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Targeting EGFR in Advanced Colorectal Cancer
Eric Chen, MD, PhD-
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Outline
• Review of clinical data• Kras and beyond• Management of common side effects• Alternative dosing regimens
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Treatment of Colorectal CancerTreatment of Colorectal Cancer
5-FULeucovorin
1962-1995
5-FULeucovorin
CapecitabineIrinotecan
1996-2002
5-FULeucovorin
CapecitabineIrinotecanOxaliplatin
BevacizumabCetuximab
Panitumumab
2004 and beyond2002 - 2004
5-FULeucovorin
CapecitabineIrinotecanOxaliplatin
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Key Milestones: • Bevacizumab
– 1971, Folkman review in NEJM, Tumor-angiogenesis factor postulated
– 1989, VEGF gene – 1997, humanized mAb
described by Ferrara et al– 1997, phase I study, 25
patients/3 months– 2000, phase III initiated,813
patients/21 months– 2004, FDA approval
• Cetuximab / panitumumab– 1962, Cohen, EGF identified– 1980, Cohen, EGFR purified– 1981, Mendelsohn and Sato,
therapeutic implication– 1983, mAb 225 described– 1991, Phase I study mAb 225,
JNCI– 1994, chimeric version, C225– 2001, Phase I study of C225,
JCO– 2001, initial application rejected
by FDA– 2004, approval by FDA– 2006, panitumumab approval
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Proliferation MetastasisAngiogenesisApoptosis Resistance
Shc
PI3-K
RafMEKK-1
MEKMKK-7
JNKERK
Ras
mTOR
Grb2
AKT
Sos-1
The Epidermal Growth Factor Receptor Pathway
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Monoclonal Antibodies Targeting the EGFRAntibody Type Affinity Kd Half-life,
hrsDosing Development
Phase
CetuximabIgG1
Chimeric MoAb
0.39 nM 75-95 q1wk (q2w) Approved
Panitumumab IgG2 Human MoAb 50 pM 305-458
q1w q2wq3w
Approved
MatuzumabIgG1
Humanized MoAb
0.01 nM 94-180q1w q2wq3w
II
NimotuzumabIgG1
Humanized MoAb
1 nM 240 q1wI/II
approved in India, Cuba
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3rd Line Trials of Anti-EGFR Therapy
• NCIC.CO17– Randomized phase III of cetuximab vs BSC
• Van Cutsem 2007– Randomized phase III of panitumumab vs BSC
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Cetuximab + BSC vs. BSC: Phase III Trial
EGFR testing by IHC†
Disease Progression
or
Unacceptable Toxicity
Primary endpoint: Overall Survival (OS)Secondary endpoints: Progression-free survival (PFS)
Objective response rate (ORR)RECIST criteria
Safety and quality of life (QoL)
REGISTER
RANDOMI ZE1:11:1
Cetuximab** + BSC
BSC alone
Failed or intolerant to all recommended therapiesECOG PS* 0-2, no prior EGFR-directed therapy
*ECOG PS: Eastern Cooperative Oncology Group Performance Status
**Cetuximab 400 mg/m2 IV week 1, then 250 mg/m2 IV weekly †IHC: Immunohistochemistry
NCIC CTG CO.17 TRIAL
Jonker DJ et al, NEJM 2007, 357;20:2040-8
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CETUXIMAB + BSCCENSORED
BSCCENSORED
SUBJECTS AT RISKCET+BSC 287 217 136 78 37 14 4 0 0 0
BSC 285 197 85 44 26 12 8 2 1 0
Pro
porti
on A
live
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months0 3 6 9 12 15 18 21 24 27
Overall Survival
HR 0.77 (95% CI: 0.64, 0.92)
Stratified log rank p = 0.0046
Study arm MS (months) 95% CI
Cetuximab + BSC 6.1 5.4 – 6.7BSC alone 4.6 4.2 – 4.9
MS = Median Survival
HR = Hazard Ratio
NCIC CTG CO.17 TRIAL
Jonker DJ et al, NEJM 2007, 357;20:2040-8
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Progression-Free Survival
CETUXIMAB + BSCCENSORED
BSCCENSORED
Prop
ortio
n Pr
ogre
ssio
n-Fr
ee
0.00.0
0.10.1
0.20.2
0.30.3
0.40.4
0.50.5
0.60.6
0.70.7
0.80.8
0.90.9
1.01.0
Months00 33 66 99 1212 1515
HR 0.68 (95% CI: 0.57, 0.80)
Stratified log rank p < 0.0001
Study arm Med PFS (months)
95% CI
Cetuximab + BSC 1.9 1.8 – 2.1BSC alone 1.8 1.8 – 1.9
NCIC CTG CO.17 TRIAL
Jonker DJ et al, NEJM 2007, 357;20:2040-8
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Panitumumab PD Follow-up6.0 mg/kg Q2W+ BSC
BSC PD Follow-up
RANDOMIZE
Optional Panitumumab
Crossover Study
Randomization stratification• ECOG score: 0-1 vs. 2• Geographic region: Western EU vs.
