Neoplasie del Colon-retto.
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Transcript of Neoplasie del Colon-retto.
Neoplasie del Colon-retto
The therapeutic spectrum in adjuvant colon cancer and neoadjuvant rectal
cancer: Chair’s welcome
Alberto SobreroOspedale San Martino
Genoa, Italy
Adjuvant chemotherapy of colon cancer: steps ahead
1990 1991 20041992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
5-FU/LEV
5-FU/LV
6 months Elderly as well
Stage II
XelodaFOLFOX
Neoadjuvant chemoradiation:treating early to optimize outcomes
Neoadjuvant chemoradiation improves1
– downstaging
– surgical resection
– sphincter-sparing surgery
1Bosset JF et al. J Clin Oncol 2005;23:5620–7
“It’s time we pay more, not less, attention to the concept of cure and give our patients the benefit of the doubt”
De Vita, Nature Clin Pract, Feb 2006
New treatments, new hope
Evolving choices in adjuvantcolon cancer
Joe McKendrickBox Hill Hospital, Box Hill, Victoria, Australia
Adjuvant chemotherapyfor colon cancer
Colon cancer
– common
– increasing
– costly
Adjuvant therapy reduces burden of disease
Advances in the adjuvant treatment of stage III CRC
3-year overall survival (%)100
80
60
401980 1985 1990 1995 2000 2005
Surgery alone
Efficacy of adjuvant chemotherapyin colon cancer widely accepted
1990 Intergroup study1
– 5-FU/levamisole improves survival in surgically resected stage III colon cancer
– 16% absolute reduction in risk of death
Efficacy of adjuvant chemotherapy in stage III colon cancer widely accepted by early 1990s
Adoption of adjuvant therapy slow and not universal
Toxicity a significant issue
Conflicting opinion about stage II disease1Moertel CG et al. N Engl J Med 1990;322:352–8
5-FU-based adjuvant chemotherapy:early modifications and improvements
NSABP C-03,1 IMPACT,2 INT0089,3 NSABP C-04,4 QUASAR5
– no advantage gained by adding levamisole to 5-FU/LV
– low dose leucovorin (LV) is adequate
– 6 months’ therapy as good as 12 months’ therapy
– weekly therapy equivalent to monthly
1Wolmark N et al. J Clin Oncol 1993;11:1879–87; 2IMPACT investigators. Lancet 1995;345:939–443Haller DG et al. J Clin Oncol 2005;23:8671–8; 4Wolmark N et al. J Clin Oncol 1999;17:3553–9
5QUASAR Collaborative Group. Lancet 2000;355:1588–96
Roswell Park regimen: equivalent efficacy with distinct safety profiles
No improvement in DFS or OS with Roswell Park versus Mayo Clinic regimen1
For Mayo Clinic, major toxicity is myelosuppression2
For Roswell Park, major toxicity is diarrhea3
Need to improve safety of 5-FU-based therapy
1Haller DG et al. J Clin Oncol 2005;23:8671–82Haydon A. Intern Med J 2003;33:119–24
3Schmoll H-J et al. Eur J Cancer Suppl 2005;3:173 (Abst 617)
Similar efficacy with infused 5-FU/LV versus bolus
Disease-free survival: stage III
0 0.5 1.0 1.5 2.0 2.5 2.8
Hazard ratio = 1.2795% CI (0.87–1.86)Log-rank p=0.21
1.0
0.8
0.6
0.4
Probability
Years
Hazard ratio = 1.02595% CI (0.78–1.35)Log-rank p=0.86
Overall survival: stage III
Years
André T et al. J Clin Oncol 2003;21:2896–903
0 0.5 1.0 1.5 2.0 2.5 2.8
Mayo (n=256)
LV5FU2 (n=257)
Better toxicity profile withLV5FU2 versus Mayo
Grade 3 / 4 adverse events (% of patients)
LV5FU2 (n=452)
Bolus 5-FU/LV (n=453)
Neutropenia 7 16
Diarrhea 4 9
Mucositis 2 7
Nausea / vomiting* 1 3
All toxicities 11 26
*Not significant André T et al. J Clin Oncol 2003;21:2896–903
