egfr inhibitors in colorectal cancer john l. marshall, md lombardi comprehensive cancer center
TRANSCRIPT
EGFR Inhibitors in Colorectal Cancer
John L. Marshall, MD
Lombardi Comprehensive Cancer Center
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.
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.
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.
•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.
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
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.
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
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.
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.
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
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
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
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)
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
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
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
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
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
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
• 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
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
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
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
% 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
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
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
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
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