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Professor Jim Cassidy Cancer Research UK Department of Oncology University of Glasgow Glasgow, UK

Evolving options in the management of metastatic colorectal cancer: stepping beyond the ‘lines’ of therapy. Professor Jim Cassidy Cancer Research UK Department of Oncology University of Glasgow Glasgow, UK. Novel options lead to novel questions in the treatment of mCRC.

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Professor Jim Cassidy Cancer Research UK Department of Oncology University of Glasgow Glasgow, UK

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  1. Evolving options in the management of metastatic colorectal cancer: stepping beyond the ‘lines’ of therapy Professor Jim CassidyCancer Research UK Department of Oncology University of GlasgowGlasgow, UK

  2. Novel options lead to novel questions in the treatment of mCRC • Can Xeloda replace 5-FU? • Multiple effective agents and regimens: what is the best strategic use of options? • What is the optimal way of combininganti-angiogenics with cytotoxics? • Do drug ‘holidays’ improve chemotherapy tolerance or confer drug resistance? • Is there a role for maintenance therapy?

  3. Novel options lead to novel questions in the treatment of mCRC • Can Xeloda replace 5-FU? • Multiple effective agents and regimens: what is the best strategic use of options? • What is the optimal way of combininganti-angiogenics with cytotoxics? • Do drug ‘holidays’ improve chemotherapy tolerance or confer drug resistance? • Is there a role for maintenance therapy?

  4. Xeloda: effectivelyreplacing 5-FU in mCRC • In mCRC, Xeloda vs bolus 5-FU1–3 • superior response rate • equivalent TTP and OS • favourable safety profile • cost-saving • Xeloda reduces risks associated with central venous catheters (e.g. deep-vein thrombosis) 1. Van Cutsem E et al. Br J Cancer 2004;90:1190–72. Cassidy J et al. Ann Oncol 2002;13:566–753. Twelves C et al. Eur J Cancer 2001;37:597–604

  5. XELOX is equivalent to FOLFOXin first-line therapy NO169661 (n=1304) AIO2 (n=466) TTD3 (n=340) French4 (n=304) *Initial two-arm open-label study (n=634) 1. Cassidy J et al. Proc ASCO GI 2007 (Abst 270) 2. Kubicka S et al. Proc ASCOGI 2006 (Abst 277) 3. Tabernero J et al. Ann Oncol 2006;17(Suppl. 6):vi23 (Abst O-15) 4. Bennouna J et al. Proc ASCO GI 2007 (Abst 272)

  6. XELOX is equivalent to FOLFOXin second-line therapy RANDO MIS ATION XELOX Xeloda 1000mg/m2 bid d115 oxaliplatin 130mg/m2 d1 q3w FOLFIRI-pretreated mCRC Prior oxaliplatin not allowedn=627 FOLFOX45-FU 400mg/m2 bolus + 600mg/m2 ci d1, 2 LV 200mg/m2 d1, 2 oxaliplatin 85mg/m2 d1 q2w • Primary endpoint: PFS • Primary endpoint met. Results to be presented at ASCO 2007

  7. Novel options lead to novel questions in the treatment of mCRC • Can Xeloda replace 5-FU? • Multiple effective agents and regimens: what is the best strategic use of options? • What is the optimal way of combininganti-angiogenics with cytotoxics? • Do drug ‘holidays’ improve chemotherapy tolerance or confer drug resistance? • Is there a role for maintenance therapy?

  8. All cytotoxic drugsshould be administered OS (months) 2 2 2 0 1 8 1 6 1 4 0 2 0 4 0 6 0 8 0 1 00 Patients with three active drugs (%) Grothey A et al. J Clin Oncol 2004;22:1209–14

  9. How to integrate all cytotoxic agents: CAPIRI and CAPOX crossover RANDO MIS ATION n=174 CAPOX CAPIRI mCRC n=161 PD CAPIRI CAPOX n=174 • CAPOX: Xeloda 1000mg/m2 bid d1–14 + oxaliplatin 70mg/m2 d1, 8 q3w • CAPIRI: Xeloda 1000mg/m2 bid d1–14 + irinotecan 80–100mg/m2 d1, 8 q3w Grothey A et al. J Clin Oncol 2004;22(Suppl. 14S):253s (Abst 3534)

  10. CAPOX and CAPIRI areeffective regardless of order • Both regimens well tolerated • Cardiac and thrombotic complications rare in both arms (<2%) Grothey A et al. J Clin Oncol 2004;22(Suppl. 14S):253s (Abst 3534)

  11. Combination vs sequential therapy: CAIRO Phase III study RANDO MIS ATION n=194 Sequential arm Xeloda irinotecan XELOX Advanced CRC n=820(382 evaluable) 1st-line 2nd-line 3rd-line XELIRI XELOX n=188 Combination arm • Primary endpoint: OS Punt C et al. Eur J Cancer 2005;(Suppl. 3):168 (Abst 600) Koopman M et al. Ann Oncol 2006;17:1523–8

  12. Combination vs sequential therapy: safety Patients (%) Grade 3/4 AEs Sequential (n=198) Combination (n=191) * HFS Fatigue Nausea/vomiting Stomatitis Diarrhoea Febrileneutropenia Neutropenia *p=0.041 Koopman M et al. Ann Oncol 2006;17:1523–8

  13. Novel options lead to novel questions in the treatment of mCRC • Can Xeloda replace 5-FU? • Multiple effective agents and regimens: what is the best strategic use of options? • What is the optimal way of combininganti-angiogenics with cytotoxics? • Do drug ‘holidays’ improve chemotherapy tolerance or confer drug resistance? • Is there a role for maintenance therapy?

