Transcript Best of ASCO 2006: Colorectal Cancer

ASCO 2009
Highlights in Gastrointestinal
Malignancies
Axel Grothey
Professor of Oncology
Mayo Clinic Rochester
Adjuvant Therapy of Colon Cancer
•
•
•
•
•
LBA 04
NSABP C-08
Wolmark
4000
Oncotype QUASAR
Kerr
4001
PETACC-3
Tejpar
4002
PETACC-3
Roth
4010
Elderly pts
McCleary
History of adjuvant therapy of colon cancer
• 5-FU/LV superior to 5• 5-FU/lev superior
FU/lev
• 6- and 12-month
to surgery alone
treatment cycles
equivalent
• 5-FU/LV superior
to surgery alone
• Lev unnecessary
• High-dose and low-
• LV5FU2 and
monthly bolus
equivalent
dose LV equivalent
• Monthly and weekly
treatment equivalent
1990
1994
Moertel et al. Ann Intern Med. 1995;122:321.
Francini et al. Gastroenterol. 1994;106:899.
Wolmark et al. Proc Am Soc Clin Oncol. 1996;15:205. Abstract
O’Connell et al. J Clin Oncol. 1998;16:295.
Haller et al. Proc Am Soc Clin Oncol. 1998;17:256a. Abstract 982.
Andre et al. Proc Am Soc Clin Oncol. 2002. Abstract 529.
1998
2002
Beyond 5-FU in the adjuvant setting
Completed studies:
• Oxaliplatin (MOSAIC, NSABP C-07)
• Irinotecan (CALGB 89803, ACCORD-2, PETACC-3)
• Capecitabine (X-ACT)
• Bevacizumab (NSABP C-08)
Ongoing studies:
• CAPOX (XELOXA)
• Bevacizumab (AVANT, E5202)
• Cetuximab in KRAS wt CC (N0147, PETACC-8)
MOSAIC: Study Design
n=2246
Enrollment:
Oct 1998–Jan 2001 (146 centres;
20 countries)
• Completely resected colon cancer
• Stage II, 40%; Stage III, 60%
(n=1123)
FOLFOX4
(LV5FU2 + oxaliplatin 85 mg/m²)
R
• Age 18–75 years
• KPS ≥60
• No prior chemotherapy
LV5FU2
(n=1123)
Primary end-point: disease-free survival
Secondary end-points: safety, overall survival
LV5FU2, Leucovorin 200 mg/m2 iv over 2 hours followed by 5-fluorouracil 400 mg/m2 bolus and 5-fluorouracil 600 mg/m2 iv
over 22 hours on Days 1 and 2, every 14 days; FOLFOX4, LV5FU2 + oxaliplatin 85 mg/m 2 iv over 2 hours on Day 1
MOSAIC: Disease-free Survival Final Update
5-year DFS %
Data cut-off: June 2006
ITT
FOLFOX4
LV5FU2
HR
[95% CI]
73.3
67.4
0.80
p-value
0.003
[0.68–0.93]
Stage III
66.4
58.9
Δ7.5
Stage II
83.7
0.78
0.005
[0.65–0.93]
79.9
0.84
0.258
[0.62–1.14]
High-risk stage II
n=576
82.1
Low-risk stage II
n=323
86.3
74.9
Δ7.2
0.74
—
[0.52–1.06]
89.1
1.22
[0.66–2.26]
—
“High-risk” Stage II Colon Cancer
• Clinico-pathological parameters (MOSAIC)
• T4 tumors
• Obstruction/perforation
• Lymphatic or vascular invasion
• Undifferentiated histology
• Less than 10 (12) Ln examined
• Molecular parameters
• LOH 18q
• MSS
• Other?
MOSAIC: OS: Stage II and Stage III
1.0
p=0.996
0.9
0.8
0.1%
p=0.029
Probability
0.7
4.4%
0.6
0.5
0.4
HR [95% CI]
0.3
0.2
0.1
Stage II
1.00 [0.71–1.42]
Stage III
0.80 [0.66–0.98]
FOLFOX4 stage II
LV5FU2 stage II
FOLFOX4 stage III
LV5FU2 stage III
0
0
6
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Data cut-off: January 2007
Overall survival (months)
Andre JCO 2009
Long-term Safety
Peripheral
Sensory
Neuropathy
60
Evaluable
patients n=811
Grade 1
Grade 2
Grade 3
50
Grade 0
84.3%
Grade 1
12.0%
30
Grade 2
2.8%
20
Grade 3
0.7%
40
10
0
During
Tx
Data cut-off: January 2007
6
months
1-year
2-year
3-year
4-year
Andre JCO 2009
Treatment of Colorectal Cancer in Elderly
Patients: ACCENT Database
• Median age of diagnosis of CRC in the United States is 71 years
• Previous analyses have shown that elderly patients (≥70 years)
with CRC benefit from treatment with IV fluoropyrimidines in
both the adjuvant and metastatic settings
• This analysis reviewed the efficacy of newer therapies in older
patients
• Patient population was derived the ACCENT database
• 10,499 pts <70 years, 2,170 pts ≥70 years
• 6 phase III trials compared IV FU to combinations with
irinotecan, oxaliplatin, or oral FU (capecitabine and
UFT/LV) in stage II/III colon cancer
• Endpoints were overall survival (OS), disease free survival
(DFS), and time to recurrence (TTR)
Folprecht. J Clin Oncol. 2008;26:1443-1451.
