Transcript CRC_CCC_2007

Challenging Cases in Cancer:
Integration of Findings from ASCO 2007
Colorectal Cancer
Metastatic Colorectal Cancer
Axel Grothey, MD
Senior Associate Consultant
Division of Medical Oncology
Mayo Clinic College of Medicine
Rochester, MN
Case 3: First-line Colorectal Cancer
• Patient was treated with adjuvant 5-FU/LV after R
hemicolectomy for T3N1M0 stage III colon cancer
• Two years later he relapses with rising CEA and 2 lung
metastases plus 3 liver metastases
• He is treated with modified FOLFOX6 plus bevacizumab
for 12-cycles (six months) but develops grade 3
neuropathy
• CT scan shows all lesions more than 50% smaller
Case 3: First-line Colorectal Cancer
• Which treatment option would you recommend?
 Continue therapy (unchanged)
 Hold all treatment until tumor progression
 Stop oxaliplatin and continue therapy with 5-FU/LV and
bevacizumab
 Stop oxaliplatin and continue therapy with bevacizumab
alone
 Switch therapy to an irinotecan-based regimen
Case 3: First-line Colorectal Cancer
• Which treatment option would you recommend?
 Continue therapy (unchanged)
 Hold all treatment until tumor progression
 Stop oxaliplatin and continue therapy with 5-FU/LV and
bevacizumab
 Stop oxaliplatin and continue therapy with bevacizumab
alone
 Switch therapy to an irinotecan-based regimen
• Recommended approach
–
Stop oxaliplatin and continue therapy with 5-FU/LV and
bevacizumab
Pertinent Issues for Case 3
• Metachronous metastases after 2-years to lung and liver
– Should always consider resectability even with extrahepatic
disease
• In this case situation it was deemed unresectable
• Good response to chemotherapy with FOLFOX + BEV,
but grade 3 neurotoxicity after 12-cycles
• Should patient have a “chemo-holiday”?
Definition of “Chemo-Holiday”
• Stop of:
– All medical therapy (chemo/biologics), no “maintenance”
(OPTIMOX2)
– Certain components of medical therapy, continuation of “chemolight” (+/- biologics) (OPTIMOX1, CONcePT)
– Conventional chemotherapeutics, continuation of biologics
(DREAM)
Definition of “Chemo-Holiday”
• Stop can occur:
–
–
–
–
After pre-defined number of cycles
When “best response” is achieved
When long-lasting SD has been documented
When toxicity threshold is reached
• Restart/re-intensify therapy:
– After pre-defined interval (OPTIMOX1, CONcePT)
– When “relevant” tumor progression noted (OPTIMOX2)
N9741: FOLFOX4 - TTP and TTF
100
% Event-free
90
TTP
80
TTF
70
60
9.3 mos
50
5.8 mos
40
63% of pts stopped
FOLFOX for other
reasons than PD
30
20
10
0
0
6
12
Time (mos)
18
24
Green et al., GI ASCO 2005
OPTIMOX Studies
FOLFOX4 until TF
OPTIMOX-1
N = 620
FOLFOX7
FOLFOX7
sLV5-FU2
Tournigand et al, JCO 2006
mFOLFOX7
OPTIMOX-2
N = 202
mFOLFOX7
sLV5-FU2
mFOLFOX7
mFOLFOX7
CFI
Maindrault-Goebel et al, ASCO 2007 Abstract #4013
Stop and Go Concept - OPTIMOX1
FOLFOX4
R
620 pts
6x FOLFOX7- 12x sLV5-FU2 - 6x FOLFOX7
Cum. Oxali
(%)
RR
PFS
DDC
OS
G3/4 NTox
780
1,560
FOLFOX4
FOLFOX7
58.5
9.0
9.0
19.3
17.9
58.3
8.7
10.6
21.2
13.3
Primary
endpoint
Tournigand et al., JCO 2006
OPTIMOX2 - 5-FU/LV Maintenance vs
Chemo-Free Intervals
Maintenance
N = 99
CFI
N = 103
Initial RR (%)
60
59
RR reintro. (%)
21
25
PFS (wks)
36
29
0.08
DDC (wks)
52
39
0.39
OS (mos)
26
19
0.0549
P
Maindrault-Goebel et al, ASCO 2007 Abstract #4013
OPTIMOX2: Progression-free Survival
1.0
Maintenance
36 weeks
0.8
P = 0.08
29 weeks
0.6
CFI
0.4
0.2
0.0
0
10
20
30
40
50
weeks
60
70
80
90
100
Maindrault-Goebel et al, ASCO 2007 Abstract #4013
OPTIMOX2: Overall Survival
1.0
Maintenance
26 months
0.8
P = 0.0549
19 months
0.6
CFI
0.4
0.2
Lesson from OPTIMOX2:
Don’t stop treatment before progression!
