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ASCO ‘04 in Perspective GI Highlights

ASCO ‘04 in Perspective GI Highlights. George A. Fisher M.D. Ph.D. Stanford University School of Medicine. ASCO ‘03 GI Highlights A Tough Act to Follow. First (+) adjuvant colon trial in >10 years Mosaic Trial: LV5FU2 vs. FOLFOX4 “Targeted” therapies in metastatic colon

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ASCO ‘04 in Perspective GI Highlights

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  1. ASCO ‘04 in PerspectiveGI Highlights George A. Fisher M.D. Ph.D. Stanford University School of Medicine

  2. ASCO ‘03 GI HighlightsA Tough Act to Follow • First (+) adjuvant colon trial in >10 years • Mosaic Trial: LV5FU2 vs. FOLFOX4 • “Targeted” therapies in metastatic colon • First line: IFL + Bevacizumab • Second line: Cetuximab + Irinotecan • Encouraging early results Phase III pancreas • GemOx vs Gem: response and DFS improvements

  3. GEM vs GEMOX (Louvet et al #4008)The GERCOR Pancreatic Trial R A N D O M I Z A T I O N Gemcitabine 1000 mg/m2 over 30 min Weekly x 7, then 3 weeks of 4 Gemcitabine 1000 mg/m2 (10 mg/m2/min) day 1 Oxaliplatin 100 mg/m2 2 hour infusion day 2 Every 2 weeks

  4. GEM vs GEMOX Efficacy

  5. Current ECOG TrialMetastatic Pancreas Cancer R A N D O M I Z A T I O N Gemcitabine 1000 mg/m2 over 30 min Weekly x 7, then 3 weeks of 4 Gemcitabine 1000 mg/m2 (10 mg/m2/min) Gemcitabine 1000 mg/m2 (10 mg/m2/min) day 1 Oxaliplatin 100 mg/m2 2 hour infusion day 2 Every 2 weeks

  6. Rectal Cancer ASTRO ‘03The German pre-op vs. post-op trial 50.4 Gy CI 5-FU Surgery 5-FU x 4 R A N D O M I Z A T I O N T3Nx Rectal Surgery 50.4 Gy 5-FU x 4 CI 5-FU

  7. Rectal Cancer ASTRO ‘03The German pre-op vs. post-op trial

  8. Capecitabine vs. Infusional 5-FU Concurrent with Neoadjuvant XRT[Randomized Phase III NSABP R-04] R A N D O M I Z A T I O N • Endpoints: • path response • local relapse • - down staging • - sphincter sparing • - quality of life • - biomarkers S U R G E R Y Capecitabine (825/m2 bid) + radiation T3-4 or N1 Rectal 5-FU infusion (225/m2 daily) + radiation

  9. Preoperative Chemoradiotherapy: A Phase I/II Rectal TrialKuo et al.Stanford University Endpoints: -toxicity -op morbidity -path response -downstaging -sphincter -molecular, imaging and circulating cell correlates S U R G E R Y Radiation therapy Cetuximab q week Capecitabine M-F Oxaliplatin q 2wks US T3/4 or N1 Rectal Cancer Biopsy Day 0 Biopsy Day 8 PET PET

  10. Origin of FOLFOX Bolus 400 Bolus 400 LV5FU2 (1984) 200 600 600 200 1997 (De Gramont et al. JCO): Better response rate with less toxicity than bolus 5-FU (Mayo regimen) Bolus 400 Bolus 400 FOLFOX4 (1995) 200 600 200 600 85 2000 (De Gramont et al. JCO):Better response rate and DFS than LV5FU2 2004 (Goldberg et al. JCO): Better response rate / DFS / OS with less toxicity than IFL (Saltz regimen)

  11. Evolution of FOLFOX Regimens Bolus 400 Bolus 400 FOLFOX4 (1995) 200 600 200 600 85 Bolus 400 FOLFOX6 (1997) 2400-3000 400 100 FOLFOX7 (1998) 400 2400 130 24 hr 48 hr Doses mg/m2: 5-FU,oxaliplatin,leucovorin

  12. FOLFOX4Reasons for Discontinuation • Reanalysis of Intergroup Study N9741 • 43% patients off study due to progressive disease • 57% for “other” reasons” • 23% neurotoxicity • 23% myelosuppression • 7% hypersensitivity • 9% Complete response or secondary resection of mets • 29% Patient refusal: unspecified • 9% Other Axel Grothey et al

  13. Optimox I [De Gramont #3525]Optimizing Oxaliplatin:Concept of Intermittent Therapy R A N D O M I Z A T I O N FOLFOX4 to progressive disease or intolerance Bolus 400 Bolus 400 200 600 200 600 85 FOLFOX7 x 6 LV5FU2 to PD FOLFOX7 400 2400 130

  14. Optimox 1 [De Gramont #3525]Optimizing OxaliplatinConcept of Intermittent Therapy FOLFOX4 FOLFOX7 Response rate 58.5% 58.3% PFS (mos) 9.0 9.2 OS (mos) 20.0 21.6 G3/4 N-Tox 18.7% 13.3% -more acute thrombocytopenia, N / V, cold sensitivity with FOLFOX 7 vs. FOLFOX 4 -variable adherence to protocol by center (resuming FOLFOX7) -protocol adherence correlated with improved survival