McCleary. ASCO 2009. Abstract 4010.
Elderly Patients: Efficacy of FOLFOX
Pooled Analysis C-07/MOSAIC
Age
Endpoint*
HR (95% CI)
Experimental vs Control IV 5-FU/LV
DFS
OS
TTP
Deaths within
6 mos
Exp vs Ctrl
% (p-value)
<70
n = 3,977
0.77
(0.68,0.86)
0.81
(0.71,0.93)
0.76
(0.67,0.86)
0.81 v 0.81
(p=1.0)
≥ 70
n = 703
1.04
(0.80,1.35)
1.19
(0.90,1.57)
0.92
(0.69,1.23)
2.57 v 1.37
(p=0.25)
0.016
0.037
0.21
Interaction
of age by
treatment
p-value
* Values < 1 favor experimental arm
McCleary, ASCO 2009, Abstract 4010
Treatment of Colorectal Cancer in Elderly
Patients: ACCENT Database
• Limitations of study
• ACCENT does not track:
• Toxicity
• Dose intensity
• Co-morbidity
• These data do not contradict earlier
studies showing the benefit of adjuvant
therapy with 5-FU/LV vs. surgery alone in
elderly patients
McCleary. ASCO 2009. Abstract 4010.
Forest Plots of Hazard Ratios – DFS
Oral
Oxaliplatin
Irinotecan
Age < 70
Overall
0.2
Age >= 70
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
2.2
Hazard Ratio
McCleary, N. ASCO 2009
2009 Update of MOSAIC Trial
No benefit in DFS with
FOLFOX vs 5-FU/LV for
patients > 65 yrs !
Andre JCO 2009
X-ACT: Cape vs Mayo - 5-year DFS
(median follow-up 6.8 years)
Estimated probability
1.0
5-year
n DFS (%)
Capecitabine
1,004
5-FU/LV
983
0.8
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)
XELOXA: phase III trial of CAPOX
in the adjuvant setting
Chemo/
radiotherapy-naïve
stage III
colon cancer
Trial open
4/03 – 10/04
Final data at
ESMO 2009
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
duration of therapy: 24 weeks
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 Trials in Colon Cancer with
Cetuximab (KRAS wild-type!)
PETACC 8
FOLFOX4 6m
Stage III colon
cancer (N=2400)
FOLFOX4 6m +
Cetuximab 6m
Intergroup N0147
mFOLFOX6 6m
Stage III colon
cancer (N=3600)
mFOLFOX6 6m +
Cetuximab 6m
Adjuvant Trials in Colon Cancer with
Bevacizumab
AVANT
Stage II/III colon
cancer (N=3450)
FOLFOX4 6m
XELOX 6m +
Bevacizumab 12m
FOLFOX4 6m +
Bevacizumab 12m
NSABP C-08
mFOLFOX6 6m
Stage II/III colon
cancer (N=2710)
25% Stage II
mFOLFOX6 6m +
Bevacizumab 12m
Reported at
ASCO2009
NSABP C-08
mFOLFOX6 q2wk X 6 mo
R
BEV* q2wk X 1 yr
N=2710 pts
25% stage II
*5mg/kg
Wolmark et al ASCO 2009
NSABP C-08
Accrual
mFF6 mFF6+B
Randomized
1356
1354
Lost / Ineval
18
16
1338
1334
Analysis
Wolmark et al ASCO 2009
NSABP C-08
Patient Characteristics
mFF6 mFF6+B
< 60 yr
Male
Stage II (0)
Stage III (1-3)
Stage III (4+)
58.3
49.8
24.9
45.4
29.7
58.2
49.9
24.9
45.5
29.6
Wolmark et al ASCO 2009
NSABP C-08 Grade 3+ Toxicities
Increased with Bevacizumab (%)
mFF6
mFF6+B
P
Hypertension
1.8
12
<0.0001
Pain
6.3
11.1
<0.0001
Proteinuria
0.8
2.7
<0.001
Wound Comp
0.3
1.7
<0.001
Median Duration of Bev = 11.5 months
Allegra et al JCO May 4, 2009
Wolmark et al ASCO 2009
40
60
80
100
NSABP C-08 – DFS
HR 0.89
P
0.15
0
20
mFF6+B
mFF6
Ev 3yDFS
291 77.4
312 75.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Wolmark et al ASCO 2009
70
80
90
100
NSABP C-08 – DFS
HR 0.89
P
0.15
60
mFF6+B
mFF6
Ev 3yDFS
291 77.4
312 75.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Wolmark et al ASCO 2009
NSABP C-08 HR over Time
0.02
0.004
0.0004
0.05
0.08
Event-free at 1 Yr
90
100
DFS at 1 Yr
80
Time-Treatment Interaction
P = 0.001
70
mFF6+B
mFF6
Ev 1yDFS
75
94.3 ∆ 3.6
122 90.7
Ev
mFF6+B
mFF6
216
190
60
HR 0.60
P 0.0004
0.0
0.5
1.0 1.0
HR 1.07
P 0.48
NSABP C-08
1.5
2.0
2.5
3.0
Wolmark et al ASCO 2009
Wolmark et al ASCO 2009
80
90
100
NSABP C-08 – DFS
70
Scans?
