Transcript Update on EGFR Monoclonal Antibody Therapy in Metastatic

Defining the Role of EGFR
Monoclonal Antibody Therapy in
Metastatic Colorectal Cancer
Author: Dr. Phil Bedard
Date Posted: December 12, 2007
www.OncologyEducation.ca
Objectives
• Review the rationale for targeting EGFR in metastatic
colorectal cancer therapy
• Outline the differences between the monoclonal
antibodies against EGFR
• Understand the common toxicities associated with EGFR
monoclonal antibodies
• Summarize the evidence supporting the use of EGFR
monoclonal antibody therapy in the first-, second-, and
third-line treatment of metastatic CRC
• Discuss possible methods of selection of patients most
likely to benefit from EGFR monoclonal antibody
blockade with metastatic CRC
www.OncologyEducation.ca
Epidermal Growth
Factor Receptor (EGFR)
• Member of the epidermal growth factor
receptor tyrosine kinase family
• Ligand binding to extracellular domain
leads to activation of intracellular signaling
cascade, including Akt and MAPK
• Results in proliferation, angiogenesis,
increased cell motility, and resistance to
chemotherapy
www.OncologyEducation.ca
EGFR in Colorectal Cancer
• Expressed in 60-80% CRC
– Risk factor for poor prognosis
• Monoclonal antibodies (mAb) demonstrate
activity as single agents and in combination with
chemotherapy in CRC
• To date, there is no proof that small molecular
tyrosine kinase inhibitors (TKIs) are of benefit
– CRC lacks EGFR mutations that have been
asssociated with response to TKIs in other disease
sites
Townsley CA Br J Cancer 2006
Rothernberg ML JCO 2005
www.OncologyEducation.ca
Monoclonal Antibodies
Against EGFR
• For treatment of metastatic colorectal
cancer:
– Cetuximab approved by Health Canada and
FDA
– Panitumumab approved by FDA
www.OncologyEducation.ca
Comparison: Cetuximab vs
Panitumumab
Cetuximab
Panitumumab
Backbone
Chimeric
Human
Class
IgG1
IgG2
Half-life
5-7.5 days
7.5 days
Loading Dose
Yes
No
Dosing
Schedule
Qweekly
Premedication
Qweekly
Q2weekly
H1-antagonist None
www.OncologyEducation.ca
First-line Therapy:
Cetuximab + Chemotherapy
www.OncologyEducation.ca
CRYSTAL Trial
10 Endpoint= PFS
R
N=1198
EGFR expression
via IHC
A
N
D
O
M
I
Z
E
FOLFIRI + Cetuximab
N=648
FOLFIRI
N=650
* Cetuximab 400 mg/m2 IV week 1 then 250 mg/m2 IV weekly
1:1
Van Custem E Proc ASCO 2007
www.OncologyEducation.ca
Toxicity
Grade 3/4 Events
FOLFIRI+
Cetuximab (%)
FOLFIRI
(%)
Febrile Neutropenia
2.7
2.2
Diarrhea
15.2
10.5
Vomiting
4.5
5.0
Fatigue
5.0
4.5
Skin Reactions
18.7
0.2
Infusion Related
Reactions
2.3
0
Hypomagnesemia
(only available for 20%
of patients)
1.8
0.2
www.OncologyEducation.ca
Efficacy
Grade 3/4 toxicity
FOLFIRI +
Cetuximab
N = 648 (%)
FOLFIRI
N = 650 (%)
Response Rate
47
39
Median PFS
8.9
p=0.0038
8.0
HR = 0.85 (0.73-0.99); p=0.048
1 yr PFS
34
23
Median OS
NR
NR
www.OncologyEducation.ca
PFS by Skin Reaction:
FOLFIRI + Cetuximab
Skin Reaction
