Better Regimens & Predictive Markers For Advanced Esophagogastric Cancer? Peter C. Enzinger, M.D. Dana-Farber Cancer Institute/Harvard Medical School

Disclosures Speaker / Consultant / Honoraria (prior to 6.09): Sanofi – Aventis Roche

Posters Discussed Kishimoto et al. Does Paclitaxel or Irinotecan improve a Japanese Standard – S1? Shah et al. Is “Docetaxel, Cisplatin + mod de Gramont” better than DCF? Al-Batran et al. Is “Docetaxel + mFOLFOX” better than DCF? Atmaca et al. What do we do with a new prognostic molecular factor?

Japan Can we improve S1?

Evolution of S1 Therapy in Gastric CA FLAGS** Cisplatin + S1 Cisplatin + 5-FU 29% 8.6 mos 32% 7.9 mos P = NS SPIRITS* S1 Cisplatin + S1 *Koizumi. Lancet Oncol 2008 **Ajani. J Clin Oncol % 11 mos 54% 13 mos P = 0.04 Japan “West” RR: OS: Less toxic

Random Phase II: S1+ CPT or S1 + Pacli Unresectable, measurable advanced or recurrent gastric cancer No prior chemotherapy except adjuvant CTX H0: 30% RR vs. HA: 50% RR power 80%; 2-sided α 5%

Phase III: START Progression-Free Survival Overall Survival HR=1.18; p=0.42HR=0.99; p=0.96 RegimenResponsePFSOS S1 alone* /# 28-31%4.2 mos mos S1 + Pacli31%4.6 mos12.0 mos S1 + Doce**88%6.5 mos12.0 mos S1 + CPT33%5.7 mos12.5 mos S1 + CPT***42%N/A12.8 mos (IRIS) S1 + CDDP*54%6.0 mos13.0 mos *Koizumi. Lancet Oncol 2008 # Boku. Lancet Oncol 2009 **Ikeda. Proc ASCO 2009 ***Imamura. Proc ASCO 2008

Conclusions The authors conclude that neither S1+ paclitaxel or S1 + irinotecan should be developed further – I agree! S1 seems to be happiest by itself … or perhaps with cisplatin. Where are the biologics – there seem to be no combinations with S1?

“West” Can we improve DCF?

DCF: What do you do with an active regimen that causes 82% G3-4 ANC and 81% G3-4 non-heme toxicity? Dose and Schedule AuthorRegimenSitePts.RRANCNon-hemeOS Van Cutsem. J Clin Oncol ‘06 DCF original Gastric22137%82%Stomatitis 21% 9.2mo. Park. Am J Clin Oncol’05 Low dose D + C F Gastric4740%68%Stomatitis 21% 9.7mo. Lorenzen. Ann Oncol 2007 DC q 2wks + AIO GEJ Gastric 6047%22%Diarrhea 20% 15.1mo Overman. Cancer 2010 Weekly DCF retrospective Esoph Gastric 9534%4%Hospital 23% 8.9mo Tebbutt. Br J Cancer 2010 Weekly D q 3 wk CF Esoph Gastric 5047%10%Diarrhea 22% 11.2mo

DCF: What do you do with an active regimen that causes 82% G3-4 ANC and 81% G3-4 non-heme toxicity? Substitutions AuthorRegimenSitePts.RRANCNon-hemeOS van Cutsem. J Clin Oncol ‘06 DCF original Gastric22137%82%Stomatitis 21% 9.2mo. Shankaran. GI Symp’09 Docetaxel Oxali /5-FU GEJ Gastric 3574%18%Neuro 21% 10.3mo Moehler. ASCO’09 Docetaxel Oxali/Cape Gastric2536%3%Diarrhea 23% N/A Sato. ASCO’08 D C S1Gastric3187%52%N/V 27%18.9mo. Enzinger. Ann Oncol ‘09 D C Cpt weekly Esoph Gastric 5654%21%Diarrhea 26% 11.9mo.

Conclusions DCF is too toxic – worst way of giving either cisplatin or fluorouracil Smaller, more frequent doses or substitutions are better but which one? or both? Randomized trials are needed to move this forward:

DCF: What do you do with an active regimen that causes 82% G3-4 ANC and 81% G3-4 non-heme toxicity? Dose and Schedule Substitutions (Shah)(Al-Batran) FLO (mFOLFOX) 5-FU 2600 mg/m² Folinic acid 200 mg/m² Oxaliplatin 85 mg/m² Every two weeks FLOT Docetaxel 50mg/m 2 5-FU 2600 mg/m² Folinic acid 200 mg/m² Oxaliplatin 85 mg/m² Every two weeks RANDOMIZATIONRANDOMIZATION DCF (original) Docetaxel 75mg/m 2 Cisplatin 75mg/m 2 5-FU 750mg/m 2 /d CI x 5d Every three weeks mDCF Docetaxel 40mg/m 2 Cisplatin 40 mg/m², day 3 Leucovorin 400 mg/m² 5-FU 400 IVP 5-FU 1000 mg/m²/d CI x 2d Every two weeks RANDOMIZATIONRANDOMIZATION

DCF: What do you do with an active regimen that causes 82% G3-4 ANC and 81% G3-4 non-heme toxicity? Dose and Schedule Substitutions (mDCF)(FLOT) Disease siteGEJ, Gastric Stageinop, metastaticinop, metast, loc adv, recurrent Response Rate 52%49% (incl loc adv) 6-month PFS63%60% (inop/metastatic) Overall Survival 15.1 mo (9.7 – 20.4) est. 17mo (incl loc adv) Neutropenia54%52% Nausea 0%21% Diarrhea 2% 9% Neuropathy 2%20% Fatigue10%11%

Conclusions Hard to choose between the two; mDCF perhaps less toxic but more complicated mDCF arm is still in progress and must wait for 6 mo PFS primary endpoint FLOT– higher RR and toxicity more suited for adjuvant comparison Randomization against ECF would require large pt numbers for significant difference

Matrix Metalloproteinase-9 mRNA expression What do we do with a new prognostic molecular factor in esophagogastric ca?

Other Molecular Prognostic Markers “Hundreds” of prognostic molecular markers for gastric cancer in the literature … HER2/neu – prognostic and antibody is effective VEGF – prognostic – AVAGAST on Monday EGFR – prognostic  REAL 3 and EXPAND

Impressive Results! Median OS: 5,5 mo vs. 11,9 mo 1 yr Survival: 25% vs. 50% 2 yr Survival: 0% vs. 26% Validation Cohort Pooled OS by Quartile MMP-9 effect only in highest quartile Independant by multivariate analysis

Questions? Training & Validation Cohorts in “cisplatin-based” therapy – same results in non-platinum regimens or Asian patients? Are there agents that target MMP-9? - ATRA*? Epigallocatechine-3-gallate**? If interacts with angiogenesis or EGFR pathway, what would be the effect in bevacizumab or anti-EFGR studies? Should one change treatment based on MMP9 status? More aggressive for high? What about adjuvant? *Dutta. Cell Adh Migr **Farabegoli. Biosci Rep. 2010

Next steps … 1 st step is for another group to run a validation cohort (West and East Asia) Ideal cohorts to test interaction with MMP-9 would be the AVAGAST, REAL 3, and EXPAND studies Too early for treatment changes – everybody gets max tolerated chemo for metastatic dz and in the adjuvant setting anyway.

Thank You!