  15. Optimox 2 Trial [using mFOLFOX7] FOLFOX7 400 2400 130 mFOLFOX7 400 3000 100 R A N D O M I Z A T I O N mFOLFOX7 x 6 no rx until PD mFOLFOX7 mFOLFOX7 x 6 LV5FU2 mFOLFOX7

  16. Oxaliplatin NeuropathyPossible Protection by Ca/Mg • Ca2+ gluconate + Mg2+ sulfate 1 gram each before and after oxaliplatin • Post-hoc analysis of 161 patients • Gamelin et al, Clin Cancer Research 2004 • % pts stopping due to neurotoxicity • 35% controls vs 5% for Ca / Mg treated • No decrement in response rate

  17. CONcePT: Optimization of FOLFOX + Bevacizumab2 x 2 randomization: 532 patients mFOLFOX7 + Bevacizumab Continued until treatment failure + placebo mFOLFOX7 + Bevacizumab Continued until treatment failure + Ca/Mg mFOLFOX7 + Bevacizumab Intermittent oxali therapy + placebo mFOLFOX7 + Bevacizumab Intermittent oxali therapy + Ca/Mg 400 (LV) *mFOLFOX7 3000 (5-FU) 85 (Ox) 5 (Bev)

  18. Integrating Parallel SuccessesBevacizumab: Role in first line FOLFOX >> IFL IFL + Bevacizumab > IFL ??FOLFOX + Bev > FOLFOX FOLFOX ~ FOLFIRI ??FOLFIRI + Bev > FOLFIRI

  19. Bevacizumab: CurrentCooperative Group Trials Second Line ECOG Trial completed; results ASCO ‘05 FOLFOX4 + Bev Results expected fall/winter ‘04; ASCO ‘05 First Line SWOG Trial: (underway) [mFOLFOX6 vs. CAPOX] + Bevacizumab Adjuvant NSABP Trial: (activation 10/04?) Stage II / III colon cancer mFOLFOX6 + Bevacizumab

  20. EGFR Inhibition with First Line FOLFOX Chemotherapy *Gefitinib at 500 mg; higher GI toxicity c/w FOLFOX **Eligibility required EGFR(+) tumors

  21. Proposed Intergroup Trial + Bevacizumab R A N D O M I Z A T I O N Investigator’s Choice: mFOLFOX6 CAPOX FOLFIRI [CAPIRI] + Cetuximab + Bevacizumab + Cetuximab

  22. First line therapy Good performance status FOLFOX (n) vs CAPOX + Bevacizumab FOLFIRI vs CAPIRI + Bevacizumab Poor KPS Capecitabine or 5-FU + Bevacizumab Liver mets only Consider resection of responders Second line therapy If first line irinotecan Capecitabine CAPOX or FOLFOX Cetuximab (if EGFR +) Cetuximab + irinotecan If first line oxaliplatin Irinotecan Irinotecan + cetuximab “Reasonable” Options for Metastatic Disease ALWAYSCONSIDER CLINICAL TRIALS

  23. Recently Completed Adjuvant Trials for Colon Cancer • Intergroup Stage III: • IFL vs Roswell Park 5-FU/LV (Saltz #3500) • NSABP Stage II/III: • *Bolus 5-FU/oxali vs Roswell Park 5-FU/LV • European Trials Stage II/III • *FOLFIRI vs LV5-FU2 • UK Study: Continuous infusion 5-FU x 3 mos vs bolus 5-FU/LV x 6 months • FOLFOX vs LV5-FU2 • Capecitabine vs bolus 5-FU Stage III (Cassidy #3509) *no efficacy data available to date

  24. Bolus 5-FU (Mayo) vs Capecitabine for Stage IIIX-ACT Trial (Cassidy # 3509) Standard Mayo Clinic bolus 5-FU regimen x 6 versus Capecitabine (1250 mg/m2 bid x 14 d q 3wks) x 8 Median follow-up 3.8 years • Significantly decreased gr 3/4 diarrhea, stomatitis and neutropenia • 3 year DSF [HR = 0.87; p = 0.0526] • 3 year Overall survival [HR = 0.84; NS]

  25. Stage II Assess risk Clinical parameters Molecular markers High risk FOLFOX vs CAPOX vs. Capecitabine Low risk Observation vs. capecitabine Stage III Good performance status FOLFOX vs. CAPOX Poor performance status Capecitabine vs. observation “Reasonable” Options for Adjuvant Therapy ALWAYS CONSIDER CLINICAL TRIALS

  26. ASCO ‘03-04: Implications • No role for IFL / Vanishing role for bolus 5-FU • “Acceptable”, even “recommended” options include regimens with no Phase II data • FOLFOX or FOLFIRI + Bevacizumab first line colon • Irinotecan + cetuximab after FOLFOX failure • Consistently high activity with EGFR inhibitors and fluoropyrimidine /oxali regimens • Three phase II studies with > 75% response rates 1st line • The Stage II dilemma continues • Less toxic adjuvant options may shift risk-benefit • Back to the drawing board: • pancreas, gastric, esophageal and hepatocellular

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