Issues with central venous catheters
Additional costs
Inconvenient for patients
Need for invasive surgical procedure
– possible complications include infections,bleeding, pneumothorax, deep-vein thrombosisand pulmonary embolism1,2
– varying level of risk (7–20%) but base rate of complications unavoidable regardless of center/experience3
1Kuter DJ. Oncologist 2004;9:207–162Verso M et al. J Clin Oncol 2003;21:3665–75
3Sobrero A and Sciallero S. Ann Oncol 2005;16:521–2
Xeloda is established in MCRC and should simplify complex adjuvant treatments
Xeloda is effective and well tolerated in MCRC
– can replace 5-FU as monotherapy and in combination regimens
– convenient home-based oral therapy
Potential to translate these advantages into adjuvant setting
Benefit of adjuvant therapy forstage II patients not always clear
Relatively few stage II patients have been randomized
Lower risk of recurrence
Contradictory meta-analyses
– IMPACT meta-analysis concluded no advantagein 1 025 patients1
– NSABP pooled data analysis showed improvedevent-free and overall survival in 1 565 patients2
1IMPACT. J Clin Oncol 1999;17:1356–632Mamounas E et al. J Clin Oncol 1999;17:1349–55
QUASAR: adjuvant chemotherapy significantly reduces recurrence in stage II
Chemotherapy 78.0Observation 73.8
Hazard ratio = 0.78(95% CI: 0.67–0.91)
p=0.001
5-year RFS (%)
Gray RG et al. J Clin Oncol 2004;23:245s (Abst 3501)
100
80
60
40
20
00 1 2 3 4 5 6 7 8 9 10
Years
Relapse-free survival (%)
QUASAR: adjuvant chemotherapy improves overall survival in stage II
Years
Gray RG et al. J Clin Oncol 2004;23:245s (Abst 3501)
ChemotherapyObservationp=0.04
100
80
60
40
20
00 1 2 3 4 5 6 7 8 9 10
Survival (%)
Dutch trial of 5-FU/LEV suggested improved OS for stage II
Taal B et al. Br J Cancer 2001;85:1437–43
100
80
60
40
20
00 1 2 3 4 5 6
5-FU/LEV (n=233)
Control (n=235)
Years
Overall survival (%)
Should high-risk stage II patientsbe offered adjuvant chemotherapy?
Some high-risk patients may benefit from adjuvant chemotherapy1
– obstruction or perforation
– venous or lymphatic invasion
– perineural invasion
– tumor adherence
Better prognostic factors could aid in patient selection
– Biomarker data collection incorporated in most ongoing studies
1NCCN Clinical Practice Guidelines in Oncology v.2.2004
Patients who could benefit are still denied adjuvant therapy
Indication of benefit of adjuvant therapy in stage II1–5
– small but significant benefit of chemotherapy
High-risk stage II patients may benefit as much as some stage III patients
Older patients and some minorities less likely to receive chemotherapy6,7
– toxicity concerns
1Gray RG et al. J Clin Oncol 2004;22:245s (Abst 3501)2Taal BG et al. Br J Cancer 2001;85:1437–43; 3IMPACT. J Clin Oncol 1999;17:1356–63
4Gill S et al. J Clin Oncol 2004;22:1797–806; 5Figueredo A et al. J Clin Oncol 2004;22:3395–4076Sargent DJ et al. N Engl J Med 2001;345:1091–7
7Grothey A et al. Proc Am Soc Clin Oncol 2002;21:129a (Abst 512)
Factors that may influence treatment decisions with adjuvant chemotherapy
Benefit torisk ratioBenefit torisk ratio
Healthcareproviders
Healthcareproviders
Treatment costsTreatment costs Resourceuse
Resourceuse
PatientsPatientsImpact onlifestyle
Impact onlifestyle
ConvenienceConvenience
TreatmentoutcomesTreatmentoutcomes
EfficacyEfficacy ToxicityToxicity
Patientcharacteristics
Patientcharacteristics
