Download Axel Grothey

Axel Grothey
Professor of Oncology
Mayo Clinic, Rochester, Minnesota, USA
 Vice Chair and Director of Cancer
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Treatment of the North Central
Cancer Treatment Group (NCCTG)
Co-chair of the gastrointestinal
program of NCCTG
Former Senior Consultant and Head
of the Oncological Research
Laboratory at the Martin-LutherUniversity in Halle, Germany
Prior posts at the MD Anderson
Cancer Center, Houston, USA and
the University of Essen and
University of Bochum, Germany
Author of many papers in
English and German
Mayo Clinic, Rochester
Mounting evidence in early CRC
Axel Grothey
Mayo Clinic, Rochester,
Minnesota, USA
Adjuvant chemotherapy of
colon cancer: steps ahead
5-FU/LV
1-year superior
to surgery alone
6- and 12-month
equivalent
Elderly
benefit
as well
Stage II
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
Bolus 5-FU/LV
superior to
surgery alone
5-FU = 5-fluorouracil
LV = leucovorin
Capecitabine
FOLFOX better
than LV5FU2
LV5FU2 equivalent
to bolus 5-FU/LV
Stage II colon cancer:
a heterogeneous population
 In 2007, approximately 80,000 patients will be diagnosed
with either stage II or III colon cancer in the USA
 28% of diagnosed colon cancer patients
 Wide spectrum of disease1
– IIa: T3, N0, M0
– IIb: T4, N0, M0
 5-year disease-free survival2
– IIa: 65–73%
– IIb: 51–60%
 25–30% of stage II patients will relapse within 5 years
1AJCC
Cancer Staging Handbook, 6th ed
2Gill S, et al. J Clin Oncol 2004;22:1797–806
Who should be offered adjuvant therapy
of colon cancer?
 All patients with stage III tumours
 Patients with ‘high-risk’ stage II tumours according to
– clinico-pathological parameters
• T4 tumours
• obstruction/perforation
• lymphatic or vascular invasion
• undifferentiated histology
• <10 (12) lymph nodes examined
– molecular parameters? (in trials)
Adjuvant therapy for stage II
colon cancer
 The role of adjuvant therapy for patients with stage II
disease is controversial
– studies have confirmed the benefits of treatment in
stage III disease1,2
 A number of factors may influence adjuvant
treatment decisions
– treatment outcomes, patient characteristics,
comorbidities, convenience, costs, etc.
 The evidence for adjuvant treatment of stage II colon
cancer comes from >13,500 patients
– relative risk reduction between 14% and 31%
1Jessup
JM, et al. JAMA 2005;294:2758–60
2de Gramont A, et al. J Clin Oncol 2007;25:(Suppl. 18):165s (Abstract 4007)
5-FU-based adjuvant therapy
for colon cancer
5-FU: historical standard
in the adjuvant setting
Observation1
5-FU/high-dose LV (Mayo)2
6 months 5-FU/LV (Mayo)1
5-FU/low-dose LV (Mayo)3
LV5FU24
55
60
65
70
75
3-year disease-free survival (%)
1IMPACT
Investigators, Lancet 1995;345:939–44
N, et al. J Clin Oncol 1993;11:1879–87
3QUASAR Group. Lancet 2000;355:1588–96
4André T, et al. J Clin Oncol 2003;21:2896–903
2Wolmark
Stage II and III colon cancer patients
PETACC-3: DFS not significantly
improved with FOLFIRI in stage III
FOLFIRI