HR 0.89
P
0.15
60
mFF6+B
mFF6
Ev 3yDFS
291 77.4
312 75.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Wolmark et al ASCO 2009
DFS Stage III
40
Ev 3yDFS
mFF6+B 40
87.4 Δ 2.7
mFF6 47 84.7
mFF6+B
mFF6
Ev 3yDFS
251 74.2 Δ 1.8
265 72.4
20
HR 0.90
P 0.25
NSABP C-08
0
0
20
HR 0.82
P 0.35
40
60
60
80
80
100
100
DFS Stage II
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
NSABP C-08
Status at 36 mo Med Follow-up
mFF6
mFF6+B
P
Recurrence (N)
248
227
NS
Death (N)
146
132
NS
Second Ca (N)
46
47
NS
2yS Post Rec (%)
41
37
NS
Rec Mult Sites (%)
18
18
NS
Sites of Rec
–
–
NS
Wolmark et al ASCO 2009
Stage II and Stage III Colon
Cancers Are Different Diseases!
ACCENT Database:
Time from Recurrence to Death by Stage
100
% Alive
Stage II (N=1153)
80
Stage III (N=4550)
60
Total
(N=5703)
Log Rank P-Value =
<0.0001
40
20
0
0
1
O’Connell, et al. JCO 2008
2
3
4
5
Time (Years)
6
7
8
PETACC 3: Stage-Specific
Molecular Markers
• PETACC 3: 5-FU/LV + irinotecan vs 5-FU/LV in stage II/III CC
• Translational study in 1404 pts with suitable biopsy material
Molecular Marker (%)
Stage II
(n = 420)
Stage III
(n = 984)
P Value
p53 overexpression
SMAD4 loss
Thymidylate synthase
Telomerase
MSI-H
18q LoH
KRAS
BRAF
30
9
43
40
22
63
36
8
37
13
29
48
12
70
37
8
.01
.02
.0001
.06
.0001
.04
.67
.90
Roth AD, et al. GI Cancers Symposium 2009. Abstract 288; ASCO 2009.
