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Clinical developments in advanced gastric cancer

Clinical developments in advanced gastric cancer. Dr Ian Chau Royal Marsden Hospital London and Surrey, UK. REAL-2: background and rationale. ECF widely used in the UK/Europe for the treatment of advanced oesophagogastric cancer Activity demonstrated in two randomised trials (n=854) 1 –3

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Clinical developments in advanced gastric cancer

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  1. Clinical developmentsin advanced gastric cancer Dr Ian ChauRoyal Marsden HospitalLondon and Surrey, UK

  2. REAL-2: background and rationale • ECF widely used in the UK/Europe for the treatment of advanced oesophagogastric cancer • Activity demonstrated in two randomised trials (n=854)1–3 • ORR: ~40% • OS: ~9 months • 1-year survival: ~35% • Addition of anthracycline to CF in gastric cancer supported by Cochrane meta-analysis4 1. Webb A et al. J Clin Oncol 1997;15:261–72. Waters JS et al. Br J Cancer 1999;80:269–72 3. Ross P et al. J Clin Oncol 2002;20:1996–2004 4. Wagner AD et al. J Clin Oncol 2006;24:2903–9

  3. REAL-2: study hypotheses • In combination treatments of oesophagogastriccancer • can Xeloda replace 5-FU? • can oxaliplatin replace cisplatin? • Primary endpoint of non-inferiority in OS (per protocol population) • Xeloda vs 5-FU, oxaliplatin vs cisplatin • based on 1-year survival rate of 35% for ECF, 1000 patients (250 per arm) would be required to demonstrate non-inferiority (80% power, 1-sided a=0.05) • upper limit of HR for experimental arms compared with standard arms should be <1.23 • superiority in OS among the four regimens (intent-to-treat) Cunningham D et al. J Clin Oncol 2006;24(Suppl. 18S):934s (Abst LBA4017)

  4. Multicentre Phase III REAL-2 trial:Xeloda vs 5-FU, oxaliplatin vs cisplatin Locally advanced or metastatic oesophagogastric cancer (n=1002) R A N D O M I S A T I O N Epirubicin Cisplatin Fluorouracil Epirubicin Oxaliplatin Fluorouracil Epirubicin Cisplatin Xeloda Epirubicin OxaliplatinXeloda • Epirubicin 50mg/m2 day 1 • Cisplatin 60mg/m2 vs oxaliplatin 130mg/m2day 1 • 5-FU 200mg/m2 ci daily vs Xeloda 500–625mg/m2bid po daily • For 24 weeks: eight cycles every 3 weeks Cunningham D et al. J Clin Oncol 2006;24(Suppl. 18S):934s (Abst LBA4017)

  5. REAL-2: primary endpoint met –Non-inferior OS with Xeloda vs 5-FU Estimated probability 1.0 Xeloda combinations (n=480) 5-FU combinations (n=484) 0.8 0.6 HR=0.86 (95% CI: 0.80–0.99) 0.4 0.2 9.6 10.9 0.0 0 12 24 36 60 72 48 Months Per protocol Cunningham D et al. J Clin Oncol 2006;24(Suppl. 18S):934s (Abst LBA4017)

  6. REAL-2: OS – Platinum comparison Estimated probability 1.0 Oxaliplatin combinations (n=474) Cisplatin combinations (n=490) 0.8 0.6 HR=0.92 (95% CI: 0.8–1.1) 0.4 0.2 10.0 10.4 0.0 0 12 24 36 60 72 48 Months Per protocol Cunningham D et al. J Clin Oncol 2006;24(Suppl. 18S):934s (Abst LBA4017)

  7. Xeloda combinations vs5-FU combinations: similar OS Median OS (months) ECF (n=249): 9.9 ECX (n=241): 9.9 EOF (n=235): 9.3 EOX (n=239): 11.2* Estimated probability 1.0 0.8 0.6 0.4 0.2 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 Months *p<0.05, compared with ECFIntent-to-treat Cunningham D et al. J Clin Oncol 2006;24(Suppl. 18S):934s (Abst LBA4017)

  8. EOX vs ECF: superior OS Median OS (months) ECF (n=249): 9.9 EOX (n=239): 11.2* Estimated probability 1.0 0.8 0.6 HR=0.80 (95% CI: 0.66–0.97)Log-rank p=0.02 0.4 0.2 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 Months Intent-to-treat Cunningham D et al. J Clin Oncol 2006;24(Suppl. 18S):934s (Abst LBA4017)

