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Johanna Bendell, MD Sarah Cannon Research Institute

Upper Gastrointestinal Overview 2007-2008: Practical Implications of the Newest Data Esophageal and Gastric Cancers. Johanna Bendell, MD Sarah Cannon Research Institute. Conflict of Interest Disclosure. Consultant or Advisory Role Amgen Array Pharmaceuticals Genentech Roche

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Johanna Bendell, MD Sarah Cannon Research Institute

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  1. Upper Gastrointestinal Overview 2007-2008: Practical Implications of the Newest DataEsophageal and Gastric Cancers Johanna Bendell, MD Sarah Cannon Research Institute

  2. Conflict of Interest Disclosure • Consultant or Advisory Role • Amgen • Array Pharmaceuticals • Genentech • Roche • Honoraria • Amgen • Roche • Genentech • Array Pharmaceuticals • Research Funding • Bristol-Myers Squibb • Genentech • Roche • Sanofi-Aventis • Novartis

  3. Esophageal Cancer • 16,470 new cases estimated for 2008 • 14,280 estimated deaths • Adenocarcinoma incidence rate increasing by 20% per year in U.S • EtOH, tobacco, obesity, genetics, diet • Barrett’s esophagus • Older trials have more patients with SCC • Adenocarcinomas predominate most trials now • Is there a difference? • GE junctional cancers • Increase in distal esophageal and proximal gastric cancers • Is there a difference?

  4. Localized disease • Controversy • Surgery alone • Preoperative chemotherapy • Preoperative chemoradiation therapy • Chemoradiation therapy alone

  5. Preoperative chemotherapy

  6. ACCORD 07-FFCD 9703 Randomization S CT + S FP (*) x 2/3 every 28 days Within 4 weeks 4 - 6 weeks Resection Resection 4 – 6 weeks FP x 3/4 or no treatment Follow-up (*) FP = 5FU: 800 mg/m² CI x 5 days - CDDP: 100 mg/m² at d1 or d2, 1-hr infusion Boige, ASCO 2007

  7. S N = 111 Preop CT (2-3 cycles) N = 98 (89%) Surgery N = 109 (96%) Surgery N = 110 (99%) Postop CT (1-4 cycles) N = 54 (51%) Trial profile CT + S N = 113 Boige, ASCO 2007

  8. Logrank p value = 0.0033 Hazard Ratio = 0.65 (95% CI 0.48-0.89) ___ S ___ CT + S years 0-0.5 1 2 3 4 5 6 7 111 57 35 28 21 14 11 6 113 77 53 44 34 25 17 14 At risk Disease-free survival 5-year DFS: 21% (14-30%) vs 34% (26-44%) Boige, ASCO 2007

  9. Overall survival Logrank p value = 0.021 Hazard Ratio = 0.69 (95% CI 0.50-0.95) ___ S ___ CT + S years At risk 5-year OS: 24% (16-33%) vs 38% (28-47%) Boige, ASCO 2007

  10. ACCORD07-FFCD 9703 • Preoperative chemotherapy • 14% improvement in 5 year OS • Similar to MAGIC (13%) • MRC Preop ECF vs. CF • Decrease in systemic recurrence • Local recurrence 26% (S) vs. 24% (CT+S) • Systemic recurrence 56% (S) vs. 42% (CT+S)

  11. Preoperative Chemoradiation

  12. POET Trial Arm A Week Arm B PLF I PLF II PLF III (3 weeks) Surgery 1 6 7 1314 17 20-21 15 x 2 Gy in 3 weeks Surgery PLF I PLF II PE (1 week) PLF: Cisplatin 50mg/m2, 1h, d 1,15,29. Leucovorin/5-FU 500mg/m2 2h / 2g/m2 24h, d 1,8,15,22,29,36 PE: Cisplatin 50 mg/m2, 1h, d 2+8. Etoposide 80 mg/m2, 1h, d 3-5 Stahl, ASCO 2007

  13. Overall Survival Logrank p = 0.07 HR Arm B vs. A 0.67 (0.41-1.07) Arm B 47.4% Arm A 27.7% Follow-up 45.6 mo Stahl, ASCO 2007

  14. Freedom from Local Tumor Progression Arm B 76.5% Logrank p = 0.06 HR Arm B vs. A 0.45 (0.19 -1.05) 59.0% Arm A Stahl, ASCO 2007

  15. Neoadjuvant vs. adjuvant approach • Roth, et al. World GI 2007 • Randomized 70 patients with locally advanced gastric cancer to 4 cycles of preoperative or adjuvant DCF • Original plan to randomize 252 patients • Closed early due to poor accrual

  16. S =>TCF N = 35 Preop CT (4 cycles) Started N=33 (97%) Completed N= 25 (74%) Surgery N = 32 (94%) Surgery N = 35 (100%) Postop CT (4 cycles) Started N = 23 (66%) Completed N = 12 (34%) SAKKNeoadjuvant vs. Adjuvant Trial TCF => S N = 34 pCR in 4 patients (12.9%) Roth, World GI 2007

  17. What do we see in local treatment of esophageal cancer? • Many of these trials are mixed populations • Adeno, SCC • Esophageal, GE junction, gastric cancers – accrual issues • Surgery alone is not enough • Preoperative chemotherapy improves survival for patients (now 3/4 trials, 1 meta-analysis) • Preoperative chemoradiation therapy likely better than surgery alone, and maybe better than chemotherapy alone • Chemoradiation more toxic • True for squamous and adenos • Subgroup of patients who do not need surgery?