Defective MMR - Colon cancer
• Characterized by presence of MSI & loss of
MLH1, MSH2, MSH6 or PMS2 expression
• ~15% of Sporadic CC, >90% loss of MLH1
• Clinical Correlations: Right sided, Female,
Early stage, Better prognosis
• Tumors: Poorly differentiated, Signet-ringcell, Lymphocytic infiltration, near diploid
• dMMR cells resistant to 5-FU1,2
1Carethers,
1999; 2Arnold 2003
Defective MMR vs MSI
• Microsatellites (MS) = small DNA segments that consist of
repetitive nucleotides of generally 100-200 base pairs
• prone to replication errors which can change their length
• DNA mismatch repair (MMR) proteins consist of hMLH1, hMSH2,
hMSH6, hPMS2, hMSH3, and hMLH3
• MMR proteins can be deficient due to
• mutations of genes (e.g. HNPCC/Lynch) – 5% of CRC
• methylation of promoter region – 15-20% of sporadic CRC
• Test method for dMMR phenptype:
• Analysis of MS lengths using 5 specific DNA markers
• MSI-H: MSI in at least 2 of 5 markers, MSI-L: MSI in only 1
marker, MSS: no instability detected
• IHC for MMR proteins: MLH1, MSH2 most important (>90%)
Pooled data (N=1027)
Trial
Treatment
N
% Stage II
% dMMR
784852
5FU/LEV
117
30%
14%
INT 0035
5FU/LEV
215
50%
18%
874651
5FU/LV
66
19%
12%
GIVIO
5FU/LV
183
52%
16%
FFCD
5FU/LV
154
66%
19%
NCIC
5FU/LV
292
61%
15%
1027
52%
16%
Total
Sargent ASCO 2008
DFS/OS in Stage II dMMR Patients
(N=102)
5-yr DFS
Untreated 87%
Treated 72%
N = 47
N = 55
HR: 2.80 (0.98-8.97)
p=0.05
5-yr OS
Untreated
Treated
93%
75%
HR: 3.15 (1.07-9.29)
p=0.03
Sargent ASCO 2008
PETACC 3: Stage-Specific
Prognostic Values
Marker
Stage II (n=420)
Stage III (n=984)
HR
P
HR
P
MSI (Hi vs Stable)
0.3
0.004
0.7
0.06
18qLOH
2.1
0.03
1
0.91
SMAD4 (any loss)
1.4
0.21
1.6
<0.0001
hTERT (High)
1.4
0.32
1.5
0.01
p53 (High)
1.0
0.98
1.3
0.03
TS (High)
0.5
0.03
0.7
0.02
KRAS (Mutated)
1.1
0.84
1.0
0.72
BRAF(Mutated)
0.9
0.90
1.2
0.28
P values from the Wald test in a univariate Cox regression
HR = hazard ratio
Roth AD, et al. ASCO 2009.
PETACC 3: Multivariate Analysis
Stage II
Markers
HR [95% CI]
P value
T4 v. T3
2.58 [1.56 - 4.28]
0.00024
MSI-H v. MSS
0.28 [0.10 - 0.72]
0.0089
18qLOH
1.37 [0.67 - 2.77]
0.38
Roth AD, et al. ASCO 2009.
Percentage of Patients (%)
5-Year Relative Survival
By AJCC Stage
100
90
80
70
60
50
40
30
20
10
0
93
85
83
p < .001
72
64
44
8
Stage I
Stage
IIA
(T1–2N0) (T3N0)
O’Connell et al., 2004.
Stage
IIB
(T4N0)
Stage
Stage
Stage Stage IV
IIIA
IIIB
IIIC
(T1–2N1) (T3–4N1) (TanyN2)
(M1)
PETACC 3: Detailed Analysis of MSI
Frequency Analysis
MSI-H
Stage II
Stage III
Stage IV
22%
12%
3.5% *
(86/395)
(104/859)
• MSI as a suppressor of lymph node and
distant metastasis?
*Br J Cancer. 2009 100(2):266-73.
Tejpar, et al. ASCO 2009. (abstract 4001)
Results: Prognostic impact of MSI
HR MSI H
(95% CI)
Stage II
(n= 391)
Stage III
(n= 842)
Both stages
* P are stage
corrected
5FU
(n= 625)
5FU/iri
(n= 608)
Both arms
RFS
0.228 (0.05-0.955)
P= 0.043
0.296 (0.091-0.968)
P=0.044
0.265(0.107- 0.661)
P= 0.0044
OS
0.18 (0.02-1.34)
P= 0.095
0.143 (0.02-1.06)
P=0.057
0.159( 0.039- 0.659)
P=0.011
RFS
0.596 (0.344-1.03)
P=0.064
0.815 (0.478-1.39)
P=0.45
0.693 (0.473-1.02)
P= 0.06
OS
0.515 (0.261-1.02)
P=0.055
0.939 (0.515-1.71)
P=0.84
0.699 (0.446- 1.09 )
P= 0.12
RFS
0.501 (0.300-0.837)
P=0.0083
0.642 (0.394-1.05)
P=0.076
0.569 ( 0.400 -0.811)
P=0.0018
OS
0.437(0.229-0.833)
P= 0.012
0.676 (0.380-1.20)
P= 0.18
0.548 (0.357-0.842)
P=0.006
Tejpar, et al. ASCO 2009. (abstract 4001)
Development and Validation of an 18-Gene RTPCR Colon Cancer Assay
Colon Cancer Technical Feasibility
761 genes
375 genes
Development Studies
Development Studies
Surgery Alone
Surgery + 5FU/LV
NSABP C-01/C-02 (n=270)
NSABP C-04 (n=308)
CCF (n = 765)
NSABP C-06 (n=508)
Selection of Final Gene List & Algorithm
18 genes
Validation of Analytical Methods
ASCO 2009
Clinical Validation Study – Stage II Colon Cancer
QUASAR (n>1200)
Test prognostic, but not predictive!