  9. EOX vs ECX: similar OS Median OS (months) ECX (n=241): 9.9 EOX (n=239): 11.2* Estimated probability 1.0 0.8 0.6 Log-rank p non-significant 0.4 0.2 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 Months Intent-to-treat Cunningham D et al. J Clin Oncol 2006;24(Suppl. 18S):934s (Abst LBA4017)

  10. Xeloda-based regimens are well tolerated ECF (n=236) ECX (n=241) EOF (n=235) EOX (n=239) Patients (%) Grade 3/4 AEs * * * * * * * HFS Nausea/vomiting Diarrhoea Stomatitis Febrileneutropenia Neutropenia Thromboembolicevents *p<0.05compared with ECF Cunningham D et al. J Clin Oncol 2006;24(Suppl. 18S):934s (Abst LBA4017) Starling N et al. Proc ASCO GI 2007 (Abst 74)

  11. REAL-2 vs ML17032: consistent efficacy with Xeloda regimens • Response evaluation every 3 months in REAL-2, every 1.5 months in ML17032 • In REAL-2, maximum treatment duration: 6 months

  12. REAL-2 vs ML17032: Xeloda regimens are well tolerated • Febrile neutropenia: 7–9% in REAL-2, <1% in ML17032

  13. REAL-2 vs ML17032: trial characteristicsXeloda can replace 5-FU }10.9 1. Kang Y-K et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abst O-003)2. Cunningham D et al. J Clin Oncol 2006;24(Suppl. 18S):934s (Abst LBA4017)

  14. Xeloda-based combinations:reduced infusion time Intended hours per 3-week treatment 504h 504h 120h 7h 9h 2h XP1 FP1 ECX2 ECF2 EOX2 EOF2 1. Kang Y-K et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abst O-003)2. Cunningham D et al. J Clin Oncol 2006;24(Suppl. 18S):934s (Abst LBA4017)

  15. Integrating docetaxel in the treatmentof AGC: high efficacy with Xeloda 1. Kang Y-K et al. J Clin Oncol 2004;22(Suppl. 14S):329s (Abst 4066) 2. Van Cutsem E et al. J Clin Oncol 2006;24:4991–7

  16. Integrating docetaxel in the treatmentof AGC: improved safety with Xeloda Patients (%) Grade 3/4 AEs DCX1 (n=40) DCF2 (n=221) HFS Anaemia Vomiting Febrileneutropenia Neutropenia Neurosensory 1. Kang Y-K Personal communication 2. Van Cutsem E et al. J Clin Oncol 2006;24:4991–7

  17. Integrating docetaxel in the treatmentof AGC: improved safety with Xeloda Patients (%) Grade 3/4 AEs DCX1 (n=40) DCF2 (n=221) 29 10 HFS Anaemia Vomiting Febrileneutropenia Neutropenia Neurosensory 1. Kang Y-K Personal communication 2. Van Cutsem E et al. J Clin Oncol 2006;24:4991–7

  18. Progress so far in AGC:OS with Xeloda-based regimens BSC1 FAMTX2 CF3 IF4 ECF5 EOF5 DCF3 XP6 ECX5 EOX5 Months 1. Murad AM et al. Cancer 1993;72:37–412. Vanhoefer U et al. J Clin Oncol 2000;18:2648–57; 3. Van Cutsem E et al. J Clin Oncol 2006;24:4991–74. Dank M et al. J Clin Oncol 2005;23(Suppl. 16S) (Abst 4003);5. Cunningham D et al. J Clin Oncol 2006;24(Suppl. 18S):934s (Abst LBA4017); 6. Kang Y-K et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abst O-003)

  19. Phase III data on S-1 pending in AGC • Phase I/II combination data • cisplatin ORR: ~50–55%; OS: ~11 months1–3 • irinotecan ORR 62%; OS: 14.6 months4 • FLAGS (n=1050): global Phase III CF vs cisplatin + S-1 • Survival benefit for adjuvant S-1 over surgery alone in stage II/III gastric cancer after D2 gastrectomy(HR: 0.68; 95% CI: 0.52–0.87; p=0.0024)5 1. Ajani J et al. J Clin Oncol 2006;24:663–72. Lenz HJ et al. Cancer 2007;109:33–403. Iwase H et al. Anticancer Res 2005;25:1297–3014. Inokuchi M et al. Br J Cancer 2006;94:1130–55. Sasako M et al. Proc Asco GI 2007 (Abst 8)