0.0
0
10
20
30
months
40
50
Maindrault-Goebel et al, ASCO 2007 Abstract #4013
Take-home Messages
OPTIMOX2
• A strategy with complete chemotherapy-free intervals
(CFI) leads to inferior outcome compared to an inductionmaintenance-reintroduction approach
• If PFS is the primary endpoint of your trial, do not stop
treatment before progression (see NO16966)
• DDC is NOT an appropriate endpoint in CRC
 In advanced CRC, the default treatment strategy should
be “treatment to progression”
Recommendation for Case 3
• In palliative situation, goal of therapy is to extend
duration and maintain the quality of life as long as
possible
• Do not “waste” potentially active agents unnecessarily
(no irinotecan here!)
• Maintenance therapy should be default position
– Infusional 5-FU/LV + BEV or capecitabine + BEV should be
considered
– No role so far for BEV single agent as maintenance therapy
Case 4: First-line Colorectal Cancer
• 52-year-old healthy restaurant owner presents with
increasing pain on bowel movement and complains of
several weeks of diarrhea and weight loss of 10 pounds
– Finally cannot move bowels and begins to vomit
• CT scan shows 12 cm mass in the LLQ with multiple liver
nodules and an elevated CEA level of 60 ng/mL
• GI evaluation with colonoscopy shows a nearly
obstructing sigmoid mass – cannot pass scope – biopsy
shows adenocarcinoma
Case 4: First-line Colorectal Cancer
• Undergoes sigmoid colon resection with primary
anastomosis and a wedge biopsy of the left lobe of
the liver
• Pathology reveals a mucinous adenocarcinoma of
the sigmoid colon metastatic to lymph nodes and
liver
• Now referred for consideration of chemotherapy
Case 4: First-line Colorectal Cancer
• Which chemotherapy would you recommend?






5-FU/LV or capecitabine
FOLFOX
CAPOX (XELOX)
FOLFIRI
IROX
FOLFOXIRI
Case 4: First-line Colorectal Cancer
• Which targeted agent would you add?






None
Bevacizumab
Cetuximab
Panitumumab
Bevacizumab + cetuximab
Bevacizumab + panitumumab
Case 4: First-line Colorectal Cancer
• Which targeted agent would you add?






None
Bevacizumab
Cetuximab
Panitumumab
Bevacizumab + cetuximab
Bevacizumab + panitumumab
• Recommended approach
–
FOLFOX + bevacizumab or FOLFIRI + bevacizumab
Pertinent Issues for Case 4
• Palliative situation with unresectable, scattered liver
metastases
• Symptomatic primary (obstruction) → resection of primary
warranted
• What is optimal chemotherapy?
• And should a biologic be added upfront?
New Agents Have Significantly Improved
Treatment and Patient Outcomes
Regimen
5-FU
First
Line
Second
Line
FDA-Approval
Year
√
√
1962
√
1996
Irinotecan (monotherapy)
IFL/irinotecan + infusional 5-FU/LV*
√
2000
Capecitabine (monotherapy)
√
2001
Oxaliplatin + infusional 5-FU/LV†
√
Cetuximab (with or without irinotecan)
Bevacizumab + IV 5-FU-based regimens‡
√
√
Second-line, 2002
First-line, 2004
√
2004
√
First-line, 2004
Second-line 2006
Panitumumab (single agent)
Salvage 2006
* FOLFIRI
† FOLFOX
‡ IFL, FOLFIRI, FOLFOX, and 5-FU/LV
More regimens provide more options for
multiple lines of therapy to extend survival
Modified from Venook A. Oncologist. 2005.
