egfr inhibitors in colorectal cancer john l. marshall, md lombardi comprehensive cancer center
TRANSCRIPT
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EGFR Inhibitors in Colorectal Cancer
John L. Marshall, MD
Lombardi Comprehensive Cancer Center
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EGF TGF
Ligand Binding
Phosphorylation
and ActivationDimerization
HeterodimerHomodimer
ATPATP ATP
High
affinity
binding
Ligand Binding and Dimerization Results in TK Activation
Source: With permission from Amgen Inc.
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P13K
FKHR
Akt
mTOR
PTEN
MEK 1/2
MAPK
BADGSK-3
SOS
Grb-2
Shc
Grb-2
SOS Ras
Raf
JunFOS Myc
p27
Cyclin D-1
LigandLigand
Signal
Adapters
and Enzymes
Signal
Cascade
EGFr dimer
MAPK = mitogen-activatedprotein kinase
P13k = phosphatidylinositol
3-kinase
TranscriptionFactors
EGFR Activation and Signaling Pathways
Source: With permission from Amgen Inc.
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Proliferation
Angiogenesis
Cell
Survival
Metastatic
Spread
EGFr ActivationTumor
Tumor
Blood
Vessel
Blood
Vessel
Spread of
cancer cells
EGFR Activation Mediates Several Processes
Source: With permission from Amgen Inc.
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•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
SCCHN = squamous cell carcinoma head and neck.
Arteaga C. Semin Oncol. 2003;30(suppl 7):3-14.
EGFR Expression (%)Tumor Type
EGFR Expression Correlates With Poor Prognosis in Selected Solid Tumors
*Responses observed in various solid tumors for gefitinib, erlotinib, and cetuximab.
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Anti-EGFr Monoclonal Antibodies
Mendelsohn J. J Clin Oncol. 2002;20(suppl 18):1s-13s. Tewes M, et al. Proc Am Soc Clin Oncol. 2002. Abstract 378. Sridhar SS, et al. Lancet Oncol. 2003;4:397-406. Vanhoefer U, et al. J Clin Onc 2004;22(1):175-184www.clinicaltrials.gov.
Monoclonal Antibody Description Status
Cetuximab (C-225)
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, NSCLCPhase I-2 Trials: Colorectal cancer
Panitumumab (ABX-EGF)
Fully human IgG2Phase 2-3 Trials: Colorectal cancer, NSCLC, Others
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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 doseregimen (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 transductionShitara 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 SquibbCompany; 2004.
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Patients with EGFR-expressing metastatic CRC progressed after
receiving irinotecan-based chemotherapy
RANDOMIZATION
CETUXIMABwith irinotecan
n = 218
Cetuximab Randomized Pivotal Trial in Metastatic Colorectal Cancer
Randomized Phase II Study Design
ERBITUX Package Insert, June 2004.
CETUXIMAB as a single agent
n = 111
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Cetuximab Randomized Pivotal
Trial in Metastatic Colorectal Cancer
Characteristic All Patients (n = 329)
Gender, %MaleFemale
6337
Age, yMedianRange
5926-84
Karnofsky Performance Status, %
< 80 80
1288
Prior oxaliplatin treatment, % 63
Patient Baseline Demographics
ERBITUX Package Insert, June 2004.
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Cetuximab/C225 in Colon Cetuximab/C225 in Colon CancerCancer
CPT-11 + C225
C225 alone
2:1
RR TTP OS
22.9 4.1 8.6
10.8 1.5 6.9
54 pts crossover
Source: Cunningham D et al. N Engl J Med 2004;351:337-45.
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The “Bond” TrialsThe “Bond” TrialsC225 C225 AloneAlone
C225 + C225 + BevBev
PP
ValueValue
C225 + C225 + CPT-11CPT-11
C225 + C225 + CPT-11 CPT-11 + Bev+ Bev
P ValueP Value
PRPR 11%11% 23%23% 0.05 23%23% 38%38% 0.03
TTPTTP 1.5 1.5 momo
5.6 5.6 momo
>0.01 4.1 4.1 momo
7.9 7.9 momo
>0.01
OSOS 6.9 6.9 momo
NRNR - 8.6 8.6 momo
NRNR -
Sources: Cunningham D et al. N Engl J Med 2004;351:337-45.Saltz L et al. Presentation. ASCO GI Symposium 2005. Abstract 169b
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Cetuximab in the first line?Cetuximab in the first line?