Kerr et al., ASCO 2009, abstr. 4000
QUASAR: OS in patients with “no clear
indication for chemo” (mostly stage II)
5-FU/LV vs surgery alone
100
Observation (n=1622)
Chemotherapy (n=1617)
% of Patients
80
60
5-yr OS difference: 2.9%
40
P = .02
20
5-year OS, Observation = 77.4% vs Chemotherapy = 80.3%
Relative risk = 0.83 (95% CI, 0.71-0.97)
0
0
1
2
3
4
5
Years
QUASAR group, Lancet 2007
6
7
8
9
10
QUASAR: Evaluable Stage II Colon Cancer
Patients
Parent QUASAR study
n=3,239
Patients with collected blocks
n=2,197 (68%)
707 cases stage III and
rectal cancer
Confirmed stage II
n=1,490 (69%)
Final evaluable population
n=1,436
Kerr et al., ASCO 2009, abstr. 4000
54 excluded (3.6%):
29 synchronous tumors
8 insufficient tissue
7 identifier queries
6 RNA quality/quantity
4 ineligible histology
QUASAR: Pre-Specified Primary Endpoint:
Recurrence Risk
Is there a significant
relationship between the risk
of recurrence and the prespecified continuous
Recurrence Score in stage II
colon cancer patients
randomized to surgery alone?
RECURRENCE SCORE
Calculated from Tumor
Gene Expression
STROMAL
FAP
INHBA
BGN
CELL CYCLE
Ki-67
C-MYC
MYBL2
GADD45B
REFERENCE
ATP5E
GPX1
PGK1
UBB
VDAC2
Kerr et al., ASCO 2009, abstr. 4000
QUASAR Results: Recurrence Risk in
Pre-specified Recurrence Risk Groups (n=711)
1.0
Low
Intermediate
High
Range
of RS
Proportion of
patients
<30
43.7%
30-40
30.7%
≥41
25.6%
0.8
Proportion Event Free
Recurrence
Risk Group
0.6
0.4
Kaplan-Meier Estimates (95% CI)
of Recurrence Risk at 3 years
Recurrence Risk Group
0.2
Low
Comparison of High vs. Low
Recurrence Risk Groups
using Cox Model: HR = 1.47
(p=0.046)
Intermediate
Hig
h
0.0
0
1
2
12%
( 9% -16%)
18%
22%
(13%-24%)
(16%-29%)
3
4
5
Years
Kerr et al., ASCO 2009, abstr. 4000
QUASAR Results: Prediction of Differential
5FU/LV Benefit for Treatment Score
• Continuous Treatment Score and Treatment Benefit
with 5FU/LV
– Treatment Score by Treatment Interaction for RFI:
interaction p = 0.19
• Selected Secondary Analyses
– Treatment Score by Treatment Interaction not
significant when adjusted for prognostic covariates
– Treatment Score by Treatment Interaction not
significant for DFS (interaction p=0.12) or OS
(interaction p=0.15)
Kerr et al., ASCO 2009, abstr. 4000
QUASAR RESULTS: Recurrence Score, T Stage, and MMR
Deficiency are Key Independent Predictors of Recurrence
in Stage II Colon Cancer
Kerr et al., ASCO 2009, abstr. 4000
Multivariate Analysis
Risk of recurrence at 3 years
QUASAR Results: Recurrence Score, T Stage, and
MMR Deficiency are Key Independent Predictors
of Recurrence in Stage II Colon Cancer
45%
40%
T4 stage (13%)
35%
30%
25%
T3 and MMR
proficient (76%)
20%
15%
10%
T3 and MMR
deficient (11%)
5%
0%
0
10
20
30
40
Recurrence Score
50
60
70
Kerr et al., ASCO 2009, abstr. 4000
Decision Algorithm in Adjuvant Therapy
Resected Colon Ca
Stage II
Stage III
yes
T4 and/or
<12 LNs
no
Low-Risk
No therapy!
yes
High-Risk
*
dMMR
no
FOLFOX
Intermed.
Risk
*
5-FU/LV or
Capecitabine
Oncotype
?
Colon ?
*pts not considered candidates for oxaliplatin
Neo-Adjuvant Therapy of Rectal
Cancer
• 4007
• 4008
• 4014
ACCORD-2
Gerard
STAR
Aschele
AIO
Hofheinz
Addition of Oxaliplatin
to Fluoropyrimidine-based Neoadjuvant
Radio-Chemotherapy
• Locally advanced rectal cancer
• High rates of distant metastases (30-35%)
• Positive circumferential resection margin in 1030% of “resectable” tumors
• Oxaliplatin
• Improves the efficacy of FU-based
•
•
chemotherapy
Radiosensitizing properties in experimental
models
Promising activity with preoperative
radiotherapy and fluorouracil
Aschele. ASCO 2009. Abstract CRA4008.
