management of metastatic colorectal cancer: focus on targeted therapy
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Jimmy Hwang, MDAssociate Professor, Hematology/Oncology
John L. Marshall, MDAssociate Professor, Hematology/Oncology
Department of MedicineLombardi Cancer CenterGeorgetown University HospitalWashington, DC
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Colorectal Cancer: Epidemiology
Data from the United States (2006)[1]
– 148,610 new cases: third highest cancer incidence
– 55,170 deaths: second leading cause of cancer-related death in men, third leading cause in women
Worldwide (2002)[2]
– 1,023,256 new cases: third highest incidence after lung, breast cancer
– 529,020 deaths: fourth overall cause of cancer-related death after lung, gastric, liver cancer
1. Jemal A, et al. CA: Cancer J Clin. 2006;56:106-130.2. Kamangar F, et al. J Clin Oncol. 2006; 24:2137-2150.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Pathophysiology of Colorectal Cancer
Normal colonic epithelial cells transformed by histopathologic, molecular events
Adenomatous polyps
– Intermediate stage in carcinogenic process
– Polyps occur in 33% of general population by age 50
– 50% incidence by age 70
Genetic basis for adenoma transformation to colorectal cancer
– Mutations in APC, K-ras, at earlier, nonmalignant stages
– p53 mutation appears to trigger malignancyJanne PA, et al. N Engl J Med. 2000;342:1960-1968.Vogelstein B, et al. N Engl J Med. 1988;319:525-532.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
The Adenoma-Carcinoma Process
Mutations leading to formation of colorectal tumor
Kinzler KW, et al. New York, The genetic basis of human cancer. NY: McGraw-Hill, 1998:565-87. Vogelstein B, et al. N Engl J Med. 1988;319:525-532. Fearon ER, et al. Cell. 1990;61:759-767.
Normal colonic epithelium
Dysplastic aberrant crypt foci
Initial adenoma develops
Intermediate adenoma
Late adenoma
Carcinoma
Metastasis
Mutation in APC
Mutation in K-ras
Mutation in DCC
Mutation in p53
Other alteration?
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Screening and Cancer Prevention
Screening with colonoscopy may detect precancerous polyps and other early-stage disease[1]
– Recommended beginning at age 50, every 10 years
– May begin at 40 years for patients at increased risk
Aspirin, cyclooxygenase-2 (COX-2) inhibitors associated with reduction in incidence of colorectal adenomas[2,3]
Despite these techniques, ~ 25% of patients present with metastatic disease[4]
– Nearly one half of patients with colorectal cancer require systemic therapy
1. Regula J, et al. N Engl J Med. 2006;355:1863-1872. 2. Baron JA, et al. N Engl J Med. 2003;348:891-899. 3. Bertagnolli MM, et al. N Engl J Med. 2006;355:873-874.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Chemotherapy for Metastatic Colorectal Cancer Thymidylate synthase inhibitors
– Fluoropyrimidines: 5-FU (intravenous), capecitabine (oral)
– Raltitrexed
Topoisomerase I inhibitors
– Irinotecan
Alkylating agents
– Oxaliplatin
Traditional 5-FU–based chemotherapy associated with modestly improved survival
– Newer agents (ie, irinotecan, oxaliplatin) lengthen survival outcomes
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Fluoropyrimidines in Metastatic Disease No increase in survival benefit regardless of schedule
– Median survival: ~ 12 months
Regimen Response, %Bolus 5-FU 7-15
Infusional 5-FU 20-30
5-FU/LV
Mayo, Roswell schedules
de Gramont (LV5-FU2)
AIO (once weekly, 24-hour infusion)
12-35
28-33
25-44
Capecitabine 20-25
Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Multiple Active Agents Associated With Increased Survival Combinations of multiple active agents associated with better
outcome
– 5-FU, irinotecan, oxaliplatin
Compared with 5-FU/LV, use of all 3 active therapies associated with improved survival
– Median survival with triple-drug regimens: ~ 20 months
First-line doublet chemotherapy
– Associated with increased exposure to all 3 active agents during therapeutic course
Grothey A, et al J Clin Oncol. 2005;23:9441-9442.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Chemotherapy Efficacy Plateau
Median survival with addition of newer agents appears to plateau at 20 months
Meta-analysis Group in Cancer. J Clin Oncol. 1998;16:301-308. Saltz LB, et al. N Engl J Med 2000;343:905-914. de Gramont A, et al. J Clin Oncol. 2000;18:2938-2947. Goldberg RM, et al. J Clin Oncol. 2002;20:4591-4596. Tournigand C, et al. J Clin Oncol. 2004;22:229-237.