AgeAgeDisease
stageDisease
stage
PreferencePreference
Comorbiditiese.g. diabetes, impaired
cardiac function
Comorbiditiese.g. diabetes, impaired
cardiac function
BiomarkersBiomarkers
Redefining adjuvant therapies
Improve efficacy with new agents
Reduce toxicity
Prospective identification of high-risk stage II patients
Tailor to ensure all patients can benefit
– effective, well-tolerated, convenient therapy
With Xeloda’s approval, the need for an effective, well-tolerated, convenient and cost-effective therapy may be addressed
The next level in adjuvant treatment: new chemotherapy combinations
Alberto SobreroOspedale San Martino
Genoa, Italy
Combinations in adjuvant chemotherapy: recent evidence
1de Gramont A et al. J Clin Oncol 2005;23:246s (Abst 3501)2Wolmark N et al. J Clin Oncol 2005;23:246s (Abst LBA3500); 3Saltz LB et al. J Clin Oncol 2004;22:245S (Abst 3500)
4Van Cutsem E et al. J Clin Oncol 2005;23:3s (Abst LBA8); 5Ychou M et al. Proc ASCO 2005 (Abst 3502)
NR = not reported
DFS
hazard ratio
p value OS
hazard ratio
p value
MOSAIC 0.77 <0.001 0.91 NR
NSABP C-072 0.79 <0.004 NR NR
Oxaliplatin combinations
Irinotecan combinations
3CALGB89803 NR 0.80 NR 0.81
PETACC-34 0.89 0.091 NR NR
ACCORD25 1.19 0.22 NR NR
1
MOSAIC: superior DFS withFOLFOX versus LV5FU2 in stage III
Months
FOLFOX4 (n=672) 72.2%
LV5FU2 (n=675) 65.3%
3-year DFS
Estimated probability
1.0
0.8
0.6
0.4
0.2
0.00 6 12 18 24 30 36 42 48 54 60
André T et al. N Engl J Med 2004;350:2343–51
Hazard ratio (95% CI) 0.76 (0.62–0.92)
NSABP C-07: superior DFS with FLOX versus 5-FU/LV in stage III
Wolmark N et al. J Clin Oncol 2005;23:246s (Abst LBA3500)
Estimated probability1.0
0.9
0.8
0.7
0.6
0.50 1 2 3 4
Years
FLOX (n=272)
76.5%5-FU/LV (n=332)
71.6%
Hazard ratio (95% CI)0.79 (0.67–0.93)
p<0.004
3-year DFS
The strength of MOSAIC: clinically relevant absolute benefit is increasing
4-year DFS (%)1 3-year DFS (%)2
II and III 6.8* 5.1*
III N1 7.0 –
III N2 12 –
III 8.7* 6.3*
II 3.8 2.7
High-risk stage II 5.4 5.1
1de Gramont A et al. J Clin Oncol 2005;23:246s (Abst 3501)2André T et al. N Engl J Med 2004;350:2343–51*p<0.05
FLOX vs FOLFOX: no difference in DFS
NSABP C-07 MOSAIC
3-year DFS (%) 76.5 78.2
Hazard ratio 0.79 0.77
Difference 4.9 5.1
FOLFOX versus LV5FU2: grade 3/4 adverse events
†
*12% grade 4†Not reported
Neutro
penia
Throm
bo-
cyto
penia
Diarrh
ea
Vomiti
ng
Neuro
pathy
(sen
sory
)
Nause
a
Allerg
ic
reac
tion
Febril
e
neutro
penia
FOLFOX4 (n=1 108)
LV5FU2 (n=1 111)
Patients (%)
*
André T et al. N Engl J Med 2004;350:2343–51
45
40
15
10
5
0
Irinotecan has significant benefitsin MCRC
Regimen N PR PFS OS Author
Douillard/AIO + Irinotecan
338 23%35%
4.46.7
14.117.4
Douillard Lancet 2000
FL (Saltz) + Irinotecan
440 21%39%
4.37.0
12.614.8
SaltzNEJM 2000
AIO + Irinotecan
430 34%62%
6.48.5
16.920.1
KöhneJCO 2005
CALGB89803: DFS not improvedwith IFL in stage III colon cancer
1.0
0.8
0.6
0.4
0.2
0.0
Proportion disease free
0 12 24 36 48 60Months
p=0.80
5-FU/LV (Roswell Park regimen)IFL
Saltz L et al. J Clin Oncol Proc ASCO 2004;22:14S (Abst 3500)
PETACC-3: DFS not significantly improved with FOLFIRI in stage III
Van Cutsem E et al. J Clin Oncol 2005;23:3s (Abst LBA8)
1.0
0.9
0.8
0.7
0.6
0.5
0.0
Estimated probability
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48Months
FOLFIRI (n=1 044) 63.35-FU/LV (n=1 050) 60.3