Central & Eastern EU vs.Rest of World
1:1
EGFR+
VanCutsem E et al, JCO 2007, 25;13:1658-1664
Primary endpoint: Progression-free survival (PFS)Secondary endpoints: Objective response
Overall survivalSafety
Panitumumab vs BSC TRIAL
Study Design
PD = Progressive disease
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Even
t-fre
e Pr
obab
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
HR 0.54 (95% CI: 0.44, 0.66)
Stratified log-rank test p < 0.001
Progression-Free SurvivalPanitumumab
BSC
Patients at risk:PanitumumabBSC
231 118 49 31 13 5 1232 75 17 7 3 1 1
All Randomly assigned analysis set
Panitumumab vs BSC TRIAL
VanCutsem E et al, JCO 2007, 25;13:1658-1664
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% S
urvi
ving
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)
HR 0.93 (95% CI: 0.73, 1.19)
Stratified log-rank p = 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
Panitumumab vs BSC TRIAL
VanCutsem E et al, JCO 2007, 25;13:1658-1664
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Objective Tumor ResponseObjective Tumor ResponseCO-17 Panitumumab
(N = 287) (N = 231)
PR, n (%) 19 (6.6) 22 (10)
SD, n (%) 84 (29.3) 62 (27)
PD, n (%) 133 (46.3) 147 (63)
PR + SD, n (%) 103 (35.9) 84 (37)
Van Cutsem, E. et al. J Clin Oncol; 25:1658-1664 2007
Jonker, D. et al AACR 2007
Not all patients benefit from anti-EGFR antibodies
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EGFR Pathway and KRAS Gene• EGFR signaling pathway is activated
in response to ligand binding to cell-surface receptors: these ligands include TGFα and EGF
• In the early part of the signaling cascade, the protein RAS (RAt Sarcoma) regulates downstream proteins involved in these effects
• Kras gene is the gene that encodes the Kras protein. It could be normal (wild-type) or mutated.
• Kras protein cycles between “on” and “off” states. It is activated (on) for a short period of time once EGFR is activated.