Oxaliplatin in Neoadjuvant RadioChemotherapy for Rectal Cancer
Author
Chemo
RT
379
5-FU 225 mg/m2/d
50.4 Gy in
28 fractions
8%
16%
50.4 Gy in
28 fractions
24%
15%
45 Gy in 25
fractions
11%
14%
50 Gy in 25
fractions
25%
19%
Aschele
(STAR)
5-FU 225 mg/m2/d
368
295
Gerard
(ACCORD)
Grade 3- Pathological
4 toxicity
CR rate
N
292
Oxaliplatin 60
mg/m2/w x 6
Capecitabine 800
mg/m2 bid
Capecitabine 800
mg/m2 bid 5 of 7 d
Oxaliplatin 50
mg/m2/w
Aschele. ASCO 2009. Abstract CRA4008. Gerard. ASCO 2009; Abstract LBA4007.
AIO Study – Rtx + Cape or 5-FU:
Disease free survival
Preliminary data
50.4 Gy +
N Pts
197
195
Log-rank:
p=0.303
Median follow-up: 1.6 years
Hofheinz. ASCO 2009. Abstract 4014.
Neoadjuvant Therapy of Rectal
Cancer – ASCO 2009
• Capecitabine had activity similar to 5-FU
• Addition of oxaliplatin did not improve response
• Increased toxicity
• Oxaliplatin does not appear to be a
radiosensitizer in these studies
• Implications for ongoing NSABP R-04?
• Cape vs ci 5-FU +/- oxaliplatin plus Rtx
• Primary EP: local disease control
• Accrual: 1260/1600 pts
Other GI Malignancies
•
•
•
•
4503
GemCis Biliary
Valle
4505
ESPAC-3
Neoptolemos
4506
LMWH in PC
Riess
4509
ToGA
Van Cutsem
Trastuzumab plus Chemotherapy in
Advanced HER2+ Gastric Cancer: ToGA
Rationale: A subpopulation of gastric cancers overexpress HER2
Screen 3807
GC patients
for HER2
expression
HER2+ GC
(n = 810,
22%)
5-FU or Capecitabine
(investigator discretion)
+ Cisplatin + Trastuzumab
(n=294)
R
(n = 584)
Stratification by
•Gastric vs GEJ
•Advanced vs metastatic
•5-FU vs capecitabine
5-FU or Capecitabine
(investigator discretion)
+ Cisplatin
(n=290)
5-FU 800 mg/m2/d infusional d1-5 q3w X 6
Capecitabine 1000 mg/m2 bid d1-14 q3w X 6
Cisplatin 80 mg/m2 q3w X 6
Trastuzumab 6 mg/kg q3w to PD (8 mg/kg loading)
Primary endpoint: OS
Van Cutsem et al. J Clin Oncol 2009; 27(suppl):798s (LBA4509)
Bang et al. J Clin Oncol 2009; 27(suppl): 215s (abstract 4556)
ToGA: Main patient selection criteria
Inclusion criteria
• Adenocarcinoma of stomach or GEJ
• Inoperable locally advanced and/or metastatic disease
• Measurable (RECIST), or non-measurable evaluable disease
• HER2-positive tumor (centrally assessed)
– IHC 3+ and/or FISH+
• Adequate organ function and ECOG performance status ≤2
• Written informed consent
Exclusion criteria
• Previous adjuvant chemotherapy within 6 months
• Chemotherapy for advanced disease
• Congestive heart failure or baseline LVEF <50%
• Creatinine clearance <60 mL/min
IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; LVEF, left ventricular ejection fraction
Van Cutsem et al. ASCO 2009 (LBA4509)
Patient demographics and baseline
characteristics
Characteristic
F+C
n=290
F+C + trastuzumab
n=294
75 / 25
77 / 23
Age, median (range) years
59.0 (21-82)
61.0 (23-83)
Weight, median (range) kg
60.3 (28-105)
61.5 (35-110)
166 (56)
26 (9)
95 (32)
9 (3)
158 (53)
27 (9)
99 (33)
14 (5)
74.2a
8.7a
17.1a
21.4
76.8b
8.9b
14.3b
24.1
Sex, %
Male / Female
Region, n (%)
Asia
C/S America
Europe
Other
Type of GC (central assessment)
Intestinal
Diffuse
Mixed
Prior gastrectomy
Highest recruitment was from Korea, Japan, China and Russia
F, fluoropyrimidine; C, cisplatin an=287; bn=293
Van Cutsem et al. ASCO 2009 (LBA4509)
ToGA: Primary end point: OS
Median
Events OS
HR
Event 1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
FC + T
FC
11.1
0
2
4
6
167
182
13.8
11.1
95% CI
p value
0.74 0.60, 0.91
0.0046
13.8
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Time (months)
No.