Median PFS
Grade 1
5.4 months
Grade 2
9.4 months
Grade 3
11.3 months
* No Grade 4 Reaction Reported
www.OncologyEducation.ca
OPUS: Phase II
R
N=338
EGFR+
Metasatic CRC
A
N
D
O
M
I
Z
E
FOLFOX + Cetuximab
N=170
FOLFOX
N=168
* Cetuximab 400 mg/m2 IV week 1 then 250 mg/m2 IV weekly
1:1
www.OncologyEducation.ca
Toxicity
Grade 3/4
events
Neutropenia
FOLFOX+
Cetuximab
27.6
FOLFOX
Diarrhea
7.1
6.0
Fatigue
3.5
3.0
Neurotoxicity
3.5
6.0
Acne-like skin
rash
14.1
0
31.5
www.OncologyEducation.ca
Efficacy
Response Rate
FOLFOX+
Cetuximab
45.6%
FOLFOX
35.7%
* No Survival Data Reported
www.OncologyEducation.ca
Response Rate
by Skin Rash
FOLFOX+
Cetuximab
Grade 0
13.0%
Grade 1
42.2%
Grade 2
53.2%
Grade 3-4
66.4%
www.OncologyEducation.ca
SWOG 80203
10 Endpoint= OS
FOLFOX + Cetuximab
R
E
G
I
S
T
E
R
FOLFOX
Inv choice
FOLFIRI
Inv choice
R
A
N
D
O
M
I
Z
E
FOLFOX alone
FOLFIRI + Cetuximab
FOLFIRI alone
N=258
1:1
Metastatic Colorectal CA
No EGFR expression required
Venook A Proc ASCO 2006
www.OncologyEducation.ca
SWOG 80203
• Planned sample size N=2200
• Trial stopped early January 2005 because
of poor accrual
– Publication of Hurwitz data with IFL +
Bevacizumab (NEJM 2004)
• Data reported with median F/U 16 months
www.OncologyEducation.ca
Efficacy
Cetuximab+
FOLFIRI
FOLFIRI
Cetuximab+
FOLFOX
FOLFOX
Response
CR + PR
44%
36%
60%
40%
Stable
Disease
32%
38%
26%
30%
Median PFS
(95% CI)
10.6 mos
(6.2-14.1)
8.4 mos
(6.5-10.3)
8.2 mos
(7.0-12.7)
9.8 mos
(8.3-12.4)
www.OncologyEducation.ca
Toxicity
Grade 3/4
Cetuximab+
FOLFIRI
FOLFIRI
Cetuximab+
FOLFOX
FOLFOX
Diarrhea
22%
15%
14%
10%
Neutropenia
34%
27%
38%
36%
www.OncologyEducation.ca
Efficacy: Cetuximab
versus Chemotherapy Alone
Cetuximab+CT
CT alone
Response Rate
52%
38%
Median PFS
(95%CI)
8.5 mos
(7.0-12.5)
9.4 mos
(8.2-10.8)
Median OS
(95%CI)
16.9 mos
(15.9-?)
?
(17.9-?)
www.OncologyEducation.ca
Medical Research Council:
COIN Trial (Ongoing)
10 Endpoint= OS
R
N=2421 (Target)
No EGFR testing
A
N
D
O
M
I
Z
E
1:1:1
FOLFOX/CapeOX until
progression/intolerance
FOLFOX/CapeOX +
Cetuximab until
progression/intolerance
FOLFOX/CapeOXx12 weeks
“Stop & Go” Strategy
www.OncologyEducation.ca
First-line Therapy:
Panitumumab + Chemotherapy
www.OncologyEducation.ca
PRIME Trial: Ongoing
10 Endpoint= PFS
R
N=900 (Target Accrual)
Metastatic Colorectal CA
No EGFR testing
A
N
D
O
M
I
Z
E
1:1
Panitumumab + FOLFOX
FOLFOX alone
Expected Completion: March 2010
www.OncologyEducation.ca
First-line Therapy:
Ceutximab + Chemotherapy +
anti-VEGF
www.OncologyEducation.ca
CALGB/SWOG 80405:
Ongoing
10 Endpoint= OS
R
A
N
D
N=2300 (Target)
Metastatic Colorectal CA O
M
No EGFR testing
I
Z
E
1:1:1
FOLFOX or FOLFIRI +
Bevacizumab + Cetuximab
FOLFOX or FOLFIRI +
Cetuximab
FOLFOX or FOLFIRI +
Bevacizumab
www.OncologyEducation.ca
Dutch Colorectal Cancer
Group CAIRO-2: Ongoing
N=750 (Target Accrual)
Metastatic Colorectal CA
No EGFR testing
10 Endpoint=
PFS & Toxicity