Combination Therapy Active Agents Median Survival, mos
5-FU/LV 1 drug 11-12
Irinotecan/5-FU 2 drugs 14-15
Oxaliplatin/5-FU ± irinotecan 3 drugs 17-20
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Molecular Targets in Metastatic Colorectal Cancer Epidermal growth factor receptor (EGFR)
Vascular endothelial growth factor receptor (VEGFR)
COX-2
Other targets
– Carcinoembryonic antigen
– Protein kinase C
– Matrix metalloproteinases
– Ras
– Cyclin dependent kinase
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
EGFR Inhibitors in Colorectal Cancer
EGFR overexpression found in up to 90% of metastatic tumors
– Activation of EGFR ultimately results in inhibition of apoptosis, malignant cell proliferation, migration, and angiogenesis
– EGFR-expressing tumors more aggressive with worse prognosis
Monoclonal antibodies targeting EGFR
– Cetuximab, panitumumab
Tyrosine kinase inhibitors (TKIs) of EGFR
– Gefitinib, erlotinib
Venook A. Oncologist. 2005;10:250-261 Mayer A, et al. Cancer. 1993;71:2454-2560.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
EGFR Inhibitors in Colorectal Cancer (cont’d) To date, few promising results with EGFR-targeted TKIs in
colorectal cancer setting
Phase II gefitinib study in 110 patients with refractory disease [1]
– 2 doses studied, only 1 response noted in higher-dose (500 mg) group
No objective responses noted in study of erlotinib in second-line setting[2]
To date, monoclonal antibodies have exhibited better activity in metastatic disease
1. Rothenberg ML, et al. J Clin Oncol. 2005;23:9265-9274.2. Townsely CA, et al. Br J Cancer. 2006;94:1136-1143.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Cetuximab ± Irinotecan: The BOND Study
Cunningham D, et al. N Engl J Med. 2004;351:337-345.
Patients with progressive
colorectal cancer on or within 3 months of
irinotecan-based chemotherapy
(N = 329)
Irinotecan dose and schedule used during progression
Cetuximab 400 mg/m2 1st infusion, then 250 mg/m2/week
(n = 218)
Cetuximab 400 mg/m2 1st infusion, then 250 mg/m2/week
(n = 111)
Irinotecan dose and schedule used during
progression Cetuximab 400 mg/m2
1st infusion, then 250 mg/m2/week
PD
PD, progressive disease.Primary endpoint: response.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
The BOND Study: Efficacy
Improved response, disease control, median TTP with irinotecan + cetuximab
Cunningham D, et al. N Engl J Med. 2004;351:337-345.
Irinotecan +
Cetuximab
Cetuximab Alone P Value
PR, % (95% CI) 22.9 (17.5-29.1) 10.8 (5.7-18.1) .0074
Disease control*,% (95% CI) 55.5 (48.6-62.2) 32.4 (23.9-42.0) .0001
Median TTP, mos 4.1 1.5 < .0001
Median survival, mos (95% CI) 8.6 (7.6-9.6) 6.9 (5.6-9.1) .48
*Disease control = complete and partial responses + stable disease.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
The BOND-2 Study
Saltz L, et al. ASCO 2005. Abstract 3508.
Bevacizumab/Cetuximab + Irinotecan*Cetuximab 400 mg/m2 loading dose followed by
250 mg/m2 weeklyBevacizumab 5 mg/kg every other week
Irinotecan at same dose and schedule given just before study entry
(n = 41)
Bevacizumab/Cetuximab*Cetuximab 400 mg/m2 loading dose followed by
250 mg/m2 weeklyBevacizumab 5 mg/kg every other week
(n = 40)
Metastatic colorectal cancer patients refractory
to irinotecan
(N = 81)
*Patients received cetuximab on Day 1 (plus irinotecan, if randomized to that arm) and bevacizumab on Day 2.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
BOND-2 Efficacy Results
Significant response for bevacizumab + cetuximab
– Addition of irinotecan improved responses
Saltz L, et al. ASCO 2005. Abstract 3508.