at
risk
294 277 246 209 173 147 113 90
290 266 223 185 143 117 90 64
T, trastuzumab
71
47
56
32
43
24
30
16
21
14
13
7
12
6
6
5
4
0
1
0
0
0
Van Cutsem et al. ASCO 2009 (LBA4509)
ToGA: Secondary end point: PFS
Event
Median
Events PFS HR
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
FC + T
FC
5.5
0
2
4
226
235
6.7
5.5
95% CI
p value
0.71 0.59, 0.85
0.0002
6.7
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time (months)
No.
at risk
294 258 201 141 95
290 238 182 99 62
60
33
41
17
28
7
21
5
13
3
9
3
8
2
6
2
6
1
6
1
4
0
2
0
0
0
Van Cutsem et al. ASCO 2009 (LBA4509)
ToGA: Efficacy: OS by HER2 status
N
Median OS
(months)
584
11.1 vs 13.8
0.74
0.60, 0.91
IHC0/FISH+
61
7.2 vs 10.6
0.92
0.48, 1.76
IHC1+/FISH+
70
10.2 vs 8.7
1.24
0.70, 2.20
IHC2+/FISH+
159
10.8 vs 12.3
0.75
0.51, 1.11
IHC3+/FISH+
256
12.3 vs 17.9
0.58
0.41, 0.81
IHC3+/FISH-
15
17.7 vs 17.5
0.83
0.20, 3.38
IHC0 or 1+/FISH+
131
8.7 vs 10.0
1.07
0.70, 1.62
IHC2+/FISH+ or IHC3+
446
11.8 vs 16.0
0.65
0.51, 0.83
Subgroup
All
Hazard 95% CI
ratio
Pre-planned analysis
Exploratory analysis
0.2
Favors T
0.4
0.6
1
Risk ratio
2
3
4 5
Favors no T
Van Cutsem et al. ASCO 2009 (LBA4509)
ToGA: OS in IHC2+/FISH+ or
IHC3+ (exploratory analysis)
Median
Events OS
HR
Event 1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
FC + T
FC
11.8
0
2
4
6
120
136
16.0
11.8
95% CI
0.65 0.51, 0.83
16.0
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Time (months)
No.
at
risk
228 218 196 170 142 122 100 84
218 198 170 141 112 96 75 53
65
39
51 39
28 20
28
13
20 12
11 4
11
3
5
3
4
0
1
0
0
0
Van Cutsem et al. ASCO 2009 (LBA4509)
ToGA: Efficacy Outcome
Fluoropyrimidine
+ Cisplatin +
Trastuzumab
(n = 294)
Fluoropyrimidine
+ Cisplatin
(n = 290)
HR [95% CI]
P Value
OS
13.8 months
11.1 months
0.74 [0.60-0.91]
.0046
PFS
6.7 months
5.5 months
0.71 [0.59-0.85]
.0002
ORR
47%
34.5%
.0017
CR
5%
2%
.0599
PR
42%
32%
.0145
• Preplanned subgroup analysis indicated improved OS benefit with
increasing HER2 expression by IHC
• Exploratory analysis of IHC2+/FISH+ and IHC3+ cohort demonstrated a
4 month increase in OS with trastuzumab (HR [95% CI], 0.65 [0.51-0.83])
Van Cutsem et al. ASCO 2009 (LBA4509)
ToGA: Select Grade 3/4 Toxicities*
Fluoropyrimidine +
Cisplatin +
Trastuzumab
(n = 294)
Fluoropyrimidine +
Cisplatin
(n = 290)
Neutropenia
27%
30%
Anemia
12%
10%
Diarrhea
9%
4%
Nausea
7%
7%
Asymptomatic LVEF drops
(< 50%)
6%
1%
Hematologic
Nonhematologic
*2 deaths due to cardiac events in each arm
Van Cutsem et al. ASCO 2009 (LBA4509)
Gemcitabine ± Cisplatin in Advanced Biliary
Tract Cancer: Phase III UK ABC-02 Trial
Eligibility criteria:
•No prior systemic
therapy
•Adequate biliary
drainage
Stratification by
•Site of primary
•LA vs metastatic
•Prior therapy
R
A
N
D
O
M
I
Z
E
Cisplatin 25 mg/m2
+ Gemcitabine 1000 mg/m2
d 1, 8 q21d for 8 cycles
(n=204)
Gemcitabine 1000 mg/m2 d
1, 8, 15 q28d for 6 cycles
(n=206)
(n = 410)
• Primary endpoint: OS
• Secondary endpoints including: PFS, toxicity