5-FU/LV
Estimated probability
1.0
n
3-year DFS (%)
1,044
1,050
63.3
60.3
0.9
0.8
0.7
0.6
HR=0.89
(95% CI: 0.77–1.11)
p=0.091
0.5
0
0
3
6
9
12 15 18 21 24 27 30 33 36 39 42 45 48
Months
DFS = disease free survival
HR = hazard ratio; CI = confidence interval
Van Cutsem E, et al. J Clin Oncol 2005;
23:(Suppl. 16):3s (Abstract LBA8)
ACCORD2: DFS not improved with
FOLFIRI in high-risk colon cancer
3-year DFS (%)
FOLFIRI
LV5FU2
Estimated probability
1.0
51
60
0.8
0.6
0.4
HR=1.19
(95% CI: 0.90–1.59)
p=0.22
0.2
0
0
1
2
3
Years
4
5
6
Ychou M, et al. J Clin Oncol 2005;(Suppl. 16):246s (Abstract 3502)
CALGB 89803: DFS and OS not improved
with IFL in stage III colon cancer
1.0
Proportion surviving
Proportion disease-free
1.0
0.8
0.6
0.4
0.2
FU/LV
IFL
0
0.8
0.6
0.4
0.2
FU/LV
IFL
0
0
FU/LV
IFL
1
2
3
4
5
6
Years
n
Events
629
635
227
248
p (stratified) = 0.85 (1-sided)
OS = overall survival; IFL = irinotecan,
5-FU plus leucovorin
7
0
FU/LV
IFL
1
2
3
4
5
6
Years
n
Events
629
635
7
171
181
p (stratified) = 0.74 (1-sided)
Saltz L, et al. J Clin Oncol 2007;25:3456–61
MOSAIC: superior DFS
with FOLFOX4 in stage III
n 3-year DFS (%)
FOLFOX4 1,123
LV5FU2
1,123
Estimated probability
1.0
72.2
65.3
0.8
0.6
0.4
0.2
HR=0.76 (95% CI: 0.62–0.92)
p=0.002
0
0
6
12
18
24
30
36
Months
42
48
54
60
André T, et al. N Engl J Med 2004;350:2343–51
MOSAIC: consistent benefit
in DFS with FOLFOX4 versus LV5FU2
4-year DFS
relative benefit (%)1
Disease stage
3-year DFS
relative benefit (%)2
II and III
6.8*
5.1*
III N1
7.0
–
III N2
12.0
–
III
8.7*
6.3*
II
3.8
2.7
High-risk stage II
5.4
5.1
*p<0.05
1de
Gramont A, et al. J Clin Oncol 2005;23(Suppl. 16)246s (Abstract 3501)
2André T, et al. N Engl J Med 2004;350:2343–51
Probability
MOSAIC: OS for
stage II and stage III patients
1.0
p=0.996
0.8
p=0.029
0.1%
4.4%
0.6
0.4
FOLFOX4 stage II
HR (95% CI)
0.2
LV5FU2 stage II
Stage II
1.00 (0.71–1.42)
FOLFOX4 stage III
Stage III
0.80 (0.66–0.98)
LV5FU2 stage III
0
0
12
24
36
48
60
72
84
96
Overall survival (months)
Data cut-off: January 2007
De Gramont A, et al. J Clin Oncol 2007;25
(Suppl. 18)165s (Abstract 4007)
NSABP C-07: superior DFS
with FLOX in stage II/III combined
FLOX
5-FU/LV
Estimated probability
1.0
n
3-year DFS (%)
1,200
1,207
76.5
71.6
0.9
0.8
0.7
HR=0.79 (95% CI: 0.67–0.93)
p<0.004
0.6
0.5
0
1
2
Years
3
4
Kuebler JP, et al. J Clin Oncol 2007;25:2156–8
Adjuvant combination therapy: summary
 Data from MOSAIC and NSABP C-07 suggest that
– oxaliplatin plus 5-FU/LV significantly improves DFS
in patients with stage II and III colon cancer
– oxaliplatin plus 5-FU/LV significantly improves OS
in patients with stage III colon cancer
 Data from PETACC-3, ACCORD and CALGB 89803
suggest that
– addition of irinotecan to LV5FU2 may reduce risk
of recurrence in patients with stage III colon cancer
– there is no clear significant benefit for irinotecan in
the adjuvant setting
Capecitabine: the potential agent of
choice for adjuvant therapy
Capecitabine mode of action:
TP-activation – proof of concept at last?