Source: www.kras-info.com
TGF α = Transforming Growth Factor alphaEGF = Epidermal Growth FactorVEGF = Vascular Endothelial Growth Factor
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• Wild-type KRAS protein is active for a short period when the EGFR is stimulated– The effects of the protein are closely controlled
• When KRAS is mutated the protein is permanently turned on (constitutively activated), even without being triggered by EGFR-mediated signaling– The effects of KRAS that lead to tumor growth and spread
continue unregulated
– 40% patients with advanced colorectal cancer have K-ras mutation
EGFR Pathway and KRAS
Adapted from www.kras-info.com
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RAS-GDP
Khambata et al JCO 2008
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KRAS Analysis
• Genomic DNA extracted from FFPET slides or sections• Assessed by bidirectional sequencing for codon 12/13 mutations• No difference between KRAS-mutated and wild-type patients re:
demographics, previous treatment or other variables
N=572 randomized: ITT subset
N=394: K-Ras assessed subset (69%)
N=164 (42%)N=164 (42%)mutantmutant
N=230 (58%)N=230 (58%)wildwild--typetype
Karapetis C et al, NEJM 2008, 359;17:1757-65
NCIC CTG CO.17 TRIAL
ITT = Intent to treatFFPET = Formalin-fixed paraffin-embedded tissue
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PFS in Wild-Type KRAS Patients
HR 0.40 (95% CI: 0.30,0.54) Stratified Log rank p<0.0001
Study arm MS (months) 95% CI
Cetuximab + BSC 3.8 3.1 – 5.1BSC alone 1.9 1.8 – 2.0
NCIC CTG CO.17 TRIAL
0
0.2
0.4
0.6
0.8
1
0 2 4 6 8 10 12
Time from Randomisation (Months)
Pro
porti
on P
rogr
essi
on F
ree
CetuximabBSC
CetuximabBSC
117 74 50 26 8 5113 43 14 2 1 1
Karapetis C et al, NEJM 2008, 359;17:1757-65
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PFS in KRAS Mutant Patients
0
0.2
0.4
0.6
0.8
1
0 2 4 6 8 10 12
Time from Randomisation (Months)
Pro
porti
on P
rogr
essi
on F
ree
CetuximabBSC
CetuximabBSC
81 21 8 383 27 9 4
HR 0.99 (95% CI: 0.73,1.35) Stratified Log rank p= 0.96
Study arm MS (months) 95% CI
Cetuximab + BSC 1.8 1.7 – 1.8BSC alone 1.8 1.7 – 1.8
NCIC CTG CO.17 TRIAL
Karapetis C et al, NEJM 2008, 359;17:1757-65
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Overall Survival in KRAS Wild-Type Patients
HR 0.55 (95% CI: 0.41,0.74) Stratified Log rank p <0.0001
Study arm MS (months) 95% CI
Cetuximab + BSC 9.5 7.7 – 10.3BSC alone 4.8 4.2 – 5.5
NCIC CTG CO.17 TRIAL
0
0.2
0.4
0.6
0.8
1
0 2 4 6 8 10 12 14 16 18Time from Randomisation (Months)
Prop
ortio
n Al
ive
CetuximabBSC
CetuximabBSC
117 108 95 81 52 34 20 9 6 2113 92 69 36 24 17 12 5 3 3
Karapetis C et al, NEJM 2008, 359;17:1757-65
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Overall Survival in KRAS Mutant Patients
0
0.2
0.4
0.6
0.8
1
0 2 4 6 8 10 12 14 16 18Time from Randomisation (Months)
Pro
porti
on A
live
CetuximabBSC
CetuximabBSC
81 69 46 27 16 11 7 483 69 42 28 20 13 11 7
HR 0.98 (95% CI: 0.70 - 1.37) Stratified Log rank p <0.0001
Study arm MS (months) 95% CI
Cetuximab + BSC 4.5 3.8 – 5.6BSC alone 4.6 3.6 – 5.5
NCIC CTG CO.17 TRIAL
Karapetis C et al, NEJM 2008, 359;17:1757-65
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Maximum Percent Decrease in Target Lesions Maximum Percent Decrease in Target Lesions Final Analysis, Final Analysis, KRASKRAS Evaluable GroupEvaluable Group
160140120100
80604020%
Cha
nge
-20-40-60-80
0
PR (0%) SD (12%) PD (70%)
Mutant
Patient
Pmab+ BSC
160140120100
80604020%
Cha
nge
-20-40-60-80
0
PR (17%) SD (34%) PD (36%)
Wild-Type
Patient160140120100
80604020
% C
hang
e
-20-40-60-80
0
PR (0%) SD (8%) PD (60%)
Patient
BSCAlone
16014012010080604020%
Cha
nge
-20-40-60-80
0
PR (0%) SD (12%) PD (75%)
Patient
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Mutant Mutant KRASKRAS Subgroup:Subgroup:PFS by TreatmentPFS by Treatment