Hazard ratio (95% CI)0.89 (0.77–1.11)
p=0.091
3-year DFS
ACCORD2: DFS not improved with FOLFIRI in high-risk colon cancer
Ychou M et al. J Clin Oncol 2005;23 (Abst 3502)
Estimated probability1.0
0.8
0.6
0.4
0.2
0.00 1 2 3 4 5 6
LV5FU2
60%FOLFIRI
51%
Hazard ratio (95% CI)1.19 (0.90–1.59)
p=0.22
3-year DFS
Years
Xeloda has the potential to replace5-FU in adjuvant combinations
Xeloda is at least as effective as 5-FU/LV with
– significantly superior relapse-free survival
– trends to improved disease-free and overall survival
– consistent benefits in all efficacy endpoints
XELOX has similar high efficacy and favorable safety profile compared with FOLFOX in metastatic CRC
Xeloda is the optimal fluoropyrimidine partner to simplify complex combination regimens
XELOXA: adjuvant Xeloda + oxaliplatin (XELOX) versus 5-FU / LV
1º endpoint: DFS – XELOX >5-FU/LV – minimal absolute difference targeted: 6%
2º endpoints: survival, tolerability, convenience, pharmacoeconomics
Recruitment completed: September 2004
XELOX 24 weeks
Bolus 5-FU/LV Mayo Clinic
or Roswell Park
24 or 32 weeks
Chemotherapy-naïve, stage III
colon cancer n=1 886
XELOX is an ideal combination in the adjuvant setting
1Schmoll H-J et al. Proc ASCO GI 2006 (Abst 278)
XELOXA1
Grade 3/4 toxicities XELOX 5-FU/LV
Diarrhea 19 20
Stomatitis <1 8
Nausea 5 4
Vomiting 6 3
Neurosensory 11 0
HFS 5 <1
Neutropenia 8 15
Febrile neutropenia <1 4
XELOX is an ideal combination in the adjuvant setting
1Schmoll H-J et al. Proc ASCO GI 2006 (Abst 278)2André T et al. N Engl J Med 2004;350:2343–51
3Smith R et al. Proc Am Soc Clin Oncol 2003;22:294 (Abst 1181; poster update)
XELOXA1 MOSAIC2 NSABP C-073 Grade 3/4 toxicities 5-FU/LV FOLFOX FLOX
Diarrhea 20 12 36
8 3 NR
Nausea 4 5 15
Vomiting 3 6 12
Neurosensory 0 12 8
HFS <1 2 NR
Neutropenia 15 41 5
Febrile neutropenia 4 2 NR
XELOX
19
<1
5
6
11
5
8
<1
Stomatitis
UK QUASAR2: adjuvant Xeloda± Avastin
1º endpoint: DFS– minimal absolute difference targeted: 6%
2º endpoints: 5-year overall survival, safety, health economics Recruitment opened 2005
Xeloda 8 cycles (24 weeks)
Xeloda8 cycles (24 weeks)
Avastin 7.5mg/kg
16 cycles (48 weeks)
Stage II / IIIcolon cancer
n=3 510
AVANT: adjuvant FOLFOXvs XELOX ± Avastin
1º endpoint: DFS– minimal absolute difference targeted: 5.3%
2º endpoints include: overall survival and tolerability Started Q4 2004
XELOX plus
Avastin
FOLFOX
Chemotherapy-naïve,stage II / III
colon cancer n=3 450
FOLFOXplus
Avastin
Xeloda provides added advantagesin adjuvant combination regimens
Xeloda should be preferred to i.v. 5-FU/LV
– consistent efficacy benefits in stage III colon cancer
– more convenient for patient and physician
– reduces hospitalizations for adverse events
– cost-saving for most healthcare systems
Adjuvant XELOX has a favorable safety profile with less neutropenia than FOLFOX
Xeloda is an ideal backbone for future development
Landmark trials: adjuvantXeloda-based combinations
2004 2005 2006 2007 2008 2009 2010 2011
XELOXA final safety
XELOXA 1° efficacy
XELOXA survival follow-up
QUASAR2 last follow-up planned
AVANT 1° efficacy
AVANT survival follow-up
Avastin® therapy: the essential basis of first-line treatment regimens
Bruce GiantonioAbramson Cancer Center, The University of Pennsylvania,
Philadelphia, USA
Mode of action suggests Avastin can be combined with all first-line chemotherapy