  18. What do we do now? • CRITICS Trial • Preoperative ECX, rand postop chemoradation or chemo alone • Korean Trial • Preoperative cisplatin/capecitabine, then randomization to chemoradiation or chemo alone • CALGB 80101 • Postoperative chemoradiation with 5-FU or ECF • MRC OEO5 • Preoperative ECF vs. CF • MAGIC 2 • Preoperative ECX with or without bevacizumab • RTOG 0436 • Preoperative chemoradiation with or without cetuximab • CALGB 80302 • PET as prognostic indicator

  19. Metastatic Gastric Cancer • Gastric cancer • 21,500 new cases expected in the U.S. in 2008, 10, 880 deaths • Unclear as to what is best metastatic regimen • ECF, DCF, IC, EOX? • Role of oral fluoropyrimidines • Is combination therapy better than sequential?

  20. S-1 • Oral fluoropyrimidine consisting of tegafur, CDHP, and OXO in a 1:0.4:1 molar ratio • tegafur is converted to 5-FU • CDHP (chloro-2.4-dihydroxypyridine) inhibits DPD, preventing 5-FU degradation • OXO (potassium oxonate) protects against drug induced diarrhea caused by phosphorylation of 5-FU by inhibiting the responsible enzyme – OPRT (oronate phosphoribosyl transferase)

  21. Phase III Study (JCOG9912) 5-FU CI 800 mg/m2/day, ci, days 1-5 q 4 weeks CPT-11 + CDDP Randomization CPT-11 70 mg/m2, div, days 1&15 CDDP 80 mg/m2, div, day 1 q 4 weeks S-1 S-140mg/m2, po, bid, days 1-28 q 6 weeks Continued until disease progression, unacceptable toxicities, patient’s refusal BSA < 1.25 80 mg/body/day 1.25 < BSA < 1.5 100 mg/body/day 1.5 < BSA 120 mg/body/day Boku, ASCO 2007

  22. Progression-free Survival and Response rate (%) 100 PFS 50 0 12 24 (months) P-value† Median n HR 95%C.I. 5-FU CI - 2.9M 234 - - CPT-11+CDDP <0.001 4.8M 236 0.69 0.57-0.83 S-1 0.001 4.2M 234 0.75 0.62-0.90 †: one-sided log-rank test (superiority) Response rate - in pts with target lesion - CR and PR were confirmed by central review Boku, ASCO 2007

  23. Overall Survival (%) 100 50 0 12 24 36 (months) Boku, ASCO 2007 Significance level‡ P-value n MST 1-yr HR 95%C.I. 5-FU CI 234 10.8M 44.0% - - - 0.05 CPT-11+CDDP 236 12.3M 52.5% 0.85 0.70-1.04 0.055† S-1 234 11.4M 47.9% 0.83 0.68-1.01 0.034† 0.025 0.025 non-inferiority <0.001 †: one-sided log-rank test (superiority) ‡: multiplicity adjusted by Holm’s method

  24. JCOG 9912 • S-1 is non-inferior to CI 5-FU • Cisplatin/irinotecan better than CI 5-FU • Cisplatin/irinotecan (this regimen) more toxic • S-1 results approximate combination therapy

  25. SPIRITS Trial • Central Randomization • (dynamic balancing) • Adjustment Factors: • Institute • PS • Unresectable vs Recurrent S-1 alone S-1: 40-60 mg BID for 28 days q6wks AGC No prior Chemo. R S-1 + CDDP S-1: 40-60 mg BID for 21 days q5wks CDDP: 60 mg/m2 iv on day 8 Narahara, ASCO 2007

  26. Overall Survival Estimated probability (%) Log-rank p-value: 0.0366 HR: 0.774 [ 95% CI: 0.608 – 0.985] Median follow-up time (M): 34.6 11.0 13.0 Months Narahara, ASCO 2007

  27. Progression-Free Survival Estimated probability (%) Log-rank p-value: <0.0001 HR:0.567 [ 95% CI: 0.437 – 0.734] 4.0 6.0 Narahara, ASCO 2007 Months

  28. Overall Response Fisher’s Exact Test p-value: 0.0018 • Criteria : RECIST (Extramural Review) Narahara, ASCO 2007

  29. IRIS GC0301/TOP-002 • Randomized phase III study • 326 patients randomized • S-1 alone vs. S-1 plus irinotecan • Response rate • 26.9% vs. 41.5% • 1-year survival • 44.9% vs. 52.0%, NS • 22% of patients were censored Imamura, GI ASCO 2008

  30. Metastatic Gastric Cancer • We still don’t know the optimal regimen for patients with metastatic disease • Combination vs. sequential therapy • Role of oral fluoropyrimidines, newer platinum agents, taxanes • More S-1 studies are forthcoming • FLAGS - 1053 pts, accrual completed 3/07 • 5-FU/cis vs. S-1/cis • Trials of biologics are underway • AVAGAST – capecitabine/cisplatin with or without bevacizumab • CALGB 80403 – FOLFOX-cetuximab, cisplatin/irinotecan-cetuximab, ECF-cetuximab • ToGA – capecitabine/cisplatin with or without trastuzumab

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