ASCO ‘04 in PerspectiveGI Highlights

George A. Fisher M.D. Ph.D.Stanford University School of Medicine

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

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

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

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)

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

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

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

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

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)

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

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

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

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

Optimox 2 Trial [using mFOLFOX7]

2400FOLFOX7 400130

3000mFOLFOX7100400

RANDOMIZATION

mFOLFOX7 x 6 no rx until PD mFOLFOX7

mFOLFOX7 x 6 LV5FU2 mFOLFOX7

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

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)

Integrating Parallel Successes Bevacizumab: Role in first line

FOLFOX >> IFL IFL + Bevacizumab > IFL

??FOLFOX + Bev > FOLFOX

FOLFOX ~ FOLFIRI

??FOLFIRI + Bev > FOLFIRI

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

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

Proposed Intergroup Trial

RANDOMIZATION

Investigator’s Choice:

mFOLFOX6

CAPOX

FOLFIRI

[CAPIRI]

+ Bevacizumab

+ Cetuximab

+ Bevacizumab + Cetuximab

“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

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

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]

“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

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