Transcript EGFR Inhibitors in Colorectal Cancer

EGFR Inhibitors in Colorectal
Cancer
John L. Marshall, MD
Lombardi Comprehensive Cancer
Center
Ligand Binding and Dimerization
Results in TK Activation
EGF
TGF
Homodimer
Heterodimer
High
affinity
binding
ATP
Ligand
Binding
ATP
ATP
Dimerization
Source: With permission from Amgen Inc.
Phosphorylation
and Activation
EGFR Activation and Signaling
Pathways
Ligand
Ligand
EGFr dimer
Signal
Adapters
and Enzymes
Grb-2
Shc
SOS
Grb-2
P13K
MAPK = mitogen-activated
protein kinase
P13k = phosphatidylinositol
3-kinase
SOS
PTEN
Ras
Raf
Akt
MEK 1/2
mTOR
Transcription
Factors
FKHR
GSK-3
BAD
MAPK
p27
Jun
FOS Myc
Source: With permission from Amgen Inc.
Cyclin D-1
Signal
Cascade
EGFR Activation Mediates
Several Processes
EGFr Activation
Tumor
Spread of
cancer cells
Blood
Vessel
Metastatic
Spread
Cell
Survival
Tumor
Blood
Vessel
Angiogenesis
Proliferation
Source: With permission from Amgen Inc.
EGFR Expression Correlates With Poor
Prognosis in Selected Solid Tumors
Tumor Type
EGFR Expression (%)
•NSCLC
•40-80
•SCCHN
•95
•Colorectal
•25-77
•Glioblastoma
•40-60
•Breast
•14-91
•Prostate
•41-100
•Ovarian
•35-70
•Esophageal
•35-88
•Pancreatic
•30-50
*Responses observed in various solid tumors for gefitinib, erlotinib, and cetuximab.
SCCHN = squamous cell carcinoma head and neck.
Arteaga C. Semin Oncol. 2003;30(suppl 7):3-14.
Anti-EGFr Monoclonal
Antibodies
Monoclonal Antibody
Description
Status
Chimeric IgG1
Approved: Colorectal cancer
Submitted: Head and Neck (H&N)
cancer
Phase 2: NSCLC, Others
Matuzumab
(EMD 72000)
Humanized IgG1
Phase 2 Trials: Recurrent ovarian
cancer, NSCLC
Phase I-2 Trials: Colorectal cancer
Panitumumab
(ABX-EGF)
Fully human IgG2
Phase 2-3 Trials: Colorectal
cancer, NSCLC, Others
Cetuximab
(C-225)
Mendelsohn J. J Clin Oncol. 2002;20(suppl 18):1s-13s.
Sridhar SS, et al. Lancet Oncol. 2003;4:397-406.
www.clinicaltrials.gov
Tewes M, et al. Proc Am Soc Clin Oncol. 2002. Abstract 378.
Vanhoefer U, et al. J Clin Onc 2004;22(1):175-184
Properties of Cetuximab
 IgG1 MAb (chimerized)
 Binds specifically to EGFR
and its heterodimers
 Binds to EGFR with high affinity
(Kd = 2.0 x 10–10 M): 1 log higher
than the natural ligand
 Following the recommended dose
regimen (400 mg/m2 initial dose/250 mg/m2
weekly dose), the mean half-life was 114 hours
(range 75-188 hours)
 Competitively inhibits ligand binding to EGFR
 Stimulates receptor internalization
 Blocks receptor dimerization, tyrosine kinase
phosphorylation,
and signal transduction
Shitara K, et al. Cancer Immunol Immunother. 1993;36:373-380.
LoBuglio AF, et al. Proc Natl Acad Sci U S A. 1989;86:4220-4224.
ERBITUX Package Insert, June 2004.
Data on file. ImClone Systems Incorporated and Bristol-Myers Squibb
Company; 2004.
Cetuximab Randomized Pivotal
Trial in Metastatic Colorectal Cancer
Randomized Phase II Study Design
Patients with
EGFR-expressing
metastatic CRC
progressed after
receiving
irinotecan-based
chemotherapy
CETUXIMAB
with irinotecan
n = 218
RANDOMIZATION
CETUXIMAB
as a single agent
n = 111
ERBITUX Package Insert, June 2004.