Valle et al. ASCO 2009 (abstract 4503)
UK ABC-02 Trial: Select Grade 3/4 Adverse
Events
Gem + Cis
(n = 159)
Gem
(n = 165)
Neutropenia
36 (23%)
29 (18%)
Leukopenia
24 (15%)
18 (11%)
Any
102 (64%)
108 (65.5%)
Elevated Bilirubin
17 (11%)
21 (13%)
Elevated ALT
15 (10%)
28 (18%)
Elevated AST
12 (8%)
17 (11%)
Fatigue
29 (19%)
27 (17%)
Hematologic
Nonhematologic
No significant differences between arms
Valle et al. ASCO 2009 (abstract 4503)
UK ABC-02 Trial: Efficacy
Gemcitabine +
Cisplatin
(n = 148)
Gemcitabine
(n = 132)
P Value
(HR [95%CI])
38 (26%)
21 (16%)
NR
CR
1 (< 1%)
1 (< 1%)
NR
PR
37 (25%)
20 (15%)
NR
SD
79 (53%)
73 (55%)
NR
CBR (CR + PR +SD)
117 (79%)
94 (71%)
.256
(n = 204)
(n = 206)
PFS
8.4 months
6.5 months
.003
(0.72 [0.57-0.90])
OS
11.7 months
8.3 months
.002
(0.70 [0.54-0.89])
ORR
Valle et al. ASCO 2009 (abstract 4503)
ABC-02 Results:
Progression-free survival (ITT)
Treatment arm
Gem
Gem + Cis
Number of patients
n=206
n=204
155 (75.2)
135 (66.2)
6.5
8.4
PFS events n(%)
Median PFS (mo)
Log rank p value
0.003
Hazard ratio (95% CI)
0.72 (0.57, 0.90)
Valle et al. ASCO 2009 (abstract 4503)
ABC-02 - Results:
Overall Survival (ITT)
Treatment arm
Gem
Gem + Cis
Number of patients
n=206
n=204
141 (68.5)
122 (59.8)
8.3
11.7
Deaths n(%)
Median survival (mo)
Log rank p value
0.002
Hazard ratio (95% CI)
0.70 (0.54, 0.89)
Valle et al. ASCO 2009 (abstract 4503)
ABC-02 - Overall Survival
Exploratory sub-group
analysis
Valle et al. ASCO 2009 (abstract 4503)
CONKO-001 Gemcitabine as
Adjuvant Therapy in Resected PC
R
a
n
d
o
m
i
z
a
t
i
o
n
Ultrasound
Ultrasound
CT Scan
after week 8
after week 16
after week 32
Gem
Gem
Gem
Gem
Gem
Gem
Obs
Obs
Obs
Obs
Obs
Obs
4 weeks
CA 19-9
4 weeks
CA 19-9
Oettle et al., JAMA 2007
4 weeks
CA 19-9
4 weeks
CA 19-9
4 weeks
CA 19-9
Follow up
every 8
weeks
4 weeks
CA 19-9
CA 19-9
Gem
Gemcitabine 1000 mg/m²: d1, 8, 15; q 4 weeks
Obs
Observation: d1; q 4 weeks
CONKO-001 ASCO 2008 Update
100%
Gemcitabine
mOS: 22.8 mos
OS Rate (%)
(95% CI, 18.5-27.2)
75%
Observation
Obs
GEM
1yr
72.5
72.0
3yrs
19.5
36.5
5yrs
9.0
21.0
mOS: 20.2 mos
(95% CI, 17.7-22.8)
50%
25%
P = 0.005
0%
0
12
24
months
Neuhaus et al., ASCO 2008
36
48
60
72
84
ESPAC-3: Adjuvant bolus 5-FU/LV vs
Gemcitabine in Pancreatic Cancer
Neoptolemos et al. ASCO 2009 (abstract 4505)
ESPAC-3: Adjuvant bolus 5-FU/LV vs
Gemcitabine in Pancreatic Cancer
Neoptolemos et al. ASCO 2009 (abstract 4505)
ESPAC-3: Adjuvant bolus 5-FU/LV vs
Gemcitabine in Pancreatic Cancer
Neoptolemos et al. ASCO 2009 (abstract 4505)
CONKO-4: LMWH vs Observation in
metastatic PC
Riess et al. ASCO 2009 (abstract 4506)
CONKO-4: LMWH vs Observation in
metastatic PC
Riess et al. ASCO 2009 (abstract 4506)
CONKO-4: LMWH vs Observation in
metastatic PC
Riess et al. ASCO 2009 (abstract 4506)
CONKO-4: LMWH vs Observation in
metastatic PC
Riess et al. ASCO 2009 (abstract 4506)
CONKO-4: LMWH vs Obs. in mPC
Riess et al. ASCO 2009 (abstract 4506)