NCCTG/Intergroup Trial N9741
R
A
N
D
O
M
I
Z
A
T
I
O
N
IFL:
Irinotecan +
5-FU/LV
FOLFOX4:
Oxaliplatin + 5-FU/LV
795 patients
IROX: Irinotecan +
oxaliplatin
Goldberg et al., JCO 2004
NCCTG/Intergroup Trial N9741
Efficacy
IFL
FOLFOXP
P-value
OS
15.0 mo
19.5 mo
0.0001
TTP
6.9 mo
8.7 mo
0.0014
RR
31%
45%
0.002
Goldberg et al., JCO 2004
Tournigand Trial (N = 220)
FOLFOX
FOLFIRI
FOLFIRI
FOLFOX
(1st line
2nd line)
(1st line
2nd line)
N pts
111
69
109
81
RR
54%
4%
56%
15%
Resection of
Hepatic Metastases
PFS (mos)
Median OS (mos)
21%
2nd line:
62%
8.1
2.5
20.6
9%
8.5
2nd line:
74%
4.2
21.5
Tournigand et al., JCO 2004
Concept of “All-3-Drugs” - Update 2005
11 Phase III Trials, 5,768 Patients
Multivariate analysis:
Effect on OS
P
First-line doublet
0.69
All 3 drugs
0.005
22
Median OS (mo)
21
20
First-Line Therapy
Infusional 5-FU/LV
+ irinotecan
Infusional 5-FU/LV
+ oxaliplatin
Bolus 5-FU/LV
+ irinotecan
Irinotecan
+ oxaliplatin
Bolus 5-FU/LV
19
18
17
16
15
14
P =.0001
13
12
LV5-FU2
0
10
20
30
40
50
60
70
80
FOLFOXIRI
Patients with 3 drugs (%)
CAIRO
OS (mos)=13.2 + (% 3 drugs x 0.1), R^2 = 0.85
2007
Grothey & Sargent, JCO 2005
Biologic Agents in Colorectal Cancer
Monoclonal Antibodies
Fab
Fc
Murine Ab
“momab”
(17-1A)
Chimeric
Mouse-Human Ab
“ximab”
Cetuximab
Humanized Ab
“zumab”
Human Ab
“mumab”
EGFR
Matuzumab
Bevacizumab
VEGF
Panitumumab
Cetuximab as Salvage Therapy for CRC
Saltz 2001
Saltz 2002
Cunningham 2003
Phase II
Phase II
Rand. Phase II
Cetux. + CPT
Cetux.
Cetux. + CPT
Cetux.
N
121
57
218
111
RR (%)
22.5
11
23*
11
RR+SD (%)
46
35
56*
32
Med. TTP (mos)
--
--
4.1*
1.5
Med. OS (mos)
--
>4
8.6
6.9
*P <0.05
CRYSTAL Study (First-line)
FOLFIRI + Cetuximab
EGFR-expressing
metastatic CRC
Stratified by:
• Regions
• ECOG PS
N = 599
R
PFS
FOLFIRI
N = 599
• Primary Endpoint: PFS (independent review)
• Secondary Endpoints: RR, DCR, OS, Safety, QoL
• Sample Size: 1,217 patients randomized, ITT: 1,198 pts
Van Cutsem et al., ASCO 2007 Abstract #4000
CRYSTAL Trial: Primary Endpoint PFS
ITT Population Independent Review
1.0
Cetuximab + FOLFIRI, N = 599
0.9
FOLFIRI, N = 599
0.8
HR = 0.851; 95% CI = [0.726-0.998]
PFS estimate
0.7
Stratified log-rank P-value = 0.0479
0.6
8.9 mo
0.5
1-year PFS rate
23% vs 34%
8.0 mo
0.4
0.3
0.2
0.1
0.0
0
2
4
8
10
12
14
16
18
20
Progression-free survival time (months)
Subjects at risk
FOLFIRI alone 599
Cetuximab + 599
FOLFIRI
6
492
499
402
392
293
298
178
196
83
103
35
58
16
7
4
1
29
12
5
1
Van Cutsem et al., ASCO 2007 Abstract #4000
CRYSTAL Trial:
Independent Assessment of Response
FOLFIRI alone, N = 599
Cetuximab + FOLFIRI, N = 599
Cetuximab
FOLFIRI
+ FOLFIRI
%
%
CR
0.3
0.5
PR
38.4
46.4
SD
46.7
37.4
PD
9.0
8.8
ORR
38.7
46.9
95%CI
[34.8 - 42.8]
[42.9 - 51.0]
85.5
84.3
60
Percentage (%)
50
P-value* = 0.0038
46.9
40
38.7
30
20
10
DCR**
0
Response rate
*Cochran-Mantel-Haenszel (CMH) test
** DCR: disease control rate
Van Cutsem et al., ASCO 2007 Abstract #4000
CRYSTAL Trial:
Subgroup Analysis of PFS Time by
On-study Skin Reactions: Cetuximab + FOLFIRI
1.00
Skin reaction grade 3*, n=112
Skin reaction grade 2, n=243
Skin reaction grade 0 or 1, n=244
PFS estimate
0.75
11.3 mo
9.4 mo
5.4 mo
0.50
0.25
0.00
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0
Progression-free survival time (months)
*There were no grade 4 skin reactions
Van Cutsem et al., ASCO 2007 Abstract #4000
KRAS Mutation Status Predictive of
Response to Cetuximab?