R
A
N
D
O
M
I
Z
E
1:1
CapeOX + Bevacizumab +
Ceutximab
CapeOX + Bevacizumab
Expected Completion: December 2007
www.OncologyEducation.ca
Preliminary Toxicity Data
Grade 3/4
Adverse Events
CAPOX-Bev+
Cetuximab
13%
CAPOX-Bev
23%
17%
Febrile
Neutropenia
0%
1%
Acne-like Rash
20%
0%
Death <60days
3%
3%
Hand-Foot
Syndrome
Diarrhea
12%
www.OncologyEducation.ca
First-line Therapy:
Panitumumab + Chemotherapy +
anti-VEGF
www.OncologyEducation.ca
Panitumumab Advanced
Colorectal Cancer Evaluation (PACCE)
R
E
G
I
S
T
E
R
Oxali-based CT
(ie FOLFOX)
Inv choice
Iri-based CT
(ie FOLFIRI)
Inv choice
R
A
N
D
O
M
I
Z
E
Panitumumab + OxaliCT + Bevacizumab
Oxali-CT +
Bevacizumab
Panitumumab + Iri-CT +
Bevacizumab
Iri-CT + Bevacizumab
1:1
Hecht JR GI World Congress 2007
www.OncologyEducation.ca
PACCE
• Trial stopped early after interim analysis
suggested excess toxicity and inferior
efficacy in treatment arm
www.OncologyEducation.ca
Toxicity
Pmab+ Bev/Ox
N=401
Bev/Ox
N=392
Gr 3 (%)
Gr 4 (%)
Gr 3 (%)
Gr 4 (%)
Skin
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
26
<1
Nausea
10
0
4
<1
Infection
16
2
7
2
DVT
6
0
7
0
PE
0
6
0
4
www.OncologyEducation.ca
Efficacy
Pmab+Bev/Ox
Bev/Ox
Pmab+Bev/Iri
Bev/Iri
Response
39%
41%
38%
31%
CR
0%
0%
<1%
0%
PR
39%
40%
38%
31%
Median
PFS
9.0 mos
10.5 mos
-----
-----
Median
OS
18.6 mos
-----
-----
HR = 1.29 (1.05-1.58)
Not reached
HR = 1.44 (1.10-1.88)
www.OncologyEducation.ca
Summary: First Line
• CRYSTAL trial suggests that Cetuximab can be safely
combined with FOLFIRI in first line setting, with very
modest lengthening of PFS of uncertain clinical
importance
• PACCE trial demonstrates significant added toxicity with
combination of chemotherapy, anti-VEGF therapy and
Panitimumab
– Similar toxicity not reported with CAIRO-2 trial using
chemotherapy, anti-VEGF therapy and Cetuximab
• Data presently do not support routine use of EGFR mAb
therapy in combination with chemotherapy +/- anti-VEGF
therapy in first-line setting
www.OncologyEducation.ca
Second-line Therapy:
Cetuximab + Chemotherapy
www.OncologyEducation.ca
Erbitux Plus Irinotecan in
Colorectal Cancer (EPIC)
10 Endpoint= PFS
R
Prior Oxaliplatin
Chemotherapy
EGFR+ (IHC)
A
N
D
O
M
I
Z
E
Cetuximab + Irinotecan
N=648
Irinotecan alone
N=650
Cetuximab 400mg/m2 week 1; then 250mg/m2 weekly
1:1
Irinotecan 350mg/m2 q3weekly
Sobrero AF AACR 2007
www.OncologyEducation.ca
Toxicity
Grade 3/4 Toxicity
Cetuximab + Irinotecan
N = 638, %
Irinotecan
N = 629, %
Any AE > 5%
71.6
56.8
Diarrhea
28.8
16.2
Vomiting
6.1
6.4
Fatigue
9.2
4.9
Acne-like Rash
8.2
0.5
Infusion Reaction
1.4
0.8
Hypomagnesemia
3.3
0.4
www.OncologyEducation.ca
Efficacy
Cetuximab +
Irinotecan
N=648
Irinotecan
N=650
P-value
Overall Response
16.4%
4.2%
0.0001
CR
1.4%
0.2%
PR
15.0%
4.0%
Disease Control
(CR+PR+SD)
61.4%
45.8%
0.0001
4.0 months
2.6 months
0.0001
Median PFS
HR = 0.69 (0.62-0.78)
Median OS
10.7 months
9.9 months
0.7115