0
20
40
60
80
100
Par
tial
Res
po
nse
(%
)
37
232311
P = .05
P = .03
CET*
CET/BEV CET/IRI/BEV
CET/IRI*
*Historical controls.
Bevacizumab extends time to tumor progression vs historical controls
Median TTP
Time to Tumor Progression (Mos)
0 2 4 6 8 10 12
7.9
5.61.5
4.0
P < .01
P < .01
CET*
CET/BEV CET/IRI/BEV
CET/IRI*
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
BOND and BOND-2: Safety
BOND: overall incidence of adverse events higher in cetuximab-irinotecan arm; 65% vs 44%; P < .001
– Diarrhea, neutropenia more common with combination therapy
Acne-like rash in 80% of patients in each treatment arm
– Rash appeared within first 3 weeks of cetuximab treatment in majority of cases (89%)
BOND-2: no synergistic toxicity noted for combined therapies
– No antibody-related grade 3 allergic reactions; 17% to 20% incidence of antibody-related grade 3 rash
– Most common irinotecan-related toxicity; grade 3/4 diarrhea (24%), neutropenia (22%)
Cunningham D, et al. N Engl J Med. 2004;351:337-345.Saltz L, et al. ASCO 2005. Abstract 3508.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
CALGB 80203: Study Design
Venook A, et al. ASCO 2006. Abstract 3509.
Patients with untreated metastatic
colorectal cancer
(N = 238)*
FOLFOXOxaliplatin 85 mg/m2 Days 1, 8
LV 20 mg/m2 over 2 hours Days 1, 85-FU 500 mg/m2 bolus, Days 1, 8
every 3 weeks
FOLFIRIIrinotecan 180 mg/m2 Day 1
LV 400 mg/m2 over 2 hours Day 15-FU 400 mg/m2 bolus, then 2400 mg/m2 46-hour infusion
Days 1-2 every 3 weeks
Cetuximab 400 mg/m2 loading
dose, then 250 mg/m2 once weekly
(n = 55)
Placebo(n = 58)
Cetuximab 400 mg/m2 loading
dose, then 250 mg/m2 once weekly
(n = 55)
Placebo(n = 58)
*Original accrual goal of 2200 patients; after bevacizumab received FDA approval, study closed and redesigned in January 2005 as phase II randomized trial.
Primary endpoint: OS.Secondary endpoints: PFS, RR.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
CALGB 80203: Preliminary Data
PFS, OS: more follow-up needed
Addition of cetuximab appears to increase response
Venook A, et al. ASCO 2006. Abstract 3509.
Response, % FOLFOX + Cetuximab
FOLFIRI + Cetuximab FOLFOX FOLFIRI
ORR (CR + PR) 60 44 40 36
Response, % (P = .029) Chemotherapy + Cetuximab Chemotherapy Alone
ORR (CR + PR) 52 38
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
CALGB/SWOG 80405: Study Design
Patients with untreated metastatic
colorectal cancer
(N = 2289)*
Patient/physician choice: mFOLFOX6
orFOLFIRI
Cetuximab 400 mg/m2 IV Day 1, then 250 mg/m2 once weekly
Cetuximab 400 mg/m2 IV Day 1, then 250 mg/m2 once weeklyBevacizumab 5 mg/kg IV
every 2 weeks
Bevacizumab 5 mg/kg IV
every 2 weeks
*~300 patients enrolled as of November 2006.
Primary endpoint: OS.Secondary endpoints: PFS, RR.
Study open through CTSU.org
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Panitumumab in Colorectal Cancer
Activity in phase II studies
Panitumumab 2.5 mg/kg weekly in 148 previously treated patients
– PR: 9%; SD: 29%
– PFS: 3.1 mos; OS: 9.4 mos
Panitumumab combined with first-line IFL (n = 19), FOLFIRI (n = 24)
– Well tolerated in combination with FOLFIRI
– PR: 33%; SD: 46%
Based on these results, phase III study conductedMalik I, et al. ASCO 2005 Abstract 3520. Hecht J. ASCO GI 2006. Abstract 237.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Panitumumab vs BSC in Metastatic Colorectal Cancer
Peeters M, et al. AACR 2006. Abstract CP-1.