Cetuximab Randomized Pivotal
Trial in Metastatic Colorectal Cancer
Patient Baseline Demographics
Characteristic
All Patients (n = 329)
Gender, %
Male
Female
63
37
Age, y
Median
Range
59
26-84
Karnofsky Performance
Status, %
< 80
 80
12
88
Prior oxaliplatin treatment, %
63
ERBITUX Package Insert, June 2004.
Cetuximab/C225 in Colon
Cancer
CPT-11 + C225
2:1
RR TTP
OS
22.9 4.1
8.6
10.8 1.5
6.9
54 pts
crossover
C225 alone
Source: Cunningham D et al. N Engl J Med 2004;351:337-45.
The “Bond” Trials
C225
Alone
C225 +
Bev
P
Value
C225 +
CPT-11
PR
11%
23%
0.05
23%
38%
0.03
TTP
1.5
mo
5.6
mo
>0.01
4.1
mo
7.9
mo
>0.01
OS
6.9
mo
NR
-
8.6
mo
NR
-
Sources: Cunningham D et al. N Engl J Med 2004;351:337-45.
Saltz L et al. Presentation. ASCO GI Symposium 2005. Abstract 169b
C225 + P Value
CPT-11
+ Bev
Cetuximab in the first line?
• FOLFIRI + Cetuximab
– 59% PR (13/22) 36% SD (8/23)
• Raoul et al ECCO 2003
• FOLFOX + Cetuximab
– 81% PR
• ASCO 2004
– 82% CR/PR, 12.5 median PFS
• ASCO 2005
Sources: Raoul et al. Proc ECCO 2003;Abstract 289.
Tabernero JM et al. Proc ASCO 2004;Abstract 3512.
Rubio ED et al. Proc ASCO 2005. Abstract 3535
Monoclonal Antibodies as Targeted Therapy:
Evolution to Fully Human Antibody
Chimeric
Humanized
Fully Human
Mouse
100% Mouse Protein
mouse
human
34% Mouse Protein
10% Mouse Protein
100% Human Protein
cetuximab
matuzumab
panitumumab
Panitumumab Phase 2 Study:
Monotherapy for CRC - Methods
• Eligibility requirements:
– Metastatic colorectal carcinoma, ECOG 0-1
– Measurable disease
– Failed prior therapy with a fluoropyrimidine
+/- leucovorin, and either irinotecan,
oxaliplatin or both
– EGFr overexpression by
immunohistochemistry
• Cohort A: 2+ or 3+ in > 10% of tumor cells
• Cohort B: 2+ or 3+ in < 10%, but 1+, 2+ or 3+ in
>10% of tumor cells
Hecht JR, et al. Proc Am Soc Clin Onc. 2004,abstract 3511. - poster
Panitumumab Phase 2 Study:
Monotherapy for CRC - Methods
• Dose: 2.5 mg/kg
– Infused over 1 hour
– No loading dose
– Administered without premedication
– Given weekly until disease progression or
unacceptable toxicity
• Assessments:
– Toxicity assessed weekly
– Tumor assessment every 8 weeks
Hecht JR, et al. Proc Am Soc Clin Onc. 2004,abstract 3511. - poster
Panitumumab Phase 2 Study:
Monotherapy for CRC – Toxicity
(Treatment-related Adverse Events)
Toxicity
All Grade
Grade 3
Grade 4
Rash
140 (95%)
5 (3%)
0
Fatigue
34 (23%)
3 (2%)
0
Diarrhea
30 (20%)
1 (1%)
0
Vomiting
10 (7%)
2 (1%)
0
Selected Treatment-emergent adverse events reported through cycle 2 as possibly, probably, or definitely
related to panitumumab
Events starting before cycle 1 or after the first infusion in cycle 3 are excluded.
Hecht JR, et al. Proc Am Soc Clin Onc. 2004,abstract 3511, poster. Data on file.
