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R.G. AmadoR.G. Amado
Analysis of Analysis of KRASKRAS Mutations in Patients With Mutations in Patients With Metastatic Colorectal Cancer Receiving Metastatic Colorectal Cancer Receiving
Panitumumab MonotherapyPanitumumab Monotherapy Abstract 0007:Abstract 0007: Wild-type Wild-type KRASKRAS is Required for Panitumumab is Required for Panitumumab
Efficacy in Patients With Metastatic Colorectal Cancer: Results Efficacy in Patients With Metastatic Colorectal Cancer: Results From a Randomized, Controlled TrialFrom a Randomized, Controlled Trial
Rafael G. Amado, Michael Wolf, Dan Freeman, Marc Peeters, Rafael G. Amado, Michael Wolf, Dan Freeman, Marc Peeters, Eric Van Cutsem, Salvatore Siena, Sid Suggs, Scott Patterson, David ChangEric Van Cutsem, Salvatore Siena, Sid Suggs, Scott Patterson, David Chang
Abstract 3014Abstract 3014: Association of Somatic : Association of Somatic KRASKRAS Gene Mutations and Gene Mutations and Clinical Outcome in Patients With Metastatic Colorectal Cancer Clinical Outcome in Patients With Metastatic Colorectal Cancer Receiving Panitumumab MonotherapyReceiving Panitumumab Monotherapy
Dan Freeman, Todd Juan, Neal J. Meropol, J. Randolph Hecht, Dan Freeman, Todd Juan, Neal J. Meropol, J. Randolph Hecht, Jordan Berlin, Eric Van Cutsem, Maureen Reiner, Robert Radinsky, Jordan Berlin, Eric Van Cutsem, Maureen Reiner, Robert Radinsky, Rafael G. Amado, Marc PeetersRafael G. Amado, Marc Peeters
R.G. AmadoR.G. Amado
The The KRASKRAS Oncogene Oncogene
• TheThe KRAS KRAS gene encodes the human cellular homolog of gene encodes the human cellular homolog of the transforming gene Kirsten rat sarcoma-2 virusthe transforming gene Kirsten rat sarcoma-2 virus
• KRAS is a self-inactivating signal transducerKRAS is a self-inactivating signal transducer– It cycles from GDP bound (“off” state) to GTP bound It cycles from GDP bound (“off” state) to GTP bound
(“on” state) in response to receptor activation(“on” state) in response to receptor activation– This response is transient due to the intrinsic GTPase This response is transient due to the intrinsic GTPase
activityactivity• KRASKRAS oncogenes harbor activating mutations yielding oncogenes harbor activating mutations yielding
proteins with reduced GTPase activityproteins with reduced GTPase activity• These activating These activating KRASKRAS mutations are among the most mutations are among the most
common oncogenic alterations in cancercommon oncogenic alterations in cancer11
1Malumbres and Barbacid. Nat Rev Cancer. 2003;3:459-465.