  14. NO16966 trial: addition of Avastin to XELOX/FOLFOX improves PFS in first-line Estimated probability 1.0 FOLFOX+Avastin/XELOX+Avastin (n=699) FOLFOX+placebo/XELOX+placebo (n=701) 0.8 0.6 HR=0.83 97.5% CI: 0.72–0.95 p=0.0023 0.4 0.2 8.0 9.4 0.0 0 5 10 15 20 25 Months Saltz LB et al. Proc ASCO GI 2007 (Abst 238)

  15. ECOG 3200 trial: addition of Avastinto FOLFOX4 improves OS in second-line Estimated probability 1.0 FOLFOX4 + Avastin (n=289) FOLFOX4 (n=290) 0.8 0.6 HR=0.76 p=0.0018 0.4 0.2 10.8 12.9 0.0 3 6 9 12 15 18 21 24 27 30 33 36 0 Months Giantonio BJ et al. J Clin Oncol 2005;23(Suppl. 16S):1s (Abst 2)

  16. ECOG 3200 trial: addition of Avastinto FOLFOX4 improves PFS in second-line Estimated probability 1.0 FOLFOX4 + Avastin (n=273) FOLFOX4 (n=273) 0.8 0.6 HR=0.64 p<0.0001 0.4 0.2 4.8 7.2 0.0 2 4 6 8 10 12 14 16 18 20 0 Months Giantonio BJ et al. J Clin Oncol 2005;23(Suppl. 16S):1s (Abst 2)

  17. Novel options lead to novel questions in the treatment of mCRC • Can Xeloda replace 5-FU? • Multiple effective agents and regimens: what is the best strategic use of options? • What is the optimal way of combininganti-angiogenics with cytotoxics? • Do drug ‘holidays’ improve chemotherapy tolerance or confer drug resistance? • Is there a role for maintenance therapy?

  18. OPTIMOX1:5-FU + stop-and-go oxaliplatin Arm A FOLFOX4 q2w, until PD ARM B 6 cycles PD FOLFOX7 LV5FU FOLFOX7 Tournigand C et al. J Clin Oncol 2006;24:394–400

  19. OPTIMOX1: stopping oxaliplatindoes not compromise efficacy – OS Estimated probability 1.0 Arm A (n=311) Arm B (n=309) 0.8 0.6 0.4 0.2 19.3 21.2 0.0 0 8 16 24 32 40 Months Tournigand C et al. J Clin Oncol 2006;24:394–400

  20. OPTIMOX2: introduction of chemotherapy-free intervals OPTIMOX1 – maintenance therapy 6 cycles PD FOLFOX7 LV5FU FOLFOX7 OPTIMOX2 – chemotherapy-free interval 6 cycles Before PD FOLFOX7 Stop chemo FOLFOX7 Maindrault-Goebel F et al. J Clin Oncol 2006;24(Suppl. 18S):147s (Abst 3504)

  21. Chemotherapy-free intervals donot affect duration of disease control Estimated probability 1.0 OPTIMOX1 OPTIMOX2 0.8 0.6 0.4 0.2 11.7 12.9 0.0 0 4 8 12 16 20 Months Maindrault-Goebel F et al. J Clin Oncol 2006;24(Suppl. 18S):147s (Abst 3504)

  22. Intermittent vs continuous FOLFIRI:no difference in efficacy Labianca R et al. J Clin Oncol 2006;24(Suppl. 18S):147s (Abst 3505)

  23. OPTIMOX3 – XELOX + Avastin vs FOLFOX7 + Avastin (Avastin maintenance ± Tarceva) RANDO MIS ATION XELOX + Avastin Avastin ± Tarceva UntreatedmCRC mFOLFOX7 + Avastin Avastin ± Tarceva • Primary endpoint: PFS

  24. Evolving ‘lines’ in a changing environment Patient potentially curable? yes no Induction chemotherapye.g. XELOX/XELIRI + Avastin Induction chemotherapye.g. XELOX/XELIRI + Avastin Surgery Maintenance Drug holiday Adjuvant therapy?e.g. XELOX Re-induction chemotherapy e.g. XELIRI/XELOX ± Avastin± cetuximab Observation Vary regime according to timing of progression

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