1 / 27

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

chad
Télécharger la présentation

Clinical developments in advanced gastric cancer

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related