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Prop
ortio
n w
ith P
FS
Pmab + BSCBSC Alone
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34Weeks
36 38 40 42 44 46 48 50 52
Patients at Risk78 76 72 26 10 8 6 5 5 5 5 4 4 4 4 2 2 2 2 2 2 2 1 1 191 77 61 37 22 19 10 9 8 6 5 5 4 4 4 4 4 4 3 3 3 2 2 2 2
84100
76/84 (90) 7.4 9.995/100 (95) 7.3 10.2
Pmab + BSCBSC Alone
Events/N (%)Median
In WeeksMean
In Weeks
HR = 0.99 (95% CI: 0.73–1.36)
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WildWild--type type KRASKRAS Subgroup: PFS by TreatmentSubgroup: PFS by Treatment
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34Weeks
36 38 40 42 44 46 48 50 52
7 7 6 5 510 9 9 6 6 6 5 4 3 3 2 2 2 2 1
124
115/124 (93) 12.3 19.0114/119 (96) 7.3 9.3
Pmab + BSCBSC Alone
Events/N (%)Median
In WeeksMean
In Weeks
HR = 0.45 (95% CI: 0.34–0.59)Stratified log-rank test, p < 0.0001
Pmab + BSCBSC Alone
Patients at Risk119 112 106 80 69 63 58 50 45 44 44 33 25 21 20 17 13 13 13 10
119 109 91 81 38 20 15 15 14 11 6
Prop
ortio
n w
ith P
FSp < 0.0001 for quantitative-interaction test comparing PFS log-HR
(pmab/BSC) between KRAS groups
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Study Treatment Total number of patients with
KRAStested/total number of
patients on trial
Mutated KRAS
patients treated with anti-EGFR antibody
Mutated KRASpatients NOTtreated with anti-EGFR antibody
Wild-type KRAS
patients treated with anti-EGFR antibody
Wild-type KRAS
patients NOTtreated with anti-EGFR antibody
Per Protocol PFSHazard Ratio (HR)
Per Protocol PFSHazard Ratio (HR)
Jonker 2007
C0.17:BSC +/-
cetuximab (3rd line)
394/572(69%)
1.8 mos 1.8 mosHR 0.99
3.8 mos 1.9 mosHR 0.40
Amado 2008
Panitumumab vs BSC (3rd line)
427 / 463 (62%)
7.4 wks 7.3 wks HR 0.99
12.3 wks 7.3 wksHR 0.45
Van Cutsem
2008
CRYSTAL: FOLFIRI +/-
cetuximab (1st line)
540 / 1198 (45%)
7.6 mos 8.1 mos HR 1.07
9.9 mos 8.7 mosHR 0.68
Bokemeyer 2008
OPUS: FOLFOX +/-
cetuximab (1st line)
233 / 337 (69%)
5.5 mos 8.6 mos HR 1.83
7.7 mos 7.2 mosHR 0.57
Punt 2008
CAIRO2: CapOx/BV +/-
cetuximab (1st line)
501 / 755 (66%)
8.6 mos 12.5 mosHR not reported
10.5 mos 10.7 mosHR not reported
KRAS Summary
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Objective Tumor Response Objective Tumor Response (Central Radiology)(Central Radiology)
KRAS
All Evaluablen (%)
Mutantn (%)
Wild-typen (%)
ResponsePmab
(N = 208)
BSC
(N = 219)
Pmab
(N = 84)
BSC
(N = 100)
Pmab
(N = 124)
BSC
(N = 119)
CR 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
PR 21 (10) 0 (0) 0 (0) 0 (0) 21 (17) 0 (0)
SD 52 (25) 22 (10) 10 (12) 8 (8) 42 (34) 14 (12)
PD 104 (50) 149 (68) 59 (70) 60 (60) 45 (36) 89 (75)
CR, PR, SD 73 (35) 22 (10) 10 (12) 8 (8) 63 (51) 14 (12)
Pmab, panitumumab; BSC, best supportive care; CR, complete response; PR partial response; SD, stable disease; PD, disease progression
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7 Common Mutations
Mutation Base Change
Gly12Ala GGT>GCT
Gly12Asp GGT>GAT
Gly12Arg GGT>CGT
Gly12Cys GGT>TGT
Gly12Ser GGT>AGT
Gly12Val GGT>GTT
Gly13Asp GGC>GAC
These mutations cover 98.5% of KRAS mutations in CRC
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Possible Reasons for resistance to anti-EGFR antibodies• detection technique
– direct sequencing with PCR vs mutation-enriched sequencing
– Mutations on other codons or in other memebers of ras family
• mutations in other members of the EGFR pathway– BRAF, PTEN
• over-production of EGFR ligands– epiregulin, amphiregulin
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Rajagopalan et al Nature 2002
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Copyright © American Society of Clinical Oncology
Di Nicolantonio, F. et al. J Clin Oncol; 26:5705-5712 2008
Fig 1. KRAS and BRAF mutations correlate with lack of response to treatment with monoclonal antibodies targeting epidermal growth factor receptor