R.G. AmadoR.G. Amado
EGFr Signal TransductionEGFr Signal Transduction
Akt
SOS
FOS Myc
P13K
FKHRmTOR
PTEN
MEK 1/2
MAPK
BADGSK-3
Shc
Grb-2
Ras
Raf
Junp27
Cyclin D-1
LigandLigandLigandLigand
SignalSignalAdaptersAdaptersand Enzymesand Enzymes
SignalSignalCascadeCascade
EGFREGFR dimerdimer
TranscriptionTranscriptionFactorsFactors
STAT
R.G. AmadoR.G. Amado
WT, wild type; MT, mutant; cmab, cetuximab; CT, chemotherapy; pmab, panitumumab
Objective Response
N (%)
Reference Treatment (panitumumab or cetuximab)
No of patients (WT:MT) MT WT
A. Liévre, et al. (AACR Proceedings, 2007) cmab ± CT 76 (49:27) 0 (0) 24 (49)
S. Benvenuti, et al. (Cancer Res, 2007) pmab or cmab or cmab + CT 48 (32:16) 1 (6) 10 (31)
W. De Roock, et al.(ASCO Proceedings, 2007) cmab or cmab + irinotecan 113 (67:46) 0 (0) 27 (40)
D. Finocchiaro, et al. (ASCO Proceedings, 2007) cmab ± CT 81 (49:32) 2 (6) 13 (26)
F. Di Fiore, et al. (Br J Cancer, 2007) cmab + CT 59 (43:16) 0 (0) 12 (28)
S. Khambata-Ford, et al. (J Clin Oncol, 2007) cmab 80 (50:30) 0 (0) 5 (10)
Single-Arm Studies Support the Hypothesis for Single-Arm Studies Support the Hypothesis for KRASKRAS as a Biomarker for EGFr Inhibitors as a Biomarker for EGFr Inhibitors
R.G. AmadoR.G. Amado
KRASKRAS Analysis of Single-Arm, Analysis of Single-Arm, Panitumumab Monotherapy StudiesPanitumumab Monotherapy Studies
• Patient samples from 3 Amgen panitumumab monotherapy, Patient samples from 3 Amgen panitumumab monotherapy, single-arm, phase 2 trials in metastatic colorectal cancer single-arm, phase 2 trials in metastatic colorectal cancer were obtained under an ancillary biomarker protocolwere obtained under an ancillary biomarker protocol
• The majority of patient samples were archived tumor The majority of patient samples were archived tumor samples from the primary resectionsamples from the primary resection
• KRASKRAS mutational status was determined using cloning and mutational status was determined using cloning and sequencing of DNA isolated from paraffin-embedded tumor sequencing of DNA isolated from paraffin-embedded tumor samplessamples
• KRASKRAS mutational status was correlated with clinical mutational status was correlated with clinical outcomes including response, progression-free survival, outcomes including response, progression-free survival, and overall survivaland overall survival
R.G. AmadoR.G. Amado
Objective Tumor ResponseObjective Tumor Response
All Patients Mutant KRAS Wild-type KRASTotal
(N = 62)Total
(N = 24)Total
(N = 38)
PR, n (%) 4 (6.5) 0 4 (11)
SD, n (%) 25 (40) 5 (21) 20 (53)
PD, n (%) 33 (53) 19 (79) 14 (37)
PR + SD, n (%) 29 (47) 5 (21) 24 (63)
PR partial response; SD, stable disease; PD, disease progression
R.G. AmadoR.G. Amado
Progression-Free Survival for Panitumumab-Progression-Free Survival for Panitumumab-Treated Patients by Treated Patients by KRASKRAS Status Status
_Median (95% CI) in WeeksMutant: 7.4 (7.1–8.0)
-- Wild-type: 16.2 (8.3–23.7)
0.00.10.20.30.40.50.60.70.80.91.0
Prop
ortio
n w
ith P
FS
5550454035302520151050
2438
Patients at Risk:MutantWild-type
2438
625
625
417
314
213
27 6 3 3
Weeks From Enrollment
R.G. AmadoR.G. Amado
Randomization stratification• ECOG score: 0-1 vs. 2• Geographic region: Western EU vs. Central & Eastern EU vs. Rest of World
1:1
Panitumumab PD Follow-up6.0 mg/kg Q2W+ BSC
BSC PD Follow-up
RANDOMIZE
Optional Panitumumab
Crossover Study
Hypothesis: The treatment effect of panitumumab monotherapy is larger in patients with wild-type KRAS compared to patients with mutant KRAS
KRAS Analysis of a Phase 3, Randomized, Controlled Trial Comparing Panitumumab vs Best
Supportive Care (BSC) in Colorectal Cancer
Van Cutsem, Peeters et al. JCO. 2007;25:1658-1664.