Panitumumab + Chemotherapy 1st Line
mCRC Phase 2 Study: Methods
• Multicenter, open-label, single-arm study consisting of 2
parts:
– Part 1: Patients (N=19) received 1st line panitumumab/IFL
therapy:
• Panitumumab 2.5 mg/kg/week administered
intravenously over 1 hour in 6-week courses (days 1, 8,
15, 22, 29 and 36), immediately followed by:
• IFL regimen: irinotecan (IR) 125 mg/m2, leucovorin (LV)
20 mg/m2,
5-fluorouracil (5FU) 500 mg/m2 on days 1, 8, 15 and 22
• Enrollment for Part 1 is closed
– Part 2: Patients received 1st line panitumumab/FOLFIRI therapy
• Part 2 is ongoing with enrollment closed (N=24); patients
are continuing therapy
Berlin J, et al. ESMO 2004. a265
Panitumumab + Chemotherapy 1st Line mCRC
Phase 2 Study, Part 1: Skin Toxicity
Skin Toxic
All Patients
(N=19)
Worst Severity
Mild
9 (47%)
Moderate
7 (37%)
Severe
3 (16%)
Life-Threatening
0 ( 0%)
Median (95% CI) Time to Onset,
days
Berlin J, et al. ESMO 2004. a265
11.0 (7.0, 15.0)
Panitumumab + Chemotherapy 1st Line
mCRC Phase 2 Study, Part 1: Efficacy
All Patients
(N=19)
Overall Response
Partial Response
Complete Response
9 (47%)
8 (42%)
1 ( 5%)
Stable Disease
6 (32%)
Progressive Disease
1 ( 5%)
No Assessment
3 (16%)
Treated pts received at least 1 dose of panitumumab or 1 dose of IFL
Berlin J, et al. ESMO 2004. a265
Randomized Controlled Phase 3 Trial in mCRC
R
A
N
D
O
M
I
Z
E
Panitumumab
6.0 mg/kg Q2W
+ BSC
BSC
PD
PD
Follow-up
Optional
Panitumumab
Crossover Study
1:1
Randomization stratification
• ECOG score:
0-1 vs. 2
• Geographic region: Western EU vs.
Central & Eastern EU vs.
Rest of World
Source: Peeters M et al. Presentation. AACR 2006. Abstract CP-1
Follow-up
Study Endpoints
Primary
• Progression-free survival (per blinded central
radiology assessment of modified-RECIST criteria)
Secondary
• Overall survival time and best overall objective
response (central radiology) - co-secondary
• Duration of and time to response
Safety
• Incidence of adverse events (including all,
grade 3/4, treatment related events), antibody
formation
Source: Peeters M et al. Presentation. AACR 2006. Abstract CP-1
Key Eligibility Criteria
• Metastatic colorectal adenocarcinoma (mCRC)
• ECOG score 0 to 2
• Radiologic documentation of disease progression
after fluoropyrimidine, irinotecan, and oxaliplatin
– During or within 6 months following most recent
chemotherapy regimen
– Failure after prespecified doses of irinotecan
and oxaliplatin
• EGFr membrane staining on ≥ 1% tumor cells
(IHC, central laboratory)
• Adequate hematologic, renal, and hepatic function
Source: Peeters M et al. Presentation. AACR 2006. Abstract CP-1
Demographics and Disease Characteristics
Panitumumab
Plus BSC
(N=231)
BSC Alone
146 (63)
85 (37)
62 (27, 82)
148 (64)
84 (36)
63 (27, 83)
ECOG status – n (%)
0-1
≥2
201 (87)
30 (13)
195 (84)
37 (15)
Number of metastatic sites – n (%)
1-2
3-5
161 (70)
70 (30)
161 (70)
69 (30)
Sex – n (%)
Men
Women
Median (range) age – years
(N=232)
Prior adjuvant chemotherapy – n (%)
Prior chemotherapy – n (%)
At least 2 lines
At least 3 lines
86 (37)
78 (34)
230 (100)
84 (36)
232 (100)
88 (38)
Mean (SD) % of tumor cells with EGFr membrane
staining
32.5 (29.3)
27.5 (26.1)
47 (20)
122 (53)
60 (26)
2 (1)
41 (18)
113 (49)
78 (34)
0 (0)
Intensity of EGFr staining – n (%)
3+ (strong)
2+ (moderate)
1+ (weak)
0 (none)
Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1
Progression-Free Survival
1.0
Panitumumab
0.9
Event-free Probability
BSC
0.8
Hazard ratio=0.54
(95% CI: 0.44, 0.66)
0.7
0.6
