1. What is the reference cytotoxic regimen in advanced gastric cancer? Florian Lordick Klinikum Braunschweig Germany

2. Chemotherapy in Advanced Gastric Cancer – What do we know? (I) Wagner et al. J Clin Oncol 2006; 24: 2903-9 Chemotherapy prolongs survival Chemotherapy improves symptom control Combinations are more active than monotherapy Elderly (>70 years age) benefit equally Trumper et al. Eur J Cancer 2006; 42: 827-34 Established standard: Platinum-fluoropyrimidine-combination

3. Oxaliplatin can substitute for cisplatin Oral fluoropyrimidines can substitute for i.v. 5-FU A 3rd drug makes CTx more effective but more toxic Al-Batran et al. J Clin Oncol 2008; 26: 1435-1442 Cunningham et al. N Engl J Med 2008; 358: 36-46 Kang et al. Ann Oncol 2009; 20: 666-673 Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7 Wagner et al. J Clin Oncol 2006; 24: 2903-9 Ajani J et al. J Clin Oncol 2010; 28: 1547-1553 Chemotherapy in Advanced Gastric Cancer – What do we know? (I)

4. Oxaliplatin

5. Oxaliplatin in Gastric Cancer Cunningham D et al. N Engl J Med 2008;358:36-46 RANDOMRANDOM RANDOMRANDOM E Epirubicin C Cisplatin F Fluorouracil E Epirubicin C Cisplatin X Xeloda (Capecitabine) E Epirubicin O Oxaliplatin F Fluorouracil E Epirubicin O Oxaliplatin X Xeloda (Capecitabine) N=964 Real-2-Study (UK)

6. Oxaliplatin in Gastric Cancer Cunningham D et al. N Engl J Med 2008;358:36-46 Real-2-Study

7. Oxaliplatin in Gastric Cancer RANDOMRANDOM RANDOMRANDOM P Cisplatin L Leucovorin F 5-Fluorouracil O Oxaliplatin L Leucovorin F 5-Fluorouracil N=220 AIO-Study (Germany) Al-Batran SE et al. J Clin Oncol 2008;26:1435-1442

8. AIO-study: FLO versus FLP Al-Batran SE et al. J Clin Oncol 2008;26:1435-1442 PFS: p = 0.077OS: p = 0.506 Overall population

9. AIO-study: FLO versus FLP Al-Batran SE et al. J Clin Oncol 2008;26:1435-1442 PFS: p = 0.029OS: p = n. s. Elderly (patients > 65 years)

10. Oxaliplatin can substitute for cisplatin in gastric cancer! Potential advantages in the elderly and frail population

11. Oral fluoropyrimidines

12. Capecitabine in Gastric Cancer Cunningham D et al. N Engl J Med 2008;358:36-46 RANDOMRANDOM RANDOMRANDOM E Epirubicin C Cisplatin F Fluorouracil E Epirubicin C Cisplatin X Xeloda (Capecitabine) E Epirubicin O Oxaliplatin F Fluorouracil E Epirubicin O Oxaliplatin X Xeloda (Capecitabine) N=964 Real-2-Study (UK)

13. Capecitabine in Gastric Cancer Cunningham D et al. N Engl J Med 2008;358:36-46 Real-2-Study

14. Capecitabine in Gastric Cancer RANDOMRANDOM RANDOMRANDOM F 5-Fluorouracil P Cisplatin N=316 ML17032-Study (Korea) X Xeloda (Capecitabine) P Cisplatin Kang YK et al. Ann Oncol 2009; 20: 666-673 Primary endpoint: overall survival (non-inferiority)

15. ML17032-Study: XP versus FP Kang YK et al. Ann Oncol 2009; 20: 666-673 Progression-free survival 5.6 vs. 5.0 monp<0.001 (non-inferior) Survival 10.5 vs. 9.3 monp=0.008 (non-inferior) Response rate 46% vs. 32%p=0.02

16. S-1/cisplatin versus 5-FU/cisplatin S-1 25mg/m 2 2x/d d1-21 Cisplatin 75mg/m 2 d1 q4w S-1 25mg/m 2 2x/d d1-21 Cisplatin 75mg/m 2 d1 q4w RANDOMRANDOM RANDOMRANDOM 5-FU 1000mg/m 2 d1-5 Cisplatin 100mg/m 2 d1 q4w 5-FU 1000mg/m 2 d1-5 Cisplatin 100mg/m 2 d1 q4w Primary endpoint: overall survival (superiority) N=1053 FLAGS-Study (multinational Western World) Ajani J et al. J Clin Oncol 2010; 28: 1547-1553

17. S-1/cisplatin versus 5-FU/cisplatin In a Non-Asian patient population S-1 was not superior to 5-FU Ajani J et al. J Clin Oncol 2010; 28: 1547-1553

18. S-1/cisplatin versus 5-FU/cisplatin Ajani J et al. J Clin Oncol 2010; 28: 1547-1553 S-1/cisplatin5-FU/cisplatin Neutropenia G3/432.3%63.4% Complicated neuropenia 5.0%14.4% Stomatitis1.3%13.6% Toxic Death2.5%4.9% Toxicity in favor of S-1/cisplatin