• FOLFIRI + Cetuximab– 59% PR (13/22) 36% SD (8/23)59% PR (13/22) 36% SD (8/23)
• Raoul et al ECCO 2003
• FOLFOX + Cetuximab– 81% PR81% 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
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Monoclonal Antibodies as Targeted Therapy: Evolution to Fully Human Antibody
100% Mouse Protein 34% Mouse Protein 10% Mouse Protein 100% Human Protein
Mouse
Fully HumanHumanizedChimeric
cetuximab matuzumab panitumumabmousehuman
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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
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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
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Panitumumab Phase 2 Study:Monotherapy for CRC – Toxicity
(Treatment-related Adverse Events)
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.
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
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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
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Panitumumab + Chemotherapy 1st Line mCRC Phase 2 Study, Part 1: Skin Toxicity
Skin Toxic All Patients
(N=19)
Worst Severity
Mild
Moderate
Severe
Life-Threatening
9 (47%)
7 (37%)
3 (16%)
0 ( 0%)
Median (95% CI) Time to Onset,
days
11.0 (7.0, 15.0)
Berlin J, et al. ESMO 2004. a265
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Panitumumab + Chemotherapy 1st Line mCRC Phase 2 Study, Part 1: Efficacy
All Patients
(N=19)
Overall Response 9 (47%)
Partial Response
Complete Response8 (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
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Panitumumab PD Follow-up6.0 mg/kg Q2W+ BSC
BSC PD Follow-up
RRAANNDDOOMMIIZZEE
Optional Optional Panitumumab Panitumumab
Crossover StudyCrossover Study
Randomization stratificationRandomization stratification• ECOG score:ECOG score: 0-1 vs. 20-1 vs. 2• Geographic region:Geographic region: Western EU vs. Western EU vs.
Central & Eastern EU vs.Central & Eastern EU vs.Rest of World Rest of World
Randomized Controlled Phase 3 Trial in mCRC
1:1
Source: Peeters M et al. Presentation. AACR 2006. Abstract CP-1
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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
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• 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
Key Eligibility Criteria
Source: Peeters M et al. Presentation. AACR 2006. Abstract CP-1
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Demographics and Disease CharacteristicsPanitumumab
Plus BSC(N=231)
BSC Alone
(N=232)
Sex – n (%)MenWomen
146 (63)85 (37)
148 (64)84 (36)
Median (range) age – years 62 (27, 82) 63 (27, 83)
ECOG status – n (%)0-1≥ 2
201 (87)30 (13)
195 (84)37 (15)
Number of metastatic sites – n (%)1-23-5
161 (70)70 (30)
161 (70)69 (30)
Prior adjuvant chemotherapy – n (%) 86 (37) 78 (34)
Prior chemotherapy – n (%)At least 2 linesAt least 3 lines 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)
Intensity of EGFr staining – n (%)
3+ (strong)2+ (moderate)1+ (weak)0 (none)
47 (20)122 (53)60 (26)
2 (1)
41 (18)113 (49)78 (34)
0 (0)
Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1
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Eve
nt-
free
Pro
bab
ility
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Weeks from Randomization0 8 16 24 32 40 48 56
Hazard ratio=0.54 (95% CI: 0.44, 0.66)
Stratified log-rank testp < 0.000000001
Progression-Free Survival
Panitumumab
BSC
Patients at risk:PanitumumabBSC
231 118 49 31 13 5 1232 75 17 7 3 1 1