Stratified log-rank test
p < 0.000000001
0.5
0.4
0.3
0.2
0.1
0.0
0
Patients at risk:
Panitumumab 231
BSC
232
8
118
75
16
49
17
24
32
40
Weeks from Randomization
31
7
13
3
Primary Analysis, All Randomized Analysis Set, Central Radiology
Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1
5
1
48
1
1
56
% Progression Free (95 % CI)
Kaplan- Meier Progression-Free Survival
Rates at Prespecified Time Points
60%
Panitumumab (N=231)
49%
BSC (N=232)
50%
40%
35%
30%
26%
30%
18%
14%
20%
10%
9%
5%
10%
4%
4%
1%
1%1%
Wk 32
Wk 40
Wk 48
0%
Wk 8
Patients at risk:
Panitumumab
BSC
118
75
Wk 12
76
31
Wk 16
Wk 24
49
17
31
7
13
3
Primary Analysis, All Randomized Analysis Set, Central Radiology
Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1
5
1
1
1
Overall Survival – Interim Analysis
(All Randomized Analysis Set)
Panitumumab (N=231)
1.0
BSC (N=232)
0.9
Hazard ratio=0.93
(95% CI 0.73, 1.19)
% Surviving
0.8
0.7
Stratified log-rank
p = 0.6065
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19
Months from Randomization
Patients at risk:
Panitumumab 231 219 204 170 136 103 81 60
232 221 199 175 139 98 76 60
BSC
47 31
41 29
21 16
20 18
Note: There were 250 events
Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1
11
12
6
8
5
7
3
5
0
3
0
1
0
0
0
0
Overall Survival: Censored BSC Patients
Who Subsequently Responded After Crossing Over
1.0
Panitumumab
Survival Probability
0.9
BSC
0.8
HR= 0.78 (95% CI: 0.61, 1.01)
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
1
2
3
4
5
6
7 8 9 10 11 12 13 14 15 16 17 18 19
Months from Randomization
Patients at risk:
Panitumumab 231 219 204 170 136 103 81 60 47
BSC
232 219 194 149 113 71 51 38 26
31 21 16
17 10 8
11
5
6
2
Note: BSC patients censored at the time that they received their first dose of panitumumab;
Included confirmed and unconfirmed responses by investigator (RECIST criteria)
Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1
5
2
3
2
0
2
0
0
0
0
0
0
Safety – Grade 3/4 Adverse Events
Panitumumab
(N = 229)
Patients with any grade 3
or 4 event
Abdominal pain
Fatigue
Dyspnea
Anorexia
Jaundice
Asthenia
Vomiting
Ascites
Diarrhea
Intestinal obstruction
Paronychia
Deep vein thrombosis
Pulmonary embolism
BSC
(N = 234)
Grade 3
75 (33)
Grade 4
4 (2)
Grade 3
41 (18)
Grade 4
4 (2)
17 (7)
10 (4)
9 (4)
7 (3)
0 (0)
0 (0)
2 (1)
0 (0)
8 (3)
7 (3)
8 (3)
5 (2)
3 (1)
0 (0)
0 (0)
0 (0)
7 (3)
6 (3)
5 (2)
3 (1)
3 (1)
3 (1)
3 (1)
2 (1)
0 (0)
1 (0)
1 (0)
0 (0)
1 (0)
0 (0)
4 (2)
0 (0)
1 (0)
1 (0)
3 (1)
5 (2)
2 (1)
2 (1)
0 (0)
2 (1)
0 (0)
0 (0)
0 (0)
1 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
MedDRA version 8.0 preferred terms; graded per NCI CTCAE version 2.0
Source: Peeters M et al. Presentation. AACR 2006. Abstract CP-1
Overall Survival by Worst Grade of Skin Toxicity
in the Panitumumab Patients
1.0
Grade 2-4
Grade 1
0.9
Survival Probability
0.8
Hazard ratio = 0.61a
(95% CI: 0.40, 0.95)
p = 0.0278
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
1
2
3
4
5
6 7 8 9 10 11 12 13 14 15 16 17
Months from Randomization
Patients at risk:
Grade 2-4
152 150 138 120 99 71 58
Grade 1
57 55 47 34 24 20 12
a
39
8
29
5
17
4
13
3
Hazard ratio for Grade 2-4 relative to Grade 1, stratified by ECOG and geographic region
Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1
9
2
6
0
5
0
1
0
0
0
0
0
Conclusions and Questions
• EGFR antibodies are active in colon
cancer
• Skin rash toxicity is the biggest barrier to
more widespread use
• Approval(s) in “last line” therapy
– Role in 1st line or adjuvant to be determined