Patients with metastatic colorectal cancer who failed prior standard
chemotherapy(N = 463)
Panitumumab 6 mg/kg every 2 weeks +BSC
(n = 231)
BSC*
(n = 232)Stratification by ECOG score
(0-1 vs 2) and geographic locale
BSC, best supportive care.*Patients who experienced progressive disease eligible for crossover to panitumumab in optional, separate trial.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Panitumumab vs BSC: Main Findings
PFS significantly better for panitumumab-treated patients*
– HR: 0.54 (95% CI: 0.44-0.66; P < .000000001)
Peeters M, et al. AACR 2006. Abstract CP-1.
*Median follow-up: 19 weeks.
0
10
20
30
40
50
Wk 8 Wk 12 Wk 16 Wk 24 Wk 32 Wk 40 Wk 48
Pro
gre
ssio
n F
ree
(%)
Panitumumab + BSCBSC
1 1 1 30 49 35 14 26 9 18 5 10 4 4
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Panitumumab vs BSC: Main Findings (cont’d) Panitumumab efficacy consistent across all subgroups
42% of 174 BSC patients who switched over to separate panitumumab study achieved disease control
Peeters M, et al. AACR 2006. Abstract CP-1.
OutcomePanitumumab + BSC
(n = 231)BSC Alone(n = 232)
Disease control, n (%) 83 (36) 24 (10)
Partial response 19 (8) 0 (0)
Stable disease 64 (28) 24 (10)
Median time to response, wks (min, max) 8 (7, 15) --
Median duration of response, wks (min, max) 17 (4, 40) --
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Panitumumab vs BSC: Other Outcomes Panitumumab generally well tolerated
– No patients experienced grade 3/4 infusion reactions
Peeters M, et al. AACR 2006. Abstract CP-1.
Safety Outcome, %Panitumumab + BSC
(n = 229)BSC Alone(n = 234)
Any grade 3/4 adverse event 34 19
Grade 3/4 skin toxicity 14 0
Dermatitis acneiform 7 0
Erythema 5 0
Pruritus 2 0
Rash 1 0
Grade 3/4 hypomagnesemia 3 0
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
VEGF-Targeted Therapy
VEGF pathway implicated in angiogenesis
– Inhibition of VEGF curbs angiogenesis, slows production of new blood vessels necessary for tumor growth
Monoclonal antibody against VEGF
– Bevacizumab
Anti-VEGFR TKIs
– Sunitinib
– Sorafenib
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Bevacizumab-Irinotecan in Metastatic Colorectal Cancer
Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342.
Patients with untreated metastatic
colorectal cancer
(N = 923)
IFLPlacebo(n = 411)
IFLBevacizumab 5 mg/kg;
every 2 weeks(n = 402)
5-FU/LVBevacizumab 5 mg/kg;
every 2 weeks(n = 110)
PD
PD*
PD*
Primary endpoint: survival.
*Patients receiving bevacizumab could continue therapy past disease progression in combination with second-line therapy.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Bevacizumab-Irinotecan in Metastatic Colorectal Cancer (cont’d)
Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342.
*By stratified log-rank test.†By chi2 test.
IFL + Placebo
(n = 411)
IFL + Bevacizumab (5
mg/kg, q2w)
(n = 402) P Value HR
Median survival, mos 15.6 20.3 < .001* 0.66
PFS, mos 6.4 10.6 < .001* 0.54
ORR, % 35 45 < .01†
Median duration of response, mos 7.1 10.4 .001 0.62 (for relapse)
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
The BICC-C Study: Original Design
Fuchs C, et al. ASCO 2006. Abstract 3506.
Patients with previously untreated metastatic
colorectal cancer
(N = 430)
FOLFIRI Irinotecan 180 mg/m2 Day 1
LV 100 mg/m2 over 2 hours Day 15-FU 400 mg/m2 bolus, then 2400 mg/m2 46-hour infusion Days 1, 2 every 2 weeks
(n = 144)
mIFLIrinotecan 125 mg/m2 Days 1, 8
LV 20 mg/m2 over 2 hours Days 1, 85-FU 500 mg/m2 bolus Days 1, 8
every 3 weeks(n = 141)
CapIRIIrinotecan 250 mg/m2 Day 1
Capecitabine 1000 mg/m2 twice daily Days 1-14 every 3 weeks
(n = 145)
Celecoxib 400 mg twice daily
Placebo
Primary endpoint: PFS for FOLFIRI vs mIFL.