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Tol et al NEJM 2009
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Loupakis et al JCO 2009
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Loupakis et al JCO 2009
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Amphiregulin and epiruglin mRNA expression in primary tumors predicts outcomes in metastatic colon cancer treated with cetuximabJacobs et al JCO 2009
• 220 patients participated in 4 trials and treated with single agent cetuximab
• gene expression and kras mutation on archival formalin-fixed paraffin-embeded primary tumor samples
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Jacobs et al JCO 2009
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Kaplan-Meier plots of (A) PFS and (B) OS by K-ras status and dichotomized epiregulin expression levels
Jacobs et al JCO 2009
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Khambata-Ford et al JCO 2008
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Cetuximab PanitumumabAntibody IgG1, chimeric IgG2, human
Approved Schedule Q weekly Q 2 weeks
Loading Dose Yes No
Mechanism other than EGFR ligand inhibition
Antibody dependent cell cytotoxicity
Not described
Approved Indication EGFR+, irinotecan-pretreated mCRC in
combination with irinotecan or as
monotherapy
EGFR+, wild-type KRAS mCRC, after
failure of 5FU, oxaliplatin and irinotecan as monotherapy
Cetuximab or Panitumumab ?
ERBITUX Product Monograph, September 2008
VECTIBIX Product Monograph, July 2008
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Managing Common Adverse Effects of anti-EGFR
Antibodies
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Hypersensitivity Reactions
• Infusion reaction: – 20% cetuximab, 4% panitumumab– usually after 1st dose
• Severe (grade 3/4) relatively rare– 0.5% for CO-17
• Grade 3/4 reaction:– symptomatic bronchospasm, associated with
edema/hypotension– anaphylaxis
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O’Neil et al JCO 2007
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Chung et al NEJM 2008
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Potential antigenic sites on cetuximab
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Management of infusion reactions
• Mild/moderate– discontinue infusion– H1 and H2 antihistamines, corticosteroids
• Severe– epinephrine, s.c. 0.2 – 0.5 mg in cases of respiratory
distress/hypotension– H1 and H2 antihistamines, corticosteroids, inhaled
bronchodilators• Subsequent treatments
– Antihistamine/corticosteroids pre-med– slower infusion rate for patients with mild/moderate
reactions– discontinue for patients with severe reactions
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Langerak et al CCC, 2009
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hypomangnesiumia
• Magnesum homeostasis– absorption: intestine– excretion: renal– re-absorption: loop of Henle
• EGFR strongly expressed in kidney– EGF: paracrine hormone in Mg reabsorption– EGFR inhibition: reduced Mg reabsorption and
wasting
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Vincenzi et al CCR 2008
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Vincenzi et al CCR 2008
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Magnesium Supplement
• IV– MgSO4, 2-5 g over 2 hours
• Oral– various magnesium salts– magnesium oxide:
• highest content of Mg2+
• 1-2 tablets BID
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1 2 3 4 5 6 7 8 9
EGFR Inhibitor–Induced Skin Reactions
Descriptionof severe
cases
Post inflammatory effectsAcne-like rash
Paronychia
Dry skin
Topical antiacnecreams (drying effect)
± tetracyclines± antihistamines
Pruritus
Pulse dye laser
Emollients Hydrocolloid dressing or propylene glycol ±acetylsalicyl
Antiseptic soaks, silver nitrate (pyogenic granuloma)
Fissura
Segaert S, et al. Ann Oncol. 2005;16:1425-1433.