Avastin’s unique mechanism of action is potentially exploited best when used with chemotherapy, but
– it shouldn’t be dependent upon any particular chemotherapy regimen
Efficacy data indicate that the magnitude of benefit achieved with Avastin is greatest when used with first-line chemotherapy
Clinically and statistically significant survival benefit is seen despite modest improvements in response rates
Treatment of metastatic CRC
CRC = colorectal cancer; IFL = irinotecan, 5-fluorouracil (5-FU)/leucovorin (LV); FOLFIRI = 5-FU/LV + irinotecan; XELIRI = Xeloda® + irinotecan; FOLFOX = 5-FU/LV + oxaliplatin; XELOX = Xeloda + oxaliplatin; BSC = best supportive care
Metastatic CRC
IFL/FOLFIRI/XELIRI
5-FU or Xeloda FOLFOX or XELOX
Irinotecan +cetuximab
FOLFOX BSC/FOLFOX/FOLFIRI
FOLFIRI 5-FU/LV
First-line
Second-line
Phase III trial of IFL ± Avastin (AVF2107g): survival
Median survivalIFL + placebo: 15.6 (95% CI: 14.3–17.0) vsIFL + Avastin: 20.3 (95% CI: 18.5–24.2)HR=0.66 (95% CI: 0.54–0.81)p<0.001
Pro
bab
ilit
y o
f su
rviv
al
1.0
0.8
0.6
0.4
0.2
00 10 20 30 40
Time (months)
IFL + Avastin
IFL + placebo
15.6 20.3
Hurwitz H, et al. N Engl J Med 2004;350:2335–42CI = confidence interval; HR = hazard ratio
Phase III trial of IFL ± Avastin: progression-free survival
Median progression-free survivalIFL + placebo: 6.2 (95% CI: 5.6–7.7)IFL + Avastin: 10.6 (95% CI: 9.0–11.0) HR=0.54 (95% CI: 0.45–0.66) p<0.001
Pro
bab
ilit
y o
f b
ein
g
pro
gre
ssio
n-f
ree
1.0
0.8
0.6
0.4
0.2
00 10 20 30
Progression-free survival (months)
6.2 10.6
IFL + Avastin
IFL + placebo
Hurwitz H, et al. N Engl J Med 2004;350:2335–42
Use of Avastin with FOLFIRI-based therapy
Avastin has proven efficacy in combination with IFL
Studies of IFL and FOLFIRI regimens suggest improved safety and comparable, if not superior, efficacy of FOLFIRI
Based on what we know, it is expected that Avastin will enhance efficacy when combined with FOLFIRI
Phase II trial of Avastin plus FOLFIRI: preliminary efficacy and safety results
Avastin plus FOLFIRI appears to be well tolerated with comparable efficacy1
It is expected that progression-free survival will surpass the 8.5 month median progression-free survival reported for FOLFIRI alone2 and be at least equivalent to the 10.6 months reported for IFL plus Avastin3
Incidence of adverse events is lower than that reported with IFL plus Avastin – no grade 3/4 diarrhoea versus 32%1
1Hoff PM, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 252. Available at http://www.asco.org. Accessed 28 February 2006
2Tournigand C, et al. J Clin Oncol 2004;22:229–37 3Hurwitz H, et al. N Engl J Med 2004;350:2335–42
Phase IV trial of Avastin plus irinotecan (AVIRI): study design
Primary endpoint: progression-free survival
Secondary endpoints: overall survival, overall response rate, duration of response and safety
Data available: 2006
Patients with previously untreated
metastatic CRC (n=202)
Avastin 5mg/kg every 2 weeks + FOLFIRI
Planned trial of Avastin plus FOLFIRI/ XELIRI: ACCORD 13 (MEXICO)
Primary endpoint: progression-free survival Secondary endpoints: overall survival, overall response rate,
duration of response and safety
Patients with untreated
metastatic CRC(n=140)
Avastin 5mg/kg every
2 weeks + FOLFIRI
Avastin 7.5mg/kg every
3 weeks + XELIRI
Duration of treatment 24 weeks
Avastin 7.5mg/kg
every 3 weeks