• 30 patients with CRC on
cetuximab
• PR: 11/30 patients (37%)
• KRAS mutation in
• 0/11 responders
• 13/19 non-responders
(68%)
• P = 0.0003
• Increased EGFR gene copy
number in 10%
• significantly associated with
response (P = 0.04)
16.3 mo
6.9 mo
Lievre et al., Cancer Res 2006
Agents Targeting the VEGF Pathway
Anti-VEGF
antibodies
Soluble
VEGF
receptors
VEGF
(bevacizumab)
(VEGF-TRAP)
Anti-VEGFR
antibodies
(IMC-1121b)
P
P
P
P
VEGFR-1
P
P
P
P
VEGFR-2
Endothelial cell
Small-molecule
VEGFR inhibitors
(Vatalanib, sunitinib, sorafenib)
Phase III Trial of Bevacizumab in MCRC:
Efficacy
IFL+ Placebo
(N = 411)
IFL+ Bevacizumab
(N = 402)
P-value
Median survival (mo)
15.6
20.3
0.00004
PFS (mo)
6.2
10.6
< 0.00001
ORR (%)
35
45
0.0036
CR
2.2
3.7
PR
32.5
41.2
7.1
10.4
Duration of resp. (mo)
0.0014
Hurwitz et al., N Engl J Med 2004
Phase III Trial of IFL ± Bevacizumab in
mCRC: Survival
Proportion surviving
1.0
HR = 0.66, P = 0.00004
Median survival: 15.6 vs. 20.3 mo
0.8
0.6
0.4
Treatment Group
0.2
IFL + placebo
IFL + bevacizumab
0
0
10
20
30
40
Duration of survival (mo)
Hurwitz et al., N Engl J Med 2004
Proportion of Patients
Who Survived
BICC-C
Period 2: Overall Survival
Regimen
Median OS
(Months)
1 Year
HR
(95% CI)
P-value
FOLFIRI+ BEV
Not Reached
87%
--
--
mIFL + BEV
19.2
61%
2.3
(1.3,4.1)
0.007
25
30
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
FOLFIRI + bevacizumab
0.2
0.1
mIFL + bevacizumab
0
0
5
10
15
20
Survival Time (months)
Fuchs et al., ASCO GI 2007
BICC-C: Summary
Period 1, no BEV
Period 2, + BEV
Efficacy
FOLFIRI
N = 144
mIFL
N = 141
CapIri
N = 145
FOLFIRI
N = 57
mIFL
N = 60
RR (%)
46.6
41.9
38
57.9
53.3
PFS (mo)
7.6
5.9
5.8
11.2
8.3
OS
23.1
17.6
18.9
NR
19.2
Diarrhea
14
19
48
11
12
Dehydr.
6
7
19
5
2
MI/stroke
0.7
4.4
0
1.8
0
60d mort.