Second randomization (all subjects)
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
The BICC-C Study: Modified Design
Fuchs C, et al. ASCO 2006. Abstract 3506.
Patients with previously untreated metastatic
colorectal cancer
After May 2004, patients
randomized to FOLFIRI or mIFL
plus bevacizumab
(N = 117)
FOLFIRI Bevacizumab 5.0 mg/kg;
every 2 weeks(n = 57)
mIFLBevacizumab 7.5 mg/kg;
every 3 weeks(n = 60)
CapIRIevery 3 weeks
Celecoxib 400 mg twice daily
Placebo
Second randomization (all subjects)
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
The BICC-C Study: Results
Longer median PFS with FOLFIRI vs mIFL or CapIRI (prior to addition of bevacizumab)
– FOLFIRI vs mIFL: 8 mos vs 6.2 mos; P = .01
– FOLFIRI vs CapIRI: 8 mos vs 5.7 mos; P = .01
Significant improvement in OS with FOLFIRI + bevacizumab compared with mIFL + bevacizumab
– HR: 2.5 (95% CI: 1.3-5.0; P = .01)
– Median OS not reached for FOLFIRI + bevacizumab vs 18.8 mos for mIFL + bevacizumab
No effect with celecoxib
Fuchs C, et al. ASCO 2006. Abstract 3506.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
BICC-C: Safety and Tolerability
More discontinuations in CapIRI group due to toxicity vs FOLFIRI or mIFL groups
– 17% vs 7% and 12%, respectively
Selected grade 3/4 events (prior to addition of bevacizumab)
Fuchs C, et al. ASCO 2006. Abstract 3506.
Grade 3/4 Adverse Events, % FOLFIRI (n = 144)
mIFL(n = 141)
CapIRI (n = 145)
Neutropenia 40 39 31
Febrile neutropenia 2 7 5
Diarrhea 13 19 48
Hand-foot syndrome 0 0 10
Dehydration 6 7 19
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
TREE 1 Study Design
mFOLFOXOxaliplatin 85 mg/m2 Day 1
LV 350 mg/m2 Day 15-FU 400 mg/m2 bolus, then 2400 mg/m2 46-hour infusion
Days 1, 2 every 2 weeks(n = 50)
bFOLOxaliplatin 85 mg/m2 Days 1, 15
LV 20 mg/m2 over 2 hours Days 1, 8, 155-FU 500 mg/m2 bolus Days 1, 8, 15 every 4 weeks
(n = 50)
CapeOxOxaliplatin 130 mg/m2 Day 1
Capecitabine 1000 mg/m2 twice daily Days 1-15 every 3 weeks
(n = 50)
Patients with inoperable, metastatic colorectal cancer
No prior chemotherapy for metastatic disease
(N = 223)
Primary endpoint: grade 3/4 toxicity.Secondary endpoints: RR, TTP, TTF.
Hochster HS, et al. ASCO 2006. Abstract 3510.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
TREE 2 Study Design*
mFOLFOX Bevacizumab 5.0 mg/kg
every 2 weeks(n = 75)
bFOL Bevacizumab 5.0 mg/kg
every 4 weeks(n = 74)
CapeOx†
Bevacizumab 7.5 mg/kgevery 3 weeks
(n = 74)
*TREE 1 study modified to include bevacizumab.†Reduced dose of capecitabine used in TREE 2: 850 mg/m2 Days 1-15.
Patients with inoperable, metastatic colorectal
cancer
(N = 223)
Hochster HS, et al. ASCO 2006. Abstract 3510.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
TREE Study: Efficacy Data
Hochster HS, et al. ASCO 2006. Abstract 3510.
TREE 1 TREE 2*
5 6
810
89
*With bevacizumab.
0
10
20
30
40
50
60
Overall Response Rate
Pat
ien
ts (
%)
Mo
nth
s
TREE 1 TREE 2*
17
22
43
48
41
53
TREE 1 TREE 2*
1719
27
20
26
35
CapeOx bFOL mFOLFOX
Median TTP Median OS
0
5
10
15
20
25
30
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
TREE: Summary of Safety and Tolerability Fewer treatment-related events in bFOL arm vs CapeOx or
FOLFOX during first 12 weeks of treatment
Increased hypertension with addition of bevacizumab
Tolerability of CapeOx improved with capecitabine dose reduction in TREE 2
Hochster HS, et al. ASCO 2006. Abstract 3510.