Primary Analysis, All Randomized Analysis Set, Central Radiology
Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1
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0%
10%
20%
30%
40%
50%
60%
Kaplan- Meier Progression-Free Survival Rates at Prespecified Time Points
49%49%
30%30%35%35%
14%14%
26%26%
9%9%5%5%
18%18%
4%4%1%1%1%1% 1%1%
4%4%
10%10%
Panitumumab (N=231)Panitumumab (N=231)
BSC (N=232)BSC (N=232)
Wk 8Wk 8 Wk 12Wk 12 Wk 16Wk 16 Wk 24Wk 24 Wk 32Wk 32 Wk 40Wk 40 Wk 48Wk 48
Primary Analysis, All Randomized Analysis Set, Central Radiology
% P
rog
ress
ion
Fre
e (9
5 %
CI)
Patients at risk:Patients at risk:PanitumumabPanitumumabBSCBSC
118118 4949 3131 1313 55 117575 1717 77 33 11 11
76763131
Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1
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% S
urvi
vin
g
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months from Randomization
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Panitumumab (N=231)
BSC (N=232)
Hazard ratio=0.93 (95% CI 0.73, 1.19)
Stratified log-rankp = 0.6065
Patients at risk:PanitumumabBSC
231 219 204 170 136 103 81 60 47 31 21 16 11 6 5 3 0 0 0232 221 199 175 139 98 76 60 41 29 20 18 12 8 7 5 3 1 0
00
Overall Survival – Interim Analysis(All Randomized Analysis Set)
Note: There were 250 events
Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1
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Note: BSC patients censored at the time that they received their first dose of panitumumab; Included confirmed and unconfirmed responses by investigator (RECIST criteria)
HR= 0.78 (95% CI: 0.61, 1.01) HR= 0.78 (95% CI: 0.61, 1.01)
PanitumumabPanitumumab
BSCBSC
Patients at risk:PanitumumabBSC
231 219 204 170 136 103 81 60 47 31 21 16 11 6 5 3 0 0 0 0
232 219 194 149 113 71 51 38 26 17 10 8 5 2 2 2 2 0 0 0
Sur
viva
l Pro
babi
lity
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19Months from Randomization
Overall Survival: Censored BSC PatientsWho Subsequently Responded After Crossing Over
Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1
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Safety – Grade 3/4 Adverse Events
Panitumumab (N = 229)
BSC(N = 234)
Grade 3 Grade 4 Grade 3 Grade 4
Patients with any grade 3or 4 event
75 (33) 4 (2) 41 (18) 4 (2)
Abdominal pain 17 (7) 0 (0) 8 (3) 3 (1)Fatigue 10 (4) 0 (0) 7 (3) 0 (0)Dyspnea 9 (4) 2 (1) 8 (3) 0 (0)Anorexia 7 (3) 0 (0) 5 (2) 0 (0)Jaundice 7 (3) 1 (0) 3 (1) 1 (0)Asthenia 6 (3) 1 (0) 5 (2) 0 (0)Vomiting 5 (2) 0 (0) 2 (1) 0 (0)Ascites 3 (1) 1 (0) 2 (1) 0 (0)Diarrhea 3 (1) 0 (0) 0 (0) 0 (0)Intestinal obstruction 3 (1) 4 (2) 2 (1) 0 (0)Paronychia 3 (1) 0 (0) 0 (0) 0 (0)Deep vein thrombosis 2 (1) 1 (0) 0 (0) 0 (0)Pulmonary embolism 0 (0) 1 (0) 0 (0) 0 (0)
MedDRA version 8.0 preferred terms; graded per NCI CTCAE version 2.0Source: Peeters M et al. Presentation. AACR 2006. Abstract CP-1
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Grade 2-4Grade 1
Sur
viva
l Pro
babi
lity
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months from Randomization0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Patients at risk:Grade 2-4Grade 1
152 150 138 120 99 71 58 39 29 17 13 9 6 5 1 0 057 55 47 34 24 20 12 8 5 4 3 2 0 0 0 0 0
Overall Survival by Worst Grade of Skin Toxicity in the Panitumumab Patients
a Hazard ratio for Grade 2-4 relative to Grade 1, stratified by ECOG and geographic region
Hazard ratio = 0.61a (95% CI: 0.40, 0.95)p = 0.0278
Source: With permission. Peeters M et al. Presentation. AACR 2006. Abstract CP-1
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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