3.4
5.1
3.5
1.8
6.8
G 3/4 (%)
NR = not reached
Fuchs et al., ASCO GI 2007
XELOX vs FOLFOX ± Bevacizumab
Roche NO16966 Study Design
Recruitment
June 2003 – May 2004
Recruitment
Feb 2004 – Feb 2005
XELOX
N = 317
XELOX + placebo
N = 350
XELOX +
bevacizumab
N = 350
FOLFOX4
N = 317
FOLFOX4 + placebo
N = 351
FOLFOX4 +
bevacizumab
N = 350
Initial 2-arm
open-label study (N = 634)
1Hurwitz
Protocol amended to 2x2 placebo-controled design
after bevacizumab phase III data1 became
available (N = 1401)
H, et al. Proc ASCO 2003;22 (Abstract 3646)
Cassidy et al., ESMO 2006
PFS XELOX Non-inferiority:
Primary Objective Met Based on ITT
1.0
HR = 1.04 [97.5% CI 0.93-1.16]
PFS estimate
0.8
Upper limit ≤ 1.23
(non-inferiority margin)
0.6
0.4
0.2
8.0
8.5
0
0
5
10
15
Months
20
FOLFOX/FOLFOX+placebo/FOLFOX+bevacizumab
XELOX/XELOX+placebo/XELOX+bevacizumab
25
30
N = 1017; 826 events
N = 1017; 813 events
Cassidy et al., ESMO 2006
PFS Chemotherapy + Bevacizumab
Superiority: Primary Objective Met
1.0
HR = 0.83 [97.5% CI 0.72–0.95] (ITT)
P = 0.0023
PFS estimate
0.8
0.6
0.4
0.2
8.0
9.4
0
0
5
10
15
20
25
Months
FOLFOX+placebo/XELOX+placebo
N = 701; 547 events
FOLFOX+bevacizumab/XELOX+bevacizumab
N = 699; 513 events
Cassidy et al., ESMO 2006
PFS estimate
PFS Chemotherapy + Bevacizumab Superiority:
XELOX and FOLFOX Subgroups
1.0
1.0
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0
0
7.4
5
9.3
10
15
Months
XELOX+placebo
XELOX+bevacizumab
20
25
N = 350; 270 events
N = 350; 258 events
XELOX subgroup
HR = 0.77 [97.5% CI 0.63–0.94] (ITT)
P = 0.0026
0
0
8.6
5
9.4
10
15
Months
20
25
FOLFOX+placebo
N = 351; 277 events
FOLFOX+bevacizumab N = 349; 255 events
FOLFOX subgroup
HR = 0.89 [97.5% CI 0.73–1.08] (ITT)
P = 0.1871
Cassidy et al., ESMO 2006
NO16966
Response Rate
Chemo +
placebo
Investigator
49%
Chemo
+ Bev
47%
FOLFOX+
FOLFOX
XELOX+
XELOX
placebo
+ Bev
placebo
+ Bev
50%
47%
48%
46%
report
P = 0.90
IRC data
38%
38%
P = 0.99
P = 0.88
36%
P = 0.91
38%
P = 0.49
39%
37%
P = 0.48
Saltz et al., ASCO GI 2007
Why Did BEV Not Increase PFS When
Added to FOLFOX in NO16966?
• No synergistic/additive effect with FOLFOX?
– No, see E3200 (second-line)
• Ceiling effect of first-line chemotherapy?
– Perhaps…
• Failure to OPTIMOXize?
– Very likely!
NO16966 Study Drug Exposure –
Median Months of Treatment
FOLFOX
+Placebo
FOLFOX
+Bev
XELOX
+Placebo
XELOX
+Bev
(N = 336)
(N = 341)
(N = 339)
(N = 353)
Oxaliplatin
6.0
6.0
5.5
5.8
Fluoropyrimidine
6.3
6.7
5.6
6.3
Placebo or Bev
6.3
6.0
5.5
6.0
* Per protocol, patients discontinuing oxaliplatin could continue with a fluoropyrimidine +
placebo or bevacizumab. Patients could also remain on a fluoropyrimidine alone or placebo
or bevacizumab alone but not oxaliplatin alone
Saltz et al., ASCO GI 2007
NO16966 PFS Subgroup Analyses:
On-treatment Population
XELOX Group
1.0
0.8
0.8
Survival
Survival
FOLFOX Group
1.0
0.6
0.4
0.2
0.6
0.4
0.2
7.0 m
9.5 m
8.4 m
0
10.6 m
0
0
100
200
300
400
500
0
100
Study day
300
400
500
Study day
HR = 0.61 [97.5% CI 0.48–0.78]
P ≤ .0001
XELOX + placebo VS.
200
XELOX + Bev
HR = 0.65 [97.5% CI 0.50–0.84]
P = .0002
FOLFOX4 +
placebo
VS.
FOLFOX4 +
Bev
Saltz et al., ASCO GI 2007
Rationale for Combining EGFR- and
Angiogenesis- Inhibitors
Targets
EGFR Inhibitors
Angiogenesis Inhibitors
• Tumor cell growth
• Synthesis of angiogenic
proteins
• Response of
endothelial cells to
angiogenic proteins
Tumor
-
Angiogenic proteins
bFGF
VEGF
TGF-
-
Endothelial cells
Herbst et al., J Clin Oncol. 2005;23:2544.