Intestine
Capecitabine
Liver
Capecitabine
Tumour >> healthy tissue
CE
5'-DFCR
5'-DFCR
CyD
CyD
5'-DFUR
5'-DFUR
Thymidine
phosphorylase (TP)
5-FU
5'-DFCR = 5'-deoxy-5-fluorocytidine; 5'-DFUR = 5'-deoxy-5-fluorouridine;
CyD = cytidine deaminase; CE = carboxylesterase
X-ACT: Xeloda (capecitabine) Adjuvant
Chemotherapy Trial of stage III colon cancer
Chemonaïve stage III
resection 8 weeks
R
A
N
D
O
M
I
S
A
T
I
O
N
n=1,004
n=983
Capecitabine
1,250mg/m2 b.i.d.
days 1–14 q3w
Bolus 5-FU/LV
5-FU 425mg/m2 +
LV 20mg/m2
days 1–5 q4w
 Primary endpoint: non-inferiority in DFS
 Secondary endpoint: OS
Data cut-off: January 2007
b.i.d. = twice daily
Twelves C, et al. Eur J Cancer Suppl
2007;5:1 (Abstract 1LB)
X-ACT: 5-year DFS
(median follow-up 6.8 years)
Estimated probability
1.0
Capecitabine
5-FU/LV
0.8
n
1,004
983
5-year
DFS (%)
60.8
56.7
0.6
0.4
HR=0.88 (95% CI: 0.77–1.01)
NI margin 1.20
0.2
0
0
6
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102
Months
Test of non-inferiority p<0.0001
Test of superiority p=0.0682
ITT (intent-to-treat) population; NI = non-inferiority
ITT population
Twelves C, et al. Eur J Cancer Suppl
2007;5:1 (Abstract 1LB)
X-ACT: 5-year OS
(median follow-up 6.8 years)
Estimated probability
1.0
Capecitabine
5-FU/LV
0.8
n
1,004
983
5-year
OS (%)
71.4
68.4
0.6
0.4
HR=0.86 (95% CI: 0.74–1.01)
NI margin 1.14
0.2
0
0
6
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102
Months
Test of non-inferiority p=0.000116
Test of superiority p=0.06
ITT population
Twelves C, et al. Eur J Cancer Suppl
2007;5:1 (Abstract 1LB)
X-ACT: improved efficacy with capecitabine
(5-year OS subgroup analysis)
Favours capecitabine
n
Favours 5-FU
ITT population
1,987
Male
1,074
Female
<40
76
40–69 years old
0.4
0.6
0.8
1.0
1.2 1.4
HR (95% CI)
CEA = carcinoembryonic antigen
ULN = upper limit of normal
1.6
912
1,513
70
396
pN1
1,389
pN2
593
Baseline CEA <ULN
1,672
Baseline CEA >ULN
155
1.8
Twelves C, et al. Eur J Cancer Suppl
2007;5:1 (Abstract 1LB)
Multivariate analysis of OS
Factor
HR
95% CI
p value
Age (years)
1.010
1.001–1.019
0.0238
Gender (female vs male)
0.770
0.654–0.908
0.0018
Regional lymph nodes
(PN1 vs PN0, PN2, PNx)
0.577
0.489–0.682
<0.0001
Baseline CEA (< vs  ULN)
0.401
0.320–0.503
<0.0001
Time from surgery to
randomisation (days)
1.004
0.997–1.012
0.2418
Treatment effect
(capecitabine vs 5-FU/LV)
0.828
0.705–0.971
0.0203
Twelves C, et al. N Engl J Med 2005;352:2696–704
Treatment duration and intensity
Capecitabine
(n=995)
Bolus 5-FU/LV
(n=974)
Completed full course of
treatment (%)
84
88
Needed dose reduction (%)
42
44
Needed dose reduction,
interruption or delay (%)
57
52
Twelves C, et al. N Engl J Med 2005;352:2696–704
X-ACT: improved safety with capecitabine
Grade 3/4 adverse events
50
Capecitabine (n=993)
Patients (%)
40