Treatment-Related Events, % (95% CI) FOLFOX bFOL CapeOx
TREE 1 59 (44-73) n = 49
36 (23-51)n = 50
67 (52-80)n = 48
TREE 2 59 (47-71)n = 71
51 (39-64)n = 70
56 (43-67)n = 72
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
ECOG E3200: Bevacizumab for Previously Treated Metastatic Disease
Giantonio BJ, et al. ASCO 2005. Abstract 2.
Previously treated, bevacizumab-naive
patients with metastatic CRC
(N = 822)
FOLFOX4 Oxaliplatin 85 mg/m2 Day 1
Leucovorin 200 mg/m2 IV over 2 hrs5-FU 400 mg/m2 bolus, then 600 mg/m2
over 22-hr continuous infusion Days 1-2 every 2 weeks(n = 290)
Bevacizumab 10 mg/kg every 2 weeks(n = 243)
FOLFOX4 + Bevacizumab Oxaliplatin 85 mg/m2 Day 1
Leucovorin 200 mg/m2 IV over 2 hrs5-FU 400 mg/m2 bolus, then 600 mg/m2
over 22-hr continuous infusion Days 1-2 every 2 weeks Bevacizumab 10 mg/kg every 2 weeks
(n = 289)
Terminated in March 2003 due to
inferiority vs other arms
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
ECOG E3200: Outcome With Addition of Bevacizumab Progression-free and overall survival increased with bevacizumab +
FOLFOX4
Increased toxicity with bevacizumab +FOLFOX4
– 3 bowel perforations reported in this groupEfficacy and Tolerability of FOLFOX4 ± Bevacizumab
Outcome FOLFOX4 + Bevacizumab FOLFOX4 P ValueMedian OS, mos 12.9 10.8 .0018Median PFS, mos 7.2 4.8 < .0001Overall response rate, % 21.8 9.2 < .001
Adverse event, % FOLFOX4 + Bevacizumab FOLFOX4 P Value
Grade 3/4 hypertension 5/1 2/< 1 .018
Grade 3/4 bleeding 3/1 < 1/0 .011Grade 3/4 neuropathy 16/< 1 9/< 1 .016Grade 3/4 vomiting 9/1 3/< 1 .010
Giantonio BJ, et al. ASCO 2005. Abstract 2.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Valatinib in Untreated Patients With Metastatic Colorectal Cancer
Hecht J, et al. ASCO 2005. Abstract LBA3.
FOLFOX4/ValatinibOxaliplatin 85 mg/m2 Day 1
Leucovorin 200 mg/m2 IV over 2 hrs +5-FU 400 mg/m2 bolus, followed by
5-FU 600 mg/m2 continuous infusion over 22 hrs on Days 1-2 every 2 weeks
Valatinib 1250 mg orally once daily(n = 585)
FOLFOX4Leucovorin 200 mg/m2 IV over 2 hrs +
5-FU 400 mg/m2 bolus5-FU 600 mg/m2 continuous infusion
over 22 hrs on Days 1-2 every 2 weeks Placebo orally once daily
(n = 583)
Patients with previously untreated
metastatic CRC
(N = 1168)
Stratification by PS (0/1 vs 2) and low vs high LDH (≤ 1.5 vs > 1.5 x ULN)
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Valatinib in Untreated Patients With Metastatic Colorectal Cancer (cont’d) Adding valatinib to FOLFOX4 did not improve response
– CR + PR = 42% vs 46% with FOLFOX4 alone
– Slight improvement in PFS in secondary investigator analysis
Patients with high LDH levels treated with FOLFOX4/valatinib showed improved PFS
– HR: 0.67; P = .010 by independent assessment
– HR: 0.61; P = .002 by investigator analysis
More patients on valatinib + FOLFOX4 discontinued treatment due to adverse events
– Most common grade 3/4 adverse events included hypertension, neutropenia, and diarrhea
Hecht J, et al. ASCO 2005. Abstract LBA3.
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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Conclusions
EGFR-, VEGF-targeting agents plus chemotherapy
– Associated with improved activity, survival in metastatic disease
Nontraditional adverse events (eg, hypertension, delayed wound-healing, rash) with targeted therapy
Ongoing studies investigating
– Maintenance therapy with targeted agents between chemotherapy-free intervals
– Combinations of several targeted agents
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