Avastin 7.5mg/kg
every 3 weeks
PD
PD
PD = progression of disease
Avastin can be combined with IFL/FOLFIRI/XELIRI-based therapy
Metastatic CRC
IFL/FOLFIRI/XELIRI
5-FU or Xeloda FOLFOX or XELOX
Irinotecan +cetuximab
FOLFOX BSC/FOLFOX/FOLFIRI
FOLFIRI 5-FU/LV
First-line
Second-line
Combined analysis of Avastin plus 5-FU-based regimens: overall survival
Su
rviv
al (
%)
100
80
60
40
20
00 10 20 30 40
Time (months)
Median survival: 14.6 vs 17.9 monthsHR=0.74, p=0.0081
5-FU/LV/Avastin 5mg/kg
5-FU/LV or IFL
14.6 17.9
Kabbinavar FF, et al. J Clin Oncol 2005;23:3706–12
Combined analysis of Avastin plus 5-FU-based regimens: progression-free survival
Pro
gre
ssio
n-f
ree
surv
ival
(%
)
100
80
60
40
20
00 10 20 30
Time (months)
Median progression-free survival: 5.6 vs 8.8 monthsHR=0.63, p=0.0001
5-FU/LV/Avastin 5mg/kg
5-FU/LV or IFL
5.6 8.8
Kabbinavar FF, et al. J Clin Oncol 2005;23:3706–12
Xeloda in metastatic CRC: significantly superior response rate versus bolus 5-FU/LV
Xeloda (n=603)
Bolus 5-FU/LV (n=604)
p value
Response rate (%) 26 17 <0.0002
Time to progression (months) 4.6 4.7 0.9535
Overall survival (months) 12.9 12.8 0.48
Van Cutsem E, et al. Br J Cancer 2004;90:1190–7
The efficacy of Xeloda versus bolus 5-FU/LV was similar to infusional 5-FU/LV versus bolus 5-FU/LV
Preclinical evidence for the use of Avastin with Xeloda-based therapy
Shen BQ, et al. Proc Am Assoc Cancer Res 2004;45 (Abstract 2203)*Sub-maximum effective doses
Combining Avastin and Xeloda resulted in a greater duration of tumour inhibition than with either agent alone
Mea
n t
um
ou
r vo
lum
e (m
m3 )
2,000
1,750
1,500
1,250
1,000
750
500
250
0
Control
Avastin*
Xeloda*
Avastin* + Xeloda*
0 7 14 21 28 35 42 49 56 63Day
Ongoing/planned trials of Xeloda plus Avastin in first-line metastatic CRC
MAX (ML18513); randomised phase II/III trial (n=333) – patients with previously untreated metastatic CRC will be
randomised to receive one of three regimens until disease progression• Xeloda• Avastin 7.5mg/kg every 3 weeks plus Xeloda• Avastin 7.5mg/kg every 3 weeks plus Xeloda plus mitomycin C
Several other trials of Avastin plus Xeloda are planned, including– ML18524, open label study comparing the effect of three
chemotherapy regimens (n=300) – ML18799, phase II trial (n=80)– ML19823, phase II trial in elderly patients (n=60)
Avastin can be combined with 5-FU/LV- or Xeloda-based therapy
Metastatic CRC
IFL/FOLFIRI/XELIRI
5-FU or Xeloda FOLFOX or XELOX
Irinotecan +cetuximab
FOLFOX BSC/FOLFOX/FOLFIRI
FOLFIRI 5-FU/LV
First-line
Second-line
Phase III trial of Avastin plus FOLFOX in second line (E3200): overall survival
Pro
bab
ility
of
surv
ival
1.0
0.8
0.6
0.4
0.2
0
Time (months)AliveDead MedianTotal
A: FOLFOX4 + Avastin 289 246 43 12.9
B: FOLFOX4 290 257 33 10.8C: Avastin 243 216 27 10.2
HR=0.76
A vs B: p=0.0018
B vs C: p=0.95
Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2)
10.2 12.9
10.8
0 3 6 9 12 15 18 21 24 27 30 33 36
Phase III trial of Avastin plus FOLFOX in second line (E3200): progression-free survival
Pro
bab
ility
of
bei
ng
p
rog
ress
ion
-fre
e
1.0
0.8
0.6
0.4
0.2
0
Progression-free survival (months)0 2 4 6 8 10 12 14 16 18 20
CensFail MedianTotal273 228 45 7.2
273 241 32 4.8229 215 14 2.7
A: FOLFOX4 + Avastin
B: FOLFOX4C: Avastin
HR=0.64
A vs B: p<0.0001
B vs C: p<0.0001
2.7 7.24.8
Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2)