5-FU/LV (n=974)
30
20
10
0
*
*p<0.001
HFS = hand foot syndrome
*
*
*
Scheithauer W, et al. Ann Oncol 2003;14:1735–43
X-ACT and MOSAIC: projection of OS in
stage III patients
X-ACT1
1.0
Capecitabine (n=1,004)
FOLFOX (n=672)
Bolus 5-FU/LV (n=983)
LV5FU2 (n=675)
Estimated probability
Estimated probability
1.0
MOSAIC2
0.8
0.6
0.4
0.8
0.6
0.4
0
2
4
Years
6
8
1Twelves
ITT population
0
2
4
Years
6
8
C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)
2De Gramont A, et al. J Clin Oncol 2007;25:(Suppl. 18):165s (Abstract 4007)
X-ACT: 5-year survival update –
conclusions
Capecitabine is known to be an effective/better
tolerated alternative to bolus 5-FU/LV (Mayo Clinic) in
the adjuvant treatment of stage III colon cancer
 Update shows that capecitabine is at least equivalent
to bolus 5-FU/LV with a trend to superiority (p=0.06)
in terms of 5-year OS
 First indication in the adjuvant setting from a
cross-trial comparison showing that capecitabine is
equivalent to infusional 5-FU
CAPOX: a new option
in the adjuvant setting
Chemo/
radiotherapy-naïve
stage III
colon cancer
R
A
N
D
O
M
I
S
A
T
I
O
N
n=944
CAPOX
Capecitabine 1,000mg/m2 b.i.d. days 1–15
Oxaliplatin 130mg/m2 day 1 q3w
Bolus 5-FU/LV
Mayo Clinic or Roswell Park
n=942
 Primary endpoint: disease-free survival
Schmoll HJ, et al. J Clin Oncol 2007;25:4217–23
Adjuvant CAPOX: favourable toxicity
compared with FOLFOX and FLOX
50
Grade 3/4 adverse events
Patients (%)
40
CAPOX1 (n=938)
FOLFOX42 (n=1,108)
30
FLOX3 (n=1,200)
20
10
0
*
*
1Schmiegel
Cross-trial comparison
*Not reported
*
WH, et al. J Clin Oncol 2007;25(Suppl. 18):172s (Abstract 4034)
2André T, et al. N Engl J Med 2004;350:2343–51
3Wolmark N, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):246s (Abstract LBA 3500)
Active patient management minimises adverse
events: before and after dose modification
20
Grade 2
Grade 3
Grade 4
Cycles (%)
15
10
5
0
Before
After
HFS
Before
After
Diarrhoea
Before
After
Stomatitis
Cassidy J, et al. J Clin Oncol 2004;22(Suppl. 14):14s (Abstract 3509)
Role of adjuvant anti-VEGF therapy
Rationale for anti-VEGF therapy
in the adjuvant setting
 The roles of angiogenesis and VEGF in colorectal tumour
growth are well established1
 Using anti-VEGF therapy such as bevacizumab when
micrometastases are dormant and potentially reliant on
VEGF may prevent the angiogenic switch,2 thereby
improving outcomes
 In preclinical studies, bevacizumab causes regression of
human tumour xenografts,3–5 and a reduction in the number
and size of liver metastases6
 Bevacizumab may have a greater impact in earlier
disease stages
1Bergers
VEGF = vascular
endothelial growth factor
G, et al. Nat Rev Cancer 2003;3:401–10; 2Poon RT, et al. J Clin Oncol
2001;19:1207–25; 3Gerber HP, et al. Cancer Res 2000;60:6253–8; 4Wildiers H, et al.