  20. Integrating Avastin in the treatment of AGC: combination with irinotecan and cisplatin 1. Shah MA et al. J Clin Oncol 2006;24:5201–6 2. Pozzo C et al. Ann Oncol 2004;15:1773–81

  21. Cetuximab plus FOLFIRI in metastatic OGJ or gastric cancer: efficacy • 91% of screened population was EGFR positive2 1. Bouche O et al. J Clin Oncol 2004;22:4319–282. Pinto C et al. J Clin Oncol 2006;24(Suppl. 18S):186s (Abst 4031)

  22. EGFR tyrosine kinase inhibitors:efficacy in oesophagogastric cancers 1. Ferry DR et al. J Clin Oncol 2004;22(Suppl. 14S) (Abst 4021)2. Janmaat ML et al. J Clin Oncol 2006;24:1612–9; 3. Adelstein DJ et al. J Clin Oncol 2005;23(Suppl. 16S) (Abst 4054); 4. Doi T et al. Proc ASCO 2003 (Abst 1036); 5. Radovich D et al. J Clin Oncol 2004;22(Suppl. 14S) (Abst 4077); 6. Tew NP et al. J Clin Oncol 2005;23(Suppl. 16S) (Abst 5); 7. Dragovich T et al. J Clin Oncol 2006;24:4922–7

  23. CALGB 80403/ECOG E-1206 randomised Phase II trial design RANDO MIS ATION ECF + cetuximab Locally recurrent or metastatic oesophageal or OGJ cancer Irinotecan + cisplatin + cetuximab FOLFOX + cetuximab • Primary endpoint: ORR • Target recruitment: 270 patients • Enrolment began September 2006

  24. TOGA Phase III trial:background and rationale • 15–20% of gastric cancers are HER2 +ve1,2 • evidence that HER2 is a negative prognostic factor • Survival benefit with Herceptin + chemotherapy in HER2 +ve breast cancer3–5 • Herceptin mode of action anticipated to be the same across different HER2 +ve tumour types • Herceptin in combination with Xeloda in breast cancer is effective and well tolerated6 • Combination of Herceptin with Xeloda and cisplatin has shownat least an additive effect in gastric cancer xenograft models7 1. Risio M et al. Int J Oncol 2003;23:1381–72. Park DI et al. Dig Dis Sci 2006;51:1371–9; 3. Slamon DJ et al. N Engl J Med 2001;344:783–924. Romond EH et al. N Engl J Med 2005;353:1673–84; 5. Smith I et al. Lancet 2007;369:29–366. Wardley A et al. Breast Cancer Res Treat 2006;100(Suppl.1) (Abst 2063)7. Fujimoto-Ouchi K et al. Cancer Chemother Pharmacol 2006 (Epub ahead of print)

  25. TOGA Phase III trial:Xeloda vs 5-FU + cisplatin ± Herceptin *Xeloda 1000mg/m2 bid d1–14 q3wOR*5-FU 800mg/m2 ci d1–5 q3w Cisplatin 80mg/m2 d1 RANDO MISATION HER2 +ve disease Stage IIIb–IV No prior treatment n=374 *Xeloda 1000mg/m2 bid d1–14 q3wOR*5-FU 800mg/m2 ci d1–5 q3w Cisplatin 80mg/m2 d1 Herceptin 8mg/kg (loading dose),6mg/kg (subsequent doses) d1 q3w (until PD) • Primary endpoint: OS • 253 patients randomised so far *Clinician’s choice

  26. Xeloda: the backbone of future standards in gastric cancer

  27. Xeloda: an effective, safe and convenient oral therapy for gastric cancer • Effective and simple with • platinum compounds • taxanes • triple combinations • Similar safety and efficacy profile to infused 5-FU • Reduced infusion times • Avastin and Herceptin are active when combined with chemotherapy • ongoing clinical trials evaluating Xeloda/Avastin and Xeloda/Herceptin combinations in gastric cancer

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