HR = 0.98 (0.85-1.11)
www.OncologyEducation.ca
Post-Study Therapy
Post-Study
Therapy
Cetuximab + Irinotecan
Irinotecan
(N = 650)
(N = 648)
Any 3rd Line
Rx
57%
65%
Cetuximab
11%
47%
Bevacizumab
16%
14%
www.OncologyEducation.ca
Survival by Skin Reaction:
Cetuximab + Irinotecan
Skin Reaction
Median OS
None
5.8 months
Grade 1/2
11.7 months
Grade 3/4
15.6 months
www.OncologyEducation.ca
MRC: EXPLORE
10 Endpoint= OS
R
Prior Irinotecan
Chemotherapy
EGFR+ (IHC)
Metastatic CRC
N=102
A
N
D
O
M
I
Z
E
Cetuximab + FOLFOX
N=52
FOLFOX
N=50
Cetuximab 400mg/m2 week 1; then 250mg/m2 weekly
1:1
Polikoff Proc ASCO 2005
www.OncologyEducation.ca
EXPLORE
• Planned sample size N=1100
• Trial stopped early December 2004
because of poor accrual
– Widespread adoption of FOLFOX in first-line
setting
www.OncologyEducation.ca
Efficacy
Cetuximab +
FOLFOX
N=43
FOLFOX
N=42
Response Rate
20.9%
9.5%
Stable Disease
Rate
46.5%
61.9%
4.4 months
4.1 months
Median PFS
p=0.48
www.OncologyEducation.ca
Second-line Therapy:
Panitumumab + Chemotherapy
www.OncologyEducation.ca
Panitumumab, Irinotecan &
Cyclosporin in COLOrectal
Cancer Therapy (PICCOLO):
Ongoing 1 Endpoint= PFS
0
R
A
N
D
N=1269 (Target)
Prior 5-FU +/- Oxali +/- Bev O
M
No EGFR testing
I
Z
E
Irinotecan + Panitumumab
Irinotecan + Cyclosporin
Irinotecan alone
1:1:1
www.OncologyEducation.ca
Second-line Therapy:
Cetuximab + Chemotherapy +
anti-VEGF
www.OncologyEducation.ca
SWOG S0600/ECOG/
NCCTG/NCIC: Ongoing
10 Endpoint= OS
R
A
N=1250 (Target)
N
Prior Oxali-based CT
D
Prior Bev allowed
O
No EGFR testing
No Prior anti-EGFR therapy M
I
Z
E
1:1:1
Irinotecan/FOLFIRI +
Cetuximab + Bevacizumab
Irinotecan/FOLFIRI +
Cetuximab
Irinotecan/FOLFIRI +
Bevacizumab
www.OncologyEducation.ca
Summary - Second Line
• EPIC trial shows that addition of Cetuximab to FOLFIRI
produces statistically significant improvement in
response rate and PFS
• PFS improvement of questionable clinical significance
with no overall survival benefit and added toxicity
– lack of OS benefit due to cross over to cetuximab setting on
progression in standard arm
• S0600 will address whether addition of Cetuximab +
anti-VEGF therapy to Irinotecan-based treatment can
improve OS after progression on oxaliplatin-based
chemotherapy
• At present, data do not support routine use of anti-EGFR
mAb therapy in 2nd line setting
www.OncologyEducation.ca
Third-line Therapy:
Cetuximab Monotherapy
www.OncologyEducation.ca
NCIC CO.17
10 Endpoint= OS
R
E
G
I
S
T
E
R
R
EGFR
testing
by IHC
A
N
D
O
M
I
Z
E
Cetuximab* + BSC
Best Supportive
Care alone
* Cetuximab 400 mg/m2 IV week 1 then
250 mg/m2 IV weekly
1:1
N=572
Prior 5FU, Iri, and Oxali-CT
EGFR expression
required
Stratification:
• Centre
• ECOG PS (0 or 1 vs. 2)
Jonker DJ NEJM 2007
www.OncologyEducation.ca
Patient Characteristics
Cetuximab +
BSC
N = 287 (%)
BSC
N = 285 (%)
GENDER
Male/ Female
64.8/35.2
63.9/36.1
AGE (years)
Median
[range]