BOND-2 Trial - Efficacy
(Historic Comparison with BOND-1)
BOND-1
BOND-2
BOND-1
BOND-2
Cetux.
Cetux.+
BEV
Cetux.+
CPT
Cetux.+ CPT
+BEV
N pts
111
40
218
41
Previous Oxaliplatin
(%)
64
90
62
85
RR (%)
11
20
23
37
TTP (mos)
1.5
5.6
4.1
7.9
Med. OS (mos)
6.9
10.2
8.6
18.0
Saltz et al., ASCO 2005; Lenz et al., ASCO GI 2007
PACCE Study Schema
PACCE: Panitumumab Advanced Colorectal Cancer Evaluation
Randomized, Open-Label, Controlled Phase 3b Trial
S
C
R
E
E
N
I
N
G
Ox-based CT
(e.g., FOLFOX)
N = 800
Inv choice
Iri-based CT
(e.g., FOLFIRI)
N = 200
1:1
R
A
N
D
O
M
I
Z
E
Panitumumab
6 mg/kg Q2W
Ox-CT
Bevacizumab
Ox-CT
Bevacizumab
1:1
Inv choice
Panitumumab
6 mg/kg Q2W
Iri-CT
Bevacizumab
Iri-CT
Bevacizumab
Stratification Factors: ECOG score, prior adjuvant Tx, disease site,
Ox doses/Iri regimen, number of metastatic organs
Tumor assessments: Q12w until disease progression or intolerability
Hecht et al., World GI Barcelona 2007
Objective Response Rate By Cohort
(Central Review)
Oxaliplatin
bev/Ox-CT
(N = 405)
%
pmab+
bev/Iri-CT
(N = 68)
%
bev/Iri-CT
(N = 67)
%
39
41
38
31
Complete response
0
<1
0
0
Partial response
39
40
38
31
Stable disease
31
33
26
37
Progressive disease
6
4
9
4
Not done/Unevaluable*
24
22
26
27
Best ORR
pmab+
bev/Ox-CT
(N = 407)
%
Irinotecan
ITT set
*Included missing and unreadable scans
Hecht et al., World GI Barcelona 2007
Limited Update of PFS – Ox-CT Cohort
(Central Review, Apr 2007 Data Cutoff)
Proportion Progression-Free
Pmab+bev/Ox-CT
# PFS
events (%)
Median (95%CI),
mos
206 (50)
9.0 (8.5-10.4)
172 (42)
10.5 (9.7-11.6)
Bev/Ox-CT
100%
HR= 1.29 (95% CI: 1.05-1.58)
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
0
5
10
267
298
92
96
Months
15
20
21
21
3
1
Patients at risk:
Pmab+bev/Ox-CT N 413
bev/Ox-CT N 410
ITT set
Hecht et al., World GI Barcelona 2007
Unplanned Interim OS (Ox-CT Cohort)
Oct 2006 Data Cutoff*
Apr 2007 Data Cutoff
# OS events
(%)
Median (95%CI),
mos
83 (20)
18.4 (13.8-NE)
58 (14)
NE
Pmab+bev/Ox-CT
Bev/Ox-CT
Pmab+bev/Ox-CT
Bev/Ox-CT
100%
90%
90%
80%
80%
Proportion Alive
Proportion Alive
100%
70%
60%
50%
40%
30%
30%
0%
0%
16
20
Months
318
333
194
184
73
76
NE
40%
10%
12
95 (23)
50%
10%
8
18.6 (16.4- 20.6)
60%
20%
4
127 (31)
70%
20%
0
Median
(95%CI), mos
HR= 1.44 (95% CI: 1.10-1.88)
HR= 1.56 (95% CI: 1.11-2.17)
Pts at risk:
Pmab+
bev/Ox-CT 407
bev/Ox-CT 405
# OS events
(%)
10
6
*Interpretation of statistical significance is
limited by the lack of a prespecified
significance boundary
0
0
0
Pts at risk:
Pmab+
bev/Ox-CT 413
bev/Ox-CT 410
5
10
15
20
25
85
96
9
6
0
0
Months
342
357
224
234
NE = not estimatable; ITT set
Hecht et al., World GI Barcelona 2007
PACCE: Grade 3/4 AEs of Interest
(Ox-CT Cohort)
Pmab+
bev/Ox-CT
(N = 401), %
bev/Ox-CT
(N = 392), %
Gr 3
Gr 4
Gr 3
Gr 4
Skin toxicity
33
<1
1
0
Diarrhea
21
2
12
1
Dehydration
14
2
4
1
Hypokalemia
8
2
3
1
Hypomagnesemia
3
1
0
0
Neutropenia
12