R.G. AmadoR.G. Amado
Objectives and Analysis MethodologyObjectives and Analysis MethodologyPrimary Objective• To assess if the effect of
panitumumab on progression-free survival (PFS) was significantly greater in patients with wild-type KRAS compared to patients with mutant KRAS
Secondary Objectives• To assess whether
panitumumab improves PFS compared with BSC alone in patients with wild-type KRAS
• To assess whether panitumumab improves OS compared with BSC alone in patients with wild-type KRAS
Compare PFS in wild-type KRAS
subset
Test for a PFS effect among all
randomized patients at a 5% level
Test for quantitative PFS effect interaction,
i.e., wild-type effect > mutant
p ≤ 0.05 p > 0.05
p ≤ 0.05 p > 0.05
Compare OR & OS in wild-type KRAS subset STOP
STOP
R.G. AmadoR.G. Amado
Assay Used to Detect Assay Used to Detect KRASKRAS Mutational Status Mutational Status
• DNA was isolated from fixed tumor samplesDNA was isolated from fixed tumor samples
• Mutant Mutant KRASKRAS was detected using a was detected using a KRASKRAS mutation kit (DxS Ltd, mutation kit (DxS Ltd, Manchester, UK) that used allele-specific, real-time PCRManchester, UK) that used allele-specific, real-time PCR
– The kit can detect approximately 1% of mutant DNA in a The kit can detect approximately 1% of mutant DNA in a background of wild-type genomic DNAbackground of wild-type genomic DNA
– The test identifies 7 somatic mutations in codons 12 and 13The test identifies 7 somatic mutations in codons 12 and 13
• Gly 12 AspGly 12 Asp
• Gly 12 AlaGly 12 Ala
• Gly 12 ValGly 12 Val
• Gly 12 SerGly 12 Ser
• Gly 12 Arg• Gly 12 Cys• Gly 13 Asp
R.G. AmadoR.G. Amado
Results: Prevalence of Mutant Results: Prevalence of Mutant KRASKRAS
Panitumumab+ BSC BSC alone Total
Patients randomized, n 231 232 463
KRAS not tested, n (%) 11 (5) 7 (3) 18 (4)
KRAS tests failed, n (%) 12 (5) 6 (3) 18 (4)
Patients included in KRAS analysis, n (%) 208 (90) 219 (94) 427 (92)
Wild-type KRAS, n (%) 124 (60) 119 (54) 243 (57)
Mutant KRAS, n (%) 84 (40) 100 (46) 184 (43)
BSC, best supportive care
R.G. AmadoR.G. Amado
Distribution of Distribution of KRASKRAS Mutations Mutations
PanitumumabPanitumumab+ BSC+ BSC BSC aloneBSC alone TotalTotal
MutationMutation nn %% nn %% nn %%
12 Ala12 Ala 88 9.59.5 77 7.07.0 1515 8.28.2
12 Asp12 Asp 3434 40.540.5 3636 36.036.0 7070 38.038.0
12 Arg12 Arg 00 0.00.0 33 3.03.0 33 1.61.6
12 Val12 Val 1515 17.917.9 2525 25.025.0 4040 21.721.7
12 Cys12 Cys 77 8.38.3 77 7.07.0 1414 7.67.6
12 Ser12 Ser 55 6.06.0 99 9.09.0 1414 7.67.6
13 Asp13 Asp 1515 17.917.9 1414 14.014.0 2929 15.815.8
R.G. AmadoR.G. Amado
Baseline Disease Characteristics Baseline Disease Characteristics KRASKRAS Evaluable Group Evaluable Group
KRAS Evaluable Mutant KRAS Wild-type
KRASTotal
(N = 427)Total
(N = 184)Total