63 [28.6 - 88.1]
64 [28.7 - 85.9]
> 65 years
38.3
44.6
0
25.1
22.5
1
51.6
54.0
2
23.3
23.5
TS Inhibitor
100.0
100.0
Irinotecan
96.5
95.8
Oxaliplatin
97.9
ECOG
Performance
Status
Type of Prior
Treatment
97.5
www.OncologyEducation.ca
Toxicity: Key Differences
Grade 3/4 toxicity
Cetuximab +
BSC
N = 287 (%)
BSC
N = 285 (%)
Rash
11.8
0.4
Non-neutropenic
Infection
12.8
5.5
Hypomagnesemia
5.8
0
Pain (other than
abdominal)
14.9
7.3
www.OncologyEducation.ca
Efficacy
Grade 3/4 toxicity
Cetuximab +
BSC
N = 287 (%)
BSC
N = 285 (%)
Partial Response
8.0
0
Stable Disease
31.4
10.9
Median PFS
1.9 months
1.8 months
HR = 0.71 (0.59-0.85)
Median OS
6.1 months
4.6 months
HR = 0.79 (0.65-0.95)
www.OncologyEducation.ca
Survival by Skin Reaction:
Cetuximab Monotherapy
Skin Reaction
Median OS
None
2.6 months
Grade 1
4.8 months
Grade 2 or
higher
8.4 months
www.OncologyEducation.ca
Quality of Life
• Improved at 8 & 16 weeks in physical
functioning and global QoL in Cetuximab +
BSC arm vs. BSC alone
Au H Proc ASCO 2007
www.OncologyEducation.ca
Panitumumab 3rd Line
Monotherapy Trial
R
E
G
I
S
T
E
R
10 Endpoint= PFS
R
EGFR
testing
by IHC
A
N
D
O
M
I
Z
E
1:1
N=463
Prior 5FU, Iri, and Oxali-CT
EGFR expression
required
Panitumumab
+ BSC
N=231
Optional Cross-Over
on Progression
Panitumumab
+ BSC
BSC alone
N=232
N=176
* Panitumumab 6 mg/m2 IV Q2weekly
Van Cutsem E JCO 2007
www.OncologyEducation.ca
Patient Characteristics
Panitumumab
+ BSC
N = 231 (%)
BSC
N = 232 (%)
GENDER
Male/ Female
63/37
64/36
AGE (years)
Median
[range]
62 [27 - 82]
64 [27 - 83]
0
46
40
1
41
45
2
3
13
0
14
1
2 lines
100
100
3 lines
36
38
ECOG
Performance
Status
Prior lines of
Chemotherapy
www.OncologyEducation.ca
Toxicity
Grade 3/4 toxicity
Panitumumab +
BSC
N = 231 (%)
BSC
N = 232 (%)
Acne-like Rash
7
0
Abdominal Pain
7
4
Erythema
5
2
General Physical
Deterioration
7
2
www.OncologyEducation.ca
Efficacy
Grade 3/4 toxicity
Panitumumab +
BSC
N = 231 (%)
BSC
N = 232 (%)
Partial Response
10
0
Stable Disease
27
10
Median PFS
2.0 months
1.8 months
HR = 0. 54 (0.44-0.66); p<0.0001
Median OS
NR
NR
HR = 1.00 (0.82-1.22)
www.OncologyEducation.ca
Survival by Skin Reaction:
Panitumumab Monotherapy
Worst Skin
Reaction
Median OS
Grade 1
5.9 months
Grade 2 or
higher
7.9 months
HR = 0.68; p=0.03
Humblet Y Proc ASCO 2007
www.OncologyEducation.ca
Quality of Life
• Trend towards improvement for Colorectal
Cancer Related symptoms and overall
health-related QoL in Panitumumab group
• Patients who developed skin rash on
Panitumumab were bothered by their
symptoms
Humblet Y Proc ASCO 2007
www.OncologyEducation.ca
Third-line Therapy:
Cetuximab + Chemotherapy
www.OncologyEducation.ca
Bowel Oncology with
Cetuximab Antibody (BOND-1)
10 Endpoint= Response
R
A
N
D
N=329
Prior Iri-CT within O
M
3 months
I
EGFR+ (IHC)
Z
E
Cetuximab +
Irinotecan
N=218
Cetuximab
alone
Cetuximab +
Irinotecan
N=111
N=56
Cetuximab 400mg/m2 week 1; then 250mg/m2 weekly
2:1