10
17
7
Neuropathy
9
<1
10
<1
Nausea
10
0
4
<1
Infectionsa
16
2
7
2
Deep venous thrombosis
6
0
7
0
Pulmonary embolismb
0
6
0
4
MedDRA v9.0 preferred terms; Graded per NCI CTCAE v3.0
aGrade
bGrade
5 infections occurred in 2 (1%) pmab + bev/Ox-CT pts and 3 (1%) bev/Ox-CT pts
5 pulmonary embolism occurred in 2 (1%) pmab + bev/Ox-CT pts
Hecht et al., World GI Barcelona 2007
CALGB/SWOG Intergroup Trial 80405
“Dealer’s Choice”
FOLFOX
or FOLFIRI
R
Bevacizumab
Cetuximab
Bevacizumab +
Cetuximab
N = 2,289
Primary endpoint: OS
HR 1.25 (22 vs 27.5 months)
http://www.cancer.gov protocol ID CALGB-80405
Case 5: Previously Treated Colorectal Cancer
• Patient has metastatic colorectal cancer
• Has been treated with FOLFOX and bevacizumab for 4
months but now CEA is rising and CT scan shows new
and increasing liver lesions
Pertinent Issues for Case 5
• Palliative situation with unresectable metastases
• Relatively short initial therapy with FOLFOX + BEV,
tumor shows PD after 4 months
• Irinotecan-based regimen appropriate
• FOLFIRI or irinotecan-mono?
• Should a biologic be added right away or sequentially?
• If yes, which one?
– Cetuximab (or panitumumab)?
– Bevacizumab?
Case 5: Previously Treated Colorectal Cancer
• Which treatment option would you recommend?
 Irinotecan (or FOLFIRI) until progression followed by
irinotecan and cetuximab
 FOLFIRI or irinotecan + bevacizimab
 FOLFIRI or irinotecan + cetuximab
 FOLFIRI or irinotecan + bevacizumab and cetuximab
Case 5: Previously Treated Colorectal Cancer
• Which treatment option would you recommend?
 Irinotecan (or FOLFIRI) until progression followed by
irinotecan and cetuximab
 FOLFIRI or irinotecan + bevacizimab
 FOLFIRI or irinotecan + cetuximab
 FOLFIRI or irinotecan + bevacizumab and cetuximab
• Recommended approach
–
FOLFIRI or irinotecan + cetuximab
NCIC CTG CO.17: Cetuximab vs. BSC
Progression-free Survival
1.0
Proportion Progression-free
0.9
Study arm
Med PFS
(months)
95% CI
Cetuximab + BSC
1.9
1.8 – 2.1
BSC alone
1.8
1.8 – 1.9
0.8
0.7
0.6
HR 0.68 (95% CI =0.57 – 0.80)
0.5
0.4
Stratified log rank P < 0.0001
0.3
0.2
0.1
0.0
0
3
6
9
12
15
MONTHS
CETUXIMAB + BSC
CENSORED
BSC
CENSORED
Jonker et al., AACR 2007
NCIC CTG CO.17: Overall Survival
1.0
0.9
Study arm
MS
(months)
95% CI
Cetuximab + BSC
6.1
5.4 – 6.7
BSC alone
4.6
4.2 – 4.9
Proportion Alive
0.8
0.7
0.6
HR 0.77 (95% CI =0.64 – 0.92)
0.5
0.4
Stratified log rank P = 0.0046
0.3
0.2
0.1
0.0
0
3
SUBJECTS AT RISK
CET+BSC 287
217
BSC 285
197
6
136
85
9
78
44
12
37
26
CETUXIMAB + BSC
CENSORED
15
14
12
18
21
24
0
2
MONTHS
0
0
1
0
4
8
BSC
CENSORED
27
Jonker et al., AACR 2007
Only a Subgroup of Patients Benefit
From EGFR Targeted Therapy
Panitumumab vs. BSC: PFS
1.0
Panitumumab
Event-free Probability
0.9
BSC
0.8
Hazard ratio = 0.54
(95% CI: 0.44, 0.66)
0.7
0.6
Stratified log-rank test
P < .000000001
0.5
0.4
No diff. in OS
(75% cross-over!)