(N = 243) Sex, n (%) Men 270 (63) 111 (60) 159 (65) Baseline age, years Median (min, max) 62.0 (27, 83) 62.0 (27, 83) 63.0 (29, 82) Primary diagnosis, n (%) Colon cancer 286 (67) 118 (64) 168 (69) Months since primary diagnosis Median 25.1 24.1 25.1 ECOG performance status, n (%) 0-1 366 (86) 155 (84) 211 (87) ≥ 2 61 (14) 29 (16) 32 (13) Prior adjuvant chemotherapy, n (%) Yes 149 (35) 67 (36) 82 (34) Cells with EGFr membrane staining, n (%) 1% to < 10% 103 (24) 43 (23) 60 (25) 10% to 100% 322 (75) 140 (76) 182 (75)ECOG, Eastern Cooperative Oncology Group; EGFr, epidermal growth factor receptor
R.G. AmadoR.G. Amado
KRASKRAS Evaluable Patients: Evaluable Patients:PFS by TreatmentPFS by Treatment
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34Weeks
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
36 38 40 42 44 46 48 50 52
197188178 106 79 71 64 55 50 49 49 37 29 25 24 19 15 15 15 12 9 9 7 6 6200168142 75 42 34 25 23 19 16 14 14 10 10 10 10 9 8 6 6 5 4 4 4 3
208219
Prop
ortio
n w
ith P
FS
Pmab + BSCBSC Alone
Patients at Risk
191/208 (92) 8.0 15.4209/219 (95) 7.3 9.6
Pmab + BSCBSC Alone
Events/N (%)Median
In WeeksMean
In Weeks
HR = 0.59 (95% CI: 0.48–0.72)
R.G. AmadoR.G. Amado
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 34
Weeks36 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)
R.G. AmadoR.G. Amado
Wild-type Wild-type KRASKRAS Subgroup: PFS by Treatment Subgroup: 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
R.G. AmadoR.G. Amado
0.17-0.47
Wild-Type Wild-Type KRASKRAS Subgroup: Subgroup:Treatment Effect on PFS by Demographic/Disease StatusTreatment Effect on PFS by Demographic/Disease Status
HR, hazard ratio; Pmab, panitumumab; BSC, best supportive careAdjusted for randomization factors (ECOG score, geographic region)
All RandomizedMaleFemaleAge: < 65Age: 65+Primary: ColonPrimary: RectalECOG: 0–1ECOG: 2–3
Prior regimens: 3+Met. Sites: 1–2Met. Sites: 3–5EGFr: 1–< 10%EGFr: 10–35%EGFr: > 35%EGFr: 1+EGFr: 2+EGFr: 3+
Prior regimens: 3Prior regimens: 2
24315984
14110216875
21132
1001726960
1018169
12747
90142
0.450.420.460.420.470.470.360.470.35
0.270.420.520.300.490.340.330.410.37
0.280.54
0.34-0.590.30-0.590.29-0.730.29-0.600.31-0.730.34-0.650.21-0.610.35-0.620.15-0.82
0.17-0.440.30-0.590.30-0.890.16-0.560.31-0.750.20-0.580.18-0.630.28-0.600.18-0.75
0.38-0.76
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2Hazard Ratio (Pmab/BSC)
Favors: Pmab BSCFactors N HR 95% CI
R.G. AmadoR.G. Amado
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
R.G. AmadoR.G. Amado
Objective Tumor Response Objective Tumor Response Extension Study 20030194Extension Study 20030194
(Investigator assessment)(Investigator assessment)
KRAS
All Evaluablen (%)
Mutantn (%)
Wild-typen (%)
Response Pmab(N = 168)
Pmab(N = 77)
Pmab(N = 91)
CR 1 (1) 0 (0) 1 (1)
PR 19 (11) 0 (0) 19 (21)
SD 55 (33) 20 (26) 35 (38)
PD 60 (36) 37 (48) 23 (25)CR, PR 20 (12) 0 (0) 20 (22)CR, PR, SD 75 (45) 20 (26) 55 (60)
Pmab, panitumumab; CR, complete response; PR partial response; SD, stable disease; PD, disease progression
R.G. AmadoR.G. Amado
Maximum Percent Decrease in Target Lesions Maximum Percent Decrease in Target Lesions Final Analysis, Final Analysis, KRASKRAS Evaluable Group Evaluable 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
160140120100
80604020
% C
hang
e
-20-40-60-80
0
PR (0%) SD (12%) PD (75%)
Patient
R.G. AmadoR.G. Amado