Therapy Suggestions
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Impact of Pre-emptive skin toxicity treatment on panitumumab-related skin
toxicities and quality of life in patients with metastatic colorectal cancer (STEPP)
LaCouture et al, ASCO GI 2009
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Prophylactic skin treatment• Skin moisturizer
– apply to face, hands, feet, neck, chest and back daily in the morning upon rising
• Sunscreen (PABA free, SPF≥ 15, UVA/UVB protection)– apply to exposed areas before going outdoors
• Topical steroids (1% hydrocortisone cream)– apply to face, hands, feet, neck, back and chest at
bedtime• Doxycycline 100 mg BID
LaCouture et al ASCO GI 2009
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Endpoints
• Primary– rates of ≥ grade 2 skin toxicity in 2 groups
• Secondary– efficacy of skin toxicity events– efficacy of panitumumab with
chemotherapy– patient-reported outcomes– safety
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Primary endpointProphylactic
skin treatment (n=48)
Reactive skin treatment
(n=47)Patients with grade 2 or higher skin toxicity, n (%)
14 (29) 29 (62)
Odd ratio (95% CI) 0.3 (0.1 – 0.6)
Total panitumumab dose administered, n 155 141
Total panitumumab dose delayed, n (%) 1 (1) 9 (8)
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Best Overall ResponseProphylactic
skin treatment (n=48)
Reactive skin treatment
(n=47)
Best Overall Response, n (%) 7 (15) 5 (11)
complete response 0 (0) 0 (0)
partial response 7 (15) 5 (11)
Stable disease 24 (50) 25 (53)
Disease progression 9 (19) 10 (21)
Not evaluable/available 8 (17) 7 (15)
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Copyright © American Society of Clinical Oncology
Scope, A. et al. J Clin Oncol; 25:5390-5396 2007
Fig 1. Study schema, patient disposition, and attrition data by study week
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Copyright © American Society of Clinical Oncology
Scope, A. et al. J Clin Oncol; 25:5390-5396 2007
Fig 2. Scatter plot of log lesion counts for minocycline and placebo groups for each of the four study time points
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Copyright © American Society of Clinical Oncology
Scope, A. et al. J Clin Oncol; 25:5390-5396 2007
Fig 5. Scatter plot of differences in lesion counts for tazarotene and observation sides of the face for each of the four study time points
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Martin-Martorell et al BJC 2008
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Martin-Martorell et al BJC 2008
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Stephenson et al CCC 2009
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Comparison of panitumumab Cmax after 30 min and 60 min infusions
Stephenson et al CCC 2009
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Summary• Anti-EGFR mAbs prolong survival in mCRC
patients with WT K-ras• Biomarkers could predict responses to
cetuximab/panitumumab• Skin toxicity could be reduced/delayed by
prophylactic use of topical and systemic treatments
• Cetuximab could be administered Q2W without compromising its efficacy or increasing toxicty