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

Chemotherapy in Advanced Gastric Cancer – What do we know? (I) Wagner et al. J Clin Oncol 2006; 24: 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: Established standard: Platinum-fluoropyrimidine-combination

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: Cunningham et al. N Engl J Med 2008; 358: Kang et al. Ann Oncol 2009; 20: Van Cutsem et al. J Clin Oncol 2006; 24: Wagner et al. J Clin Oncol 2006; 24: Ajani J et al. J Clin Oncol 2010; 28: Chemotherapy in Advanced Gastric Cancer – What do we know? (I)

Oxaliplatin

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)

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

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:

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

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

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

Oral fluoropyrimidines

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)

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

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: Primary endpoint: overall survival (non-inferiority)

ML17032-Study: XP versus FP Kang YK et al. Ann Oncol 2009; 20: 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

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:

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:

S-1/cisplatin versus 5-FU/cisplatin Ajani J et al. J Clin Oncol 2010; 28: 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

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

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

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

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

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)

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: Stage IV n=445 Tax-325-Study (multinational)

Van Cutsem et al. J Clin Oncol 2006; 24: 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

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

Alternative docetaxel-based regimen (AIO studies) Lorenzen et al. Ann Oncol 2007; 18: 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: FLOT regimen Docetaxel 50mg/m 2 + modified FOLFOX 2-weekly Response rate 53% Time to progression 5.3 months Survival11.3 months

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)

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)

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

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

3 + 1 = X …when the unpredictable comes true Wardell et al. ASO 2012; abstract LBA EOC EOC-P Number at risk 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 = HR 1.37 (95% CI: 1.07 – 1.76) 61830

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)

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

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