Br J Cancer 2003;88:1979–86; 5Shen B-Q, et al. Proc Amer Assoc Cancer Res
2004;45 (Abstract 2203); 6Warren RS, et al. J Clin Invest 1995;95:1789–97
Anti-VEGF therapy regresses some
existing tumour microvasculature
 Reduction in tumour vessel blood flow after 1 day of
anti-VEGF therapy
Control
*AG013736 (VEGF tyrosine kinase inhibitor)
Anti-VEGF therapy*
Inai T, et al. Am J Pathol 2004;165:35–52
Rugo HS, et al. J Clin Oncol 2005;23:5474–83
Abnormal vasculature normalised
following VEGF inhibition*
*AG013736 (VEGF tyrosine kinase inhibitor)
Inai T, et al. Am J Pathol 2004;165:35–52
Rugo HS, et al. J Clin Oncol 2005;23:5474–83
Normalisation of tumour vasculature
improves delivery of chemotherapy
 46% increase in intratumoral availability of irinotecan after
pretreatment with an anti-VEGF antibody*
15.98
Tumour irinotecan
concentration (mg/g)
20
15
10.93
10
5
0
Placebo
*In a preclinical model
A4.6.1
Wildiers H, et al. Br J Cancer 2003;88:1979–86
Withdrawal of anti-VEGF therapy
results in vessel regrowth
CD31
Untreated
AG-013736, 7d
Withdrawal, 2d
Withdrawal, 7d
RIP-Tag2
Continue anti-angiogenic therapy to avoid vessel regrowth
Mancuso MR, et al. J Clin Invest 2006;116:2610–21
Linking the MoA of bevacizumab with
clinical benefit in adjuvant CRC
EARLY EFFECTS
1
Regression
Prevent growth of
small, unresected
tumours
2
Normalisation
Improve delivery of
chemotherapy
Eliminate residual
cancer cells
following surgery
Improve DFS
CONTINUED EFFECTS
3
Inhibition
Suppress the ‘angiogenic
switch’ in dormant cells
QUASAR-2 (phase III): study design
Colon cancer (stage II/III)
(n=2,240)
Bevacizumab (7.5mg/kg)
+ capecitabine every 3 weeks
(bevacizumab 16 cycles and
capecitabine 8 cycles over
24 weeks)
Capecitabine
(8 cycles over 24 weeks)
 Primary endpoint: DFS
 Secondary endpoints include survival and tolerability
 Recruitment
– started September 2006
– 306 patients enrolled (March 2007)
Phase III trial BO17920 (AVANT):
study design
Randomised, open-label study
Surgery for high-risk
stage II + stage III
colon cancer
(n=3,450)
Duration of treatment phases
FOLFOX4
Observation
FOLFOX4 +
bevacizumab
(5mg/kg every
2 weeks)
Bevacizumab alone
(7.5mg/kg every
3 weeks)
CAPOX +
bevacizumab
(7.5mg/kg every
3 weeks)
Bevacizumab alone
(7.5mg/kg every
3 weeks)
24 weeks
24 weeks
 Primary endpoint: DFS at 3 years for stage III
 Secondary endpoints: OS and safety
 Accrual completed Q2 2007
NSABP C-08: study design
Dukes’ C colon cancer
(n=2,714)
mFOLFOX6
Observation
mFOLFOX6 +
bevacizumab
5mg/kg every
2 weeks
Bevacizumab
5mg/kg every
2 weeks
24 weeks
24 weeks
 Primary endpoint: DFS at 3 years
 Secondary endpoints include survival and tolerability
 Trial design
– 90% power for 25% reduction in risk of progression after 3 years
– 82% power for 25% reduction in risk of death after 7 years
 Patient recruitment is complete, efficacy results expected for ASCO 2009
Trials of bevacizumab/capecitabine
in the adjuvant setting
Trial
n
Cancer
Treatment
E5202
(Cooperative)
3,610 Stage II colon
FOLFOX ± bevacizumab (high risk)
Observation (low risk)
NSABP C-08
(Cooperative)
2,714 Stage II/III colon
FOLFOX ± bevacizumab
QUASAR-2
(Cooperative)
2,240 Stage II/III colon
Capecitabine ± bevacizumab
XELOXA
(Cooperative)
1,886 Stage III colon
CAPOX vs bolus 5-FU
(Mayo Clinic or Roswell Park regimen)
AVANT
(Roche)
3,450 Stage II/III colon
FOLFOX vs FOLFOX + bevacizumab
vs XELOX + bevacizumab
Important adjuvant capecitabine/
bevacizumab-based combination trials
AVANT 1° efficacy
NSABP C-08 1° efficacy
QUASAR-2 1° efficacy
XELOXA survival follow-up
XELOXA 1° efficacy
XELOXA final safety
2004
2005
2006
2007
2008
2009
2010
2011
Conclusions
 Adjuvant capecitabine is as effective as bolus
5-FU/LV, with fewer grade 3/4 toxicities
 Capecitabine in combination with oxaliplatin is a
promising option in the adjuvant setting
 There is a strong rationale for the use of bevacizumab
in the adjuvant setting
 Adjuvant bevacizumab and capecitabine clinical
development programme is ongoing, results
expected soon