Phase II trial of Avastin with oxaliplatin/ fluoropyrimidine (TREE-2): study design
First-line metastatic CRC (n=223)
mFOLFOX6 + Avastin5mg/kg every 2 weeks
(n=75)
XELOX + Avastin7.5mg/kg every 3 weeks
(n=74)
bFOL + Avastin 5mg/kg every 2 weeks
(n=74)
PD
PD
PD
Primary endpoint: grade 3/4 toxicity Secondary endpoints include overall response rate, time to
progression and overall survival
Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 244. Available at
http://www.asco.org. Accessed 28 February 2006mFOLFOX = modified FOLFOXbFOL = bolus 5-FU/LV + oxaliplatin
Phase II trial of Avastin with oxaliplatin/ fluoropyrimidine: overall response rate
0
10
20
30
40
50
60 TREE-1(without Avastin)1
TREE-2(with Avastin)2
Res
po
nse
rat
e (%
)
mFOLFOX6 bFOL XELOX
46.9
32.0
37.5
52.1
34.3
45.8
Regimen*
*Avastin is added to eachof the regimens in TREE-2
1Hochster HS, et al. J Clin Oncol 2005;23(June 1 Suppl.):249s (Abstract 3515)2Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium;
26–28 January 2006; San Francisco, Ca. Abstract 244. Available at http://www.asco.org. Accessed 28 February 2006
Phase II trial of Avastin with oxaliplatin/ fluoropyrimidine: time to tumour progression
Pro
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y o
f b
ein
g
pro
gre
ssio
n-f
ree
XELOX + Avastin
FOLFOX + Avastin
bFOL + Avastin
1.0
0.8
0.6
0.4
0.2
0
Time (months)0 5 10 15 20
Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 244. Available at http://www.asco.org. Accessed 28 February 2006
Phase II trial of Avastin with oxaliplatin/fluoropyrimidine: toxicity
40
30
20
10
0 Neutropenia Febrile Vomiting Dehydration Diarrhoea Grade 3 Bleeding Thrombo- neutropenia neurotoxicity embolic event
mFOLFOX6 + Avastin
bFOL + Avastin
XELOX + Avastin
Ove
rall
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den
ce o
f g
rad
e 3/
4 to
xici
ties
Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 244. Available at http://www.asco.org. Accessed 28 February 2006
Phase II trial of Avastin with three oxaliplatin/ fluoropyrimidine regimens: conclusion
Avastin given in combination with each of three oxaliplatin-fluoropyrimidine regimens is effective
and well tolerated
Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 244. Available at http://www.asco.org. Accessed 28 February 2006
Phase II trial of XELOX plus Avastin (XELOX-A): study design
Primary endpoint: response rate
Secondary endpoints: safety and tolerability, time to progression, disease-free and overall survival
Exclusion criteria include: unstable or poorly controlled hypertension, arterial or venous thrombosis within the last 3 months, coagulopathy and anticoagulation therapy
Xeloda 1,000mg/m2 b.i.d. days 1–5 and days 8–12, every 2 weeks
oxaliplatin 85mg/m2 every 2 weeksAvastin 10mg/kg every 2 weeks
PD
Previously untreated
metastatic CRC (n=50)
Fernando N, et al. J Clin Oncol 2005;23(June 1 Suppl.):260s (Abstract 3556)
Phase II trial of XELOX plus Avastin (XELOX-A): response rate
Response (RECIST criteria) n=30 (%) Complete response 1 (3)
Partial response 16 (53)
Stable disease 11 (37)
PD 2 (7)
Overall response rate* 17/30 (57)
Time to progression (months) 11.9 (9.8–∞)
*Overall response rate = complete response plus partial responseRECIST = Response Evaluation Criteria in Solid Tumors
Fernando N, et al. J Clin Oncol 2005;23(June 1 Suppl.):260s (Abstract 3556)