Cunningham DR NEJM 2004
www.OncologyEducation.ca
Prior Therapy
Cetuximab +
Irinotecan
N = 218 (%)
Cetuximab
alone
N = 111 (%)
1st line
18.8
24.3
2nd line
36.2
36.9
≥3rd line
45.0
38.7
61.9
64.0
Lines of Prior Therapy
Prior Oxaliplatin
www.OncologyEducation.ca
Toxicity
Grade 3/4 toxicity
Cetuximab +
Irinotecan
N = 218 (%)
Cetuximab
alone
N = 111 (%)
Diarrhea
21.2
1.7
Acne-like Rash
9.4
5.2
Neutropenia
9.4
0
Hypersensitivity
Reaction
0
3.5
www.OncologyEducation.ca
Efficacy
Cetuximab +
Irinotecan
N = 218 (%)
Cetuximab
alone
N = 111 (%)
Response
22.7
10.8
Disease Control
55.1
32.4
Time to Progression
4.1 months
1.9 months
HR = 0.54 (0.42-0.71)
Median OS
8.6 months
6.9 months
HR = 0.91 (0.69-1.21)
www.OncologyEducation.ca
Response Rate by
EGFR staining
EGFR
staining
intensity
Cetuximab+
Irinotecan
Cetuximab
alone
Faint
20.8%
4.8%
Weak or
Moderate
24.7%
12.8%
Strong
22.7%
11.7%
p=0.64
www.OncologyEducation.ca
Response Rate by
Skin Reaction
Skin
Reaction
Cetuximab+
Irinotecan
Cetuximab
alone
None
6.3%
0
Grade 1 or 2
20.4%
11.6%
Grade 3 or 4
55.3%
33.3%
p<0.0001
www.OncologyEducation.ca
BOND-2: Phase II
R
A
N
N=81
Prior Iri-CT within D
O
3 months
EGFR expression M
I
not required
Z
E
Cetuximab +
Bevacizumab +
Irinotecan
N=40
Cetuximab +
Bevacizumab
N=41
Cetuximab 400mg/m2 week 1; then 250mg/m2 weekly
1:1
Bevacizumab 5mg/kg every Q2weekly
Saltz L Proc ASCO 2005
www.OncologyEducation.ca
Prior Therapy
Cetuximab +
Bevacizumab +
Irinotecan
N = 40
Cetuximab +
Bevacizumab
N = 41
Median # Lines of
Prior Therapy
3
3
Prior Oxaliplatin
85%
90%
www.OncologyEducation.ca
Toxicity
Grade 3/4 toxicity
Cetuximab +
Bevacizumab +
Irinotecan
N = 40 (%)
Cetuximab +
Bevacizumab
N = 41(%)
Diarrhea
24
0
Acne-like Rash
17
20
Neutropenia
22
0
Fatigue
10
0
www.OncologyEducation.ca
Efficacy
Cetuximab +
Bevacizumab +
Irinotecan
N = 40 (%)
Cetuximab +
Bevacizumab
N = 41 (%)
Partial Response
37%
20%
Disease Control
NR
NR
Median Time to
Progression
7.9 months
5.6 months
Median OS
NR
NR
www.OncologyEducation.ca
Third-line Therapy:
Cetuximab + Chemotherapy +
anti-VEGF
www.OncologyEducation.ca
BOND-3: Phase II
(Ongoing)
R
A
N
Prior Bevacizumab
+ Chemotherapy D
O
M
I
Z
E
Cetuximab +
Bevacizumab +
Irinotecan
Cetuximab +
Bevacizumab
Cetuximab 400mg/m2 week 1; then 250mg/m2 weekly
1:1
Bevacizumab 5mg/kg every Q2weekly
www.OncologyEducation.ca
Summary – Third line
• Cetuximab monotherapy after progression on
oxaliplatin and irinotecan based chemotherapy
is the only setting in which EGFR monoclonal
antibody therapy has shown a survival benefit in
colorectal cancer
– Survival benefit modest but cetuximab monotherapy
also associated with significant improvement in
quality of life
• Panitumumab alone and Cetuximab + Irinotecan
both demonstrate a significant improvement in
PFS in the third-line setting
www.OncologyEducation.ca
Summary – Third line
• Should Cetuximab be given with Irinotecan in
3rd line?