0.3
0.2
0.1
0.0
0
8
16
24
32
40
48
56
Weeks from Randomization
Van Cutsem et al., JCO 2007
EPIC Study (Second-line)
Irinotecan + Cetuximab
Failure of
Oxaliplatin-Based
Therapy
Stratified by:
• Study site
• ECOG PS (0 - 1, 2)
N = 648
Survival
R
Irinotecan
N = 650
• Primary Endpoint: Survival
• Secondary Endpoints: PFS, RR, DCR, Safety, QoL
• Sample Size: 1,298 patients in 221 centers
Sobrero et al., AACR 2007
EPIC Results
Irinotecan
Irinotecan/
Cetuximab
P-value
RR (%)
4.2
16.4
< 0.0001
PFS (mos)
2.6
4
< 0.0001
OS (mos)
10
10.7
0.71
OS (mos) w/o
post-study cetux.
6.2
10.2
Exploratory
analysis!
50% cross-over to cetuximab!
Sobrero et al., AACR 2007
If We Cannot Increase First-line PFS, Why Does
OS Increase?
10 months
1st PFS
17 months
Post-1st PD Survival
OS
27 Months
• More effective use of all active agents?
• Continuum of care…
• Use of EGFR-mAbs?
• Use of bevacizumab beyond PD?
BRiTE Registry - Patients with Bevacizumab
Beyond Progression (BBP)
Evaluable
patients
(N = 1953)
BRiTE:
Total N = 1953
1445 pts with 1st PD
932 deaths (1/21/07 cut-off)
Median follow-up 19.6 mo
1st Progression
(N = 1445)
Physician decision: no randomization
No Post-PD
Treatment
(N = 253)
No BBP
(N = 531)
BBP
(N = 642)
Grothey et al., ASCO 2007 Abstract #4036
BRiTE: Patient Outcome Based on
Treatment Post 1st PD
No Post-PD
Treatment
(N = 253)
No BBP
(N = 531)
BBP
(N = 642)
# of deaths (%)
168
(66%)
306
(58%)
260
(41%)
Median OS (mo)
12.6
19.9
31.8
1-yr OS rate (%)
52.5
77.3
87.7
OS after 1st PD (mo)
3.6
9.5
19.2
Grothey et al., ASCO 2007 Abstract #4036
Limitations of the Analysis
• Patients were not randomized
• Actual administration dates for BV and CT not collected;
missing BV and CT stop dates
• Potential bias that patients who survived longer had a
greater potential to be treated with BBP
• Possibility of unmeasured factors that may have biased
these results
Grothey et al., ASCO 2007 Abstract #4036
SWOG/NCCTG/NCIC Second-line Trial:
S0600/iBET (Intergroup BEV Continuation Trial)
Open since June 15
mCRC pretreated with
FOLFOX + BEV or
CAPOX + BEV or
OPTIMOX + BEV
(FOLF)IRI/CETUX
(FOLF)IRI/CETUX
+ BEV 5 mg/kg
(FOLF)IRI/CETUX
+ BEV 10 mg/kg
N = 1,260
Primary endpoint: OS (HR 1.30; 12  15.6 mos)
PIs: Phil Gold, Axel Grothey
Patient Potentially Curable?
Yes
RR
No
Time, QOL
Induction Ctx (3-4 mos)
e.g. FOLF?? + BEV/CETUX
e.g. FOLF?? + BEV
Re-evaluation
of resectability
Evaluation of
tumor biology
yes
Surgery
with curative intent
Maintenance
CFI ??
yes
“Adjuvant” Ctx
Re-Induction Ctx
Observation
“All 5-drugs”
Treatment Continuum
Curative Approach
Induction Ctx (3-4 mos)
Conclusion
• Optimize treatment strategies, mainly in the palliative
setting with the idea that we should keep patients on
some sort of maintenance therapy
• Refined approaches in the adjuvant setting confirming
the survival benefit at six years for a stage III patient with
FOLFOX
• Proof of efficacy of a perioperative chemotherapy
approach in resectable stage IV disease
Future Direction
•
•
•
•
mTOR inhibitors
Biomarker driven trials
KRAS
Tailored treatment approaches