ASCO ‘04 in Perspective GI Highlights
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Transcript of ASCO ‘04 in Perspective GI Highlights
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ASCO ‘04 in PerspectiveGI Highlights
George A. Fisher M.D. Ph.D.Stanford University School of Medicine
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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
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GEM vs GEMOX (Louvet et al #4008)
The GERCOR Pancreatic Trial
RANDOMIZATION
Gemcitabine 1000 mg/m2 over 30 minWeekly x 7, then 3 weeks of 4
Gemcitabine 1000 mg/m2 (10 mg/m2/min) day 1Oxaliplatin 100 mg/m2 2 hour infusion day 2Every 2 weeks
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GEM vs GEMOX EfficacyGEM GEMOX p value
Response rate 17.3% 26.8% .044 Locally adv. 14.9% 27.4% Metastatic 18.3 26.4%Prog. Free Surv. 3.7 mos 5.8 mos .038Clinical Benefit 26.9% 38.2% .03Overall Survival 7.1 mos 9.0 mos ns1-yr survival 27.8% 34.7% ns
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Current ECOG TrialMetastatic Pancreas Cancer
RANDOMIZATION
Gemcitabine 1000 mg/m2 over 30 minWeekly x 7, then 3 weeks of 4
Gemcitabine 1000 mg/m2 (10 mg/m2/min) day 1Oxaliplatin 100 mg/m2 2 hour infusion day 2Every 2 weeks
Gemcitabine 1000 mg/m2 (10 mg/m2/min)
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Rectal Cancer ASTRO ‘03The German pre-op vs. post-op trial
RANDOMIZATION
T3NxRectal
50.4 GyCI 5-FU Surgery 5-FU x 4
Surgery 50.4 Gy 5-FU x 4 CI 5-FU
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Rectal Cancer ASTRO ‘03The German pre-op vs. post-op trial
Saur et al ASTRO ‘03
Post-opN= 394
Pre-opN= 405
p value
5 yr Local Failure 12% 6% .006
5 yr survival 74% 74% ns
Acute Toxicity 40% 28% .005
Chronic Toxicity 23% 10% .04
Sphincter Preservation
20%(17/85)
39%(43/109)
.004
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Capecitabine vs. Infusional 5-FU Concurrent with Neoadjuvant XRT
[Randomized Phase III NSABP R-04]
T3-4orN1
Rectal
Capecitabine (825/m2 bid)+ radiation
5-FU infusion (225/m2 daily)+ radiation
SURGERY
Endpoints:-path response-local relapse- down staging- sphincter sparing- quality of life- biomarkers
RANDOMIZATION
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Preoperative Chemoradiotherapy: A Phase I/II Rectal Trial
Kuo et al. Stanford University
US T3/4or N1RectalCancer
BiopsyDay 8
BiopsyDay 0
Radiation therapyCetuximab q weekCapecitabine M-FOxaliplatin q 2wks
SURGERY
PET PET
Endpoints:-toxicity-op morbidity-path response-downstaging-sphincter-molecular, imaging and circulating cell correlates
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Origin of FOLFOX
600600FOLFOX4(1995)
200
Bolus 400Bolus 400
85 200
Bolus 400Bolus 400
600600LV5FU2(1984) 200
Bolus 400Bolus 400
200
Bolus 400Bolus 400
1997 (De Gramont et al. JCO): Better response rate with less toxicity than bolus 5-FU (Mayo regimen)
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)
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600600FOLFOX4(1995)
Doses mg/mDoses mg/m22: 5-FU,: 5-FU, oxaliplatinoxaliplatin,, leucovorinleucovorin
Bolus 400Bolus 400
FOLFOX6(1997)
2400FOLFOX7(1998)
Evolution of FOLFOX Regimens
200
Bolus 400Bolus 400
85200
400100
2400-3000
400130
Bolus 400Bolus 400
48 hr24 hr
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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
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Optimox I [De Gramont #3525]Optimizing Oxaliplatin:
Concept of Intermittent Therapy
RANDOMIZATION
FOLFOX4 to progressive disease or intolerance
FOLFOX7 x 6 LV5FU2 to PD FOLFOX7
600600200
Bolus 400Bolus 400
85200
Bolus 400Bolus 400
2400400130
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FOLFOX4 FOLFOX7Response rate 58.5% 58.3%PFS (mos) 9.0 9.2OS (mos) 20.0 21.6G3/4 N-Tox 18.7% 13.3%
Optimox 1 [De Gramont #3525]Optimizing Oxaliplatin
Concept of Intermittent Therapy
-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
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Optimox 2 Trial [using mFOLFOX7]
2400FOLFOX7 400130
3000mFOLFOX7100400
RANDOMIZATION
mFOLFOX7 x 6 no rx until PD mFOLFOX7
mFOLFOX7 x 6 LV5FU2 mFOLFOX7
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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
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CONcePT: Optimization of FOLFOX + Bevacizumab
2 x 2 randomization: 532 patients
mFOLFOX7 + Bevacizumab Continued until treatment failure + placebo
mFOLFOX7 + Bevacizumab Intermittent oxali therapy + placebo
mFOLFOX7 + Bevacizumab Intermittent oxali therapy + Ca/Mg
mFOLFOX7 + Bevacizumab Continued until treatment failure + Ca/Mg
3000 (5-FU)*mFOLFOX7 85 (Ox)400 (LV)
5 (Bev)
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Integrating Parallel Successes Bevacizumab: Role in first line
FOLFOX >> IFL IFL + Bevacizumab > IFL
??FOLFOX + Bev > FOLFOX
FOLFOX ~ FOLFIRI
??FOLFIRI + Bev > FOLFIRI
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Bevacizumab: CurrentCooperative Group Trials
Second Line ECOG Trial completed; results ASCO ‘05FOLFOX4 + BevResults 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 cancermFOLFOX6 + Bevacizumab
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EGFR Inhibition with First Line EGFR Inhibition with First Line FOLFOX ChemotherapyFOLFOX Chemotherapy
ASCO‘04
Treatment Number ofPatients
ResponseRate
Fisher et al#3514
*Gefitinib +FOLFOX 4
36 78%
Taberneroet al #3512
**Cetuximab + FOLFOX 4
42 81%
*Gefitinib at 500 mg; higher GI toxicity c/w FOLFOX**Eligibility required EGFR(+) tumors
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Proposed Intergroup Trial
RANDOMIZATION
Investigator’s Choice:
mFOLFOX6
CAPOX
FOLFIRI
[CAPIRI]
+ Bevacizumab
+ Cetuximab
+ Bevacizumab + Cetuximab
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“Reasonable” Options for Metastatic Disease
• 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
ALWAYS CONSIDER CLINICAL TRIALS
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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
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Bolus 5-FU (Mayo) vs Capecitabine for Stage III
X-ACT Trial (Cassidy # 3509)
Standard Mayo Clinic bolus 5-FU regimen x 6 versusCapecitabine (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]
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“Reasonable” Options for Adjuvant Therapy
• 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
ALWAYS CONSIDER CLINICAL TRIALS
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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