Overall Survival by Treatment and Overall Survival by Treatment and KRASKRAS
124 92 58 35 18 9 3 2 1119 82 54 28 18 10 5 1 084 51 21 10 6 3 3 1 0100 55 30 18 11 3 0 0 0
Pmab–Wild-typeBSC–Wild-type
Pmab–MutantBSC–Mutant
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Surv
ival
Pro
babi
lity
Pmab–Wild-type 107 / 124 (86)110 / 119 (92)
8.17.6
Events/N (%)Median
In Months
BSC–Wild-type
Wild-type vs. Mutant(treatment arms combined)
Pmab–MutantBSC–Mutant
79 / 84 (94)95 / 100 (95)
4.94.4
HR = 0.67 (95% CI: 0.55–0.82)(adjusted for treatment andrandomization factors; ECOG, region)
R.G. AmadoR.G. Amado
Overview of Safety From Overview of Safety From KRASKRAS Analysis Analysis ( (Panitumumab-Treated Patients)Panitumumab-Treated Patients)
KRAS Evaluable
Mutant KRAS
Wild-type KRAS
Exposure: Mean number of infusions per patient 7.9 4.9 10.0 Any AE, % 100 100 100 Grade 3 or 4 AE, % 37 28 44 Treatment-related grade 3 AE, % 20 12 25 Any grade integument-related AE, % 92 90 93 Grade 3 20 13 25 Grade 4 < 1 1 0 Any grade diarrhea, % 22 19 24 Grade 3 2 1 2 Any grade infections, % 47 35 55 Grade 3 7 5 8 Hypomagnesemia as an AE, % 1 0 2 Infusion reactions, % 4 7 2 AE leading to withdrawal, % 6 5 7AE, Adverse Event
R.G. AmadoR.G. Amado
ConclusionsConclusions• The efficacy of panitumumab monotherapy in metastatic The efficacy of panitumumab monotherapy in metastatic
CRC seems confined to patients with wild-type CRC seems confined to patients with wild-type KRASKRAS
• KRASKRAS genotyping of tumors should be strongly genotyping of tumors should be strongly considered in patients with metastatic CRC being treated considered in patients with metastatic CRC being treated with panitumumab monotherapywith panitumumab monotherapy
• Ongoing studies in 1Ongoing studies in 1stst and 2 and 2ndnd lines will prospectively lines will prospectively examine the effect of panitumumab in combination with examine the effect of panitumumab in combination with chemotherapy in patients with wild-type and mutant chemotherapy in patients with wild-type and mutant KRAS KRAS tumorstumors
• Future studies should investigate the role of Future studies should investigate the role of KRASKRAS mutational status in the adjuvant setting in colon cancer mutational status in the adjuvant setting in colon cancer and in other indicationsand in other indications
R.G. AmadoR.G. Amado
AcknowledgmentsAcknowledgments• We wish to thank the patients and their families for We wish to thank the patients and their families for
study participationstudy participation
• We also thank all investigators and study personnelWe also thank all investigators and study personnel
DisclosuresDisclosures• This study was sponsored by Amgen Inc.• R.G. Amado, M. Wolf, D. Freeman, S. Suggs, S. Patterson, D. Chang,
T. Juan, M. Reiner, and R. Radinsky are Amgen employees and own Amgen Inc. stock.
• M. Peeters, Amgen advisory board and Amgen honoraria; E. Van Cutsem, Amgen advisory board and Amgen honoraria; N.J. Meropol, consultant for Amgen, Genentech, and Imclone; J. Berlin, advisory boards for Amgen, BMS, and Imclone.