19. Oral fluoropyrimidines can substitute for i.v. 5-FU in gastric cancer! Less severe toxicity for S-1/cisplatin

20. Doublets or triplets? And which is the relevant third drug?

21. Cisplatinum Wagner et al. J Clin Oncol 2006; 24: 2903-9 HR = 0.83 (95% CI 0,76 – 0,91) in favor of cisplatinum

22. Anthracyclines Wagner et al. J Clin Oncol 2006; 24: 2903-9 HR = 0.77 (95% CI 0,62 – 0,95) in favor of anthracyclines

23. Anthracyclines ECF versus EOX Cunningham D et al. N Engl J Med 2008;358:36-46 HR = 0.80 (95% CI, 0.66 to 0.97; P=0.02) Real-2-Study (UK)

24. Docetaxel Docetaxel 75mg/m 2 d1 Cisplatin 75mg/m 2 d1 5-FU 750mg/m 2 d1-5 q3w Docetaxel 75mg/m 2 d1 Cisplatin 75mg/m 2 d1 5-FU 750mg/m 2 d1-5 q3w RANDOMRANDOM RANDOMRANDOM Cisplatin 100mg/m 2 d1 5-FU 1000mg/m 2 d1-5 q4w Cisplatin 100mg/m 2 d1 5-FU 1000mg/m 2 d1-5 q4w Primary endpoint: time to progression (TTP) Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7 Stage IV n=445 Tax-325-Study (multinational)

25. Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7 Time to progression 5.6 vs. 3.7 monthsp<0.01 Survival 9.2 vs. 8.6 monthsp=0.02 Response rate 37% vs. 25%p=0.01 Kaplan-Meier curve: time to progression Docetaxel as 3rd Drug TAX-325

26. DCF Toxicity Hematologic toxicity in DCF Neutropenia grade 3/482% Febrile neutropenia30% Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7

27. Alternative docetaxel-based regimen (AIO studies) Lorenzen et al. Ann Oncol 2007; 18: 1673-9 GastroTax-1 regimen Docetaxel 40mg/m 2 + cisplatin 40mg/m 2 2-weekly 5-FU 2000mg/m 2 – folinic acid 200mg/m 2 weekly Response rate 46.6% Time to progression (metastatic) 8.1 months Survival (metastatic)15.1 months Al-Batran et al. Ann Oncol 2008; 19:1882-87 FLOT regimen Docetaxel 50mg/m 2 + modified FOLFOX 2-weekly Response rate 53% Time to progression 5.3 months Survival11.3 months

28. Alternative docetaxel-based regimen (MSKCC) Shah et al. ASO 2010; abstract 4014 Fraction Surviving Months 15.1 mo 12.6 mo Modified DCF Classic DCF Median follow up 10.3 mo Modified DCF vs. classic DCF + G-CSF (rand. Ph. II)

29. The future of triplets in gastric cancer: Sequential treatment? Arm A(120 pat.) R 2:1 Arm B(80 pat.) Induction 6 cycles FLOT (3 months) CR, PR, SD FLOT Progression De-escalation S-1 AIO – YMO – Maintain Study (proposal)

30. Triplets are more effective than doublets! But… Side effects are an issue! Patients‘ preferences matter! Watch out for overlapping side effects and interactions, when combining with biologics

31. 3 + 1 = X …when the unpredictable comes true Arm A: EOX Arm B: EOX-Panitumumab R EOX (Arm A): –Epirubicin 50mg/m 2 IV D1 –Oxaliplatin 130mg/m 2 IV D1 –Capecitabine 1250mg/m 2 /day PO in two divided doses D1-21 mEOX-P (Arm B) 1: –Epirubicin 50mg/m 2 IV D1 –Oxaliplatin 100mg/m 2 IV D1 –Capecitabine 1000mg/m 2 /day PO in two divided doses D1-21 –Panitumumab 9mg/kg IV D1 Wardell et al. ASO 2012; abstract LBA 4000 REAL-3 study

32. 3 + 1 = X …when the unpredictable comes true Wardell et al. ASO 2012; abstract LBA 4000 349275EOC 238278EOC-P Number at risk 0 20 40 60 80 100 0122436 Months from Randomisation Probability of Survival (%) EOX EOX-P Median OS (95% CI) % alive at 1 year (95% CI) 11.3m (9.6 – 13.0)46% (38% - 54%) 8.8m (7.7 – 9.8)33% (26% - 41%) HR 1.37, p = 0.013 HR 1.37 (95% CI: 1.07 – 1.76) 61830

33. Reference regimens for advanced gastric cancer in 2012 Triplets Indication: Severe tumor symptoms Patient preference (most active tx) Intact organ functions Regimens:EOX (epirubicine, oxaliplatin, cape.) mod. DCF (docetaxel, cisplatin, 5FU) FLOT (docetaxel + mod. FOLFOX)

34. Doublets Indication: Patient preference for less toxicity Impaired organ functions Combination with biologics Regimens:Capecitebine-cisplatin S-1-cisplatin FOLFOX-like / CapOx (elderly) Reference regimens for advanced gastric cancer in 2012

35. Doublet or Triplet? 2 : 0 or 3 : 0 Let‘s win the match!