mg/m2 + LV 400mg/m2, day 1; 5-FU 2400mg/m2 days 1–2, q14d Tarceva nil • Primary endpoint: PFS Principal investigator: Aimery de Gramont

  18. German AIO, randomized phase II trial:Xeloda combinations + Avastin RANDO MIZATION XELOX + Avastin n=160 First-line MCRC XELIRI + Avastin Principal investigator: Wolff Schmiegel

  19. RANDO MIZATION XELOX + cetuximab n=120 First-line MCRC XELIRI + cetuximab German AIO, randomized phase II trial:Xeloda combinations + cetuximab Principal investigator: Volker Heinemann

  20. Xeloda1 XELIRI2 XELOX3 ? XELOX or XELIRI + biological Overall survival: first-line fluoropyrimidine combination regimens 5-FU/LV (Saltz) 5-FU/LV (Douillard) 5-FU/LV (de Gramont) IFL (Goldberg) IFL (Saltz) FOLFIRI (Douillard) FOLFOX (de Gramont) FOLFOX (Goldberg) FUFOX (Schmoll) IFL+ Avastin (Hurwitz) ? FOLFOX + Avastin 0 5 10 15 20 25 Median OS (months) 1Van Cutsem E et al. Br J Cancer 2004;90:1190–7 2 Patt YZ et al. Ann Oncol 2004;15(Suppl. 3):iii88 (Abst 238P) 3Cassidy J et al. J Clin Oncol 2004;22:2084–91

  21. Xeloda: refining the next generation of treatment with biologicals • Strong preclinical rationale for combining Xeloda with EGF and VEGF inhibitors • Oral Xeloda simplifies complex combinations and improves convenience for the patient • Emerging data with Avastin support high efficacy and good tolerability of Xeloda-based combinations • In conclusion, Xeloda-based regimens are an excellent basis for combination with new biologicals

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