– Cetuximab + Irinotecan combination demonstrates
best response rates and TTP benefits (cross trial
comparisons) but unable to determine impact of
irinotecan on QOL
www.OncologyEducation.ca
FIRST
LINE
SECOND
LINE
THIRD
LINE
# pts
RR %
Median
PFS/TTP
Median OS
QoL
PACCE
(Oxali only)
793
39 vs 41
9.0 vs 10.5
18.6 vs NR
?
CRYSTAL
1198
47 vs 39
8.9 vs 8.0
?
?
SWOG
80203
238
52 vs 38
8.5 vs 9.4
? vs 16.9
?
OPUS
338
46 vs 37
?
?
?
EPIC
1298
16 vs 4
4.0 vs 2.6
10.7 vs 9.9
Improved
EXPLORE
102
21 vs 10
4.4 vs 4.1
?
?
BOND-1
329
23 vs 11
4.1 vs 1.9
8.6 vs 6.9
?
P-mab
3rd line
463
10 vs 0
2.0 vs 1.8
NS
?Improved
NCIC CO.17
572
8 vs 0
1.9 vs 1.8
6.1 vs 4.6
Improved
statistically significant results in RED
www.OncologyEducation.ca
The Bottom Line for
Canadian Medical Oncologists
www.OncologyEducation.ca
Efficacy and Toxicity
• EGFR monoclonal antibody therapy is active in
metastatic disease with relatively mild toxicity as
monotherapy
• Clinical trial data most strongly support use of
EGFR monoclonal antibody therapy in the thirdline setting, after progression on Oxaliplatin and
Irinotecan based therapy
– According to BOND-1 data, combination of
Cetuximab + Irinotecan in 3rd line more active than
Cetuximab alone
www.OncologyEducation.ca
Efficacy and Toxicity
• Cetuximab and Panitumumab appear to have
similar efficacy and toxicity in the third line
setting as monotherapy
• Access to Cetuximab and Panitumumab is
difficult in Canada
– Only cetuximab is approved by Health Canada and it
is not being marketed (or funded)
www.OncologyEducation.ca
Anti-EGFR and
Anti-VEGF Combinations
• Results of PACCE suggest that the combination of
Panitumumab, Bevacizumab, and chemotherapy is toxic
with less efficacy in the first line setting
• Excess toxicity of anti-EGFR therapy with anti-VEGF
agent and chemotherapy not seen with Cetuximab in
BOND 2 or CAIRO-2
– Suggests that Cetuximab may be more easily combined with
anti-VEGF and chemotherapy than Panitumumab
– Results of SWOG 80405 and CAIRO-2 trial will provide further
insight
www.OncologyEducation.ca
Patient Selection for
anti-EGFR Therapy
• Future biomarker studies will attempt to address which
subgroups of patients will derive benefit from EGFR
blockade
• To date, studies suggests that level of EGFR expression
via IHC is NOT a useful predictor of response
• CRYSTAL, BOND-1, NCIC CO.17, and Panitumumab 3rd
line monotherapy trial demonstrate that skin rash may be
an early surrogate marker for favourable clinical outcome
– However, it is not clear from the current data if skin rash on
EGFR monoclonal antibody therapy is an early surrogate marker
for BENEFIT from EGFR blockade or simply an early surrogate
marker of a favourable prognosis
– Early data from EVEREST raises the intriguing possibility that
“early skin rash non-responders” may benefit from doseescalation of Cetuximab  needs further testing
www.OncologyEducation.ca
Patient Selection for
anti-EGFR Therapy
• Preliminary data from Panitumumab 3rd
line monotherapy trial suggests that
patients with K-RAS mutation do not
benefit from EGFR blockade (Amado
ECCO 2007)
– Similar to data from EGFR therapy in nonsmall cell lung cancer and pancreatic cancer
– Analyses of K-RAS status from other EGFR
monoclonal antibody trials are in progress
www.OncologyEducation.ca
Acknowledgements
We would like to thank Dr. Mark Rother for his
helpful contributions to this educational program
www.OncologyEducation.ca