Ongoing phase III trial: XELOX ± Avastin versus FOLFOX4 ± Avastin (NO16966C)
2 x 2 factorial, randomised phase III trial
Primary objectives
– at least equivalent time to progression with XELOX (± Avastin) versus FOLFOX4 (± Avastin)
– superior time to progression with Avastin + XELOX/FOLFOX4 versus XELOX/FOLFOX4
Previously untreated
patients with metastatic CRC
(n=1,920)
Avastin 5mg/kg every
2 weeks (n=330)
Placebo (n=330)
Avastin 7.5mg/kg every
3 weeks (n=330)
Placebo (n=330)
FOLFOX4 (n=300)
XELOX (n=300)
DREAM study
mFOLFOX7 x6
mFOLFOX7 x6
XELOX4 x6
XELOX4 x6
mFOLFOX7 x6
mFOLFOX7 x6
XELOX4 x6
XELOX4 x6
Avastin
Avastin
AvastinPreviously untreated
patients with metastatic CRC
(n=640)
Primary endpoint: progression-free survival Secondary endpoints include: overall survival, response rate, duration of disease control,
tolerance and quality of life mFOLFOX7 or XELOX4: Avastin 5mg/kg every 2 weeks ± Tarceva 100mg/day During chemotherapy pause: Avastin 7.5mg/kg every 3 weeks ± Tarceva 150mg/day
AvastinAvastin +Tarceva®
Avastin AvastinAvastin +Tarceva
Ongoing phase IV optimisation trial (CONcePT) in first-line metastatic CRC
Primary endpoint: time to treatment failure
mFOLFOX7 + AvastinCONTINUOUS
oxaliplatin‘treat-to-failure’
± intravenous Ca/Mg
mFOLFOX7 + AvastinINTERMITTENT
oxaliplatinPatients with metastatic CRC
(n=532)
2x2 randomised, multicentre study
CONcePT: intermittent oxaliplatinStage 1 Avastin 5mg/kg CI 5-FU/LV Oxaliplatin 85mg/m2
Stage 2 Avastin 5mg/kg CI 5-FU/LV
Stage 3 Avastin 5mg/kg CI 5-FU/LV Oxaliplatin 85mg/m2
CI = continuous infusion *Cumulative dose
x8 cycles, months 5–8
x8 cycles, months 1–4 Oxaliplatin 680mg/m2*
x8 cycles, months 9–12 Oxaliplatin 1,360mg/m2*
Avastin therapy: the essential basis of first-line treatment regimens
Metastatic CRC
Avastin + IFL/FOLFIRI/
XELIRI
Avastin + 5-FU or Xeloda
Avastin +FOLFOX or XELOX
Irinotecan +cetuximab
FOLFOX BSC/FOLFOX/FOLFIRI
FOLFIRI 5-FU/LV
First-line
Second-line
Large observational study of Avastin plus first-line chemotherapy for
metastatic CRC (BRiTE) Median progression-free survival is at least as good as that reported in
trial conditions despite the fact that this is a clinical practice population treated with many different chemotherapy regimens
Pro
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1.0
0.8
0.6
0.4
0.2
00 2 4 6 8 10 12 14 16 18 20
Time (months)
11.3
Kozloff M, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006;San Francisco, Ca. Abstract 247. Available at http://www.asco.org. Accessed 28 February 2006
Ongoing and planned trials of Avastin in CRC
Data from ongoing and planned trials are expected to support and investigate– optimisation of Avastin use with chemotherapy– optimisation of chemotherapy use with Avastin– incorporation of targeted agents with Avastin– activity of Avastin across multiple lines of therapy
• first-line use is currently recommended to maximise benefit
Studies are ongoing to examine continued efficacy after progression
Avastin in first-line treatment of metastatic CRC
Avastin has shown consistent efficacy improvements in metastatic CRC, regardless of the regimen with which it is combined
Metastatic CRC
Avastin + IFL/FOLFIRI/
XELIRI
Avastin + 5-FU or Xeloda
Avastin + FOLFOX or XELOX
Irinotecan + cetuximab
FOLFOX BSC/FOLFOX/FOLFIRI
FOLFIRI 5-FU/LV
First-line
Second-line