R.G. Amado R.G. Amado Analysis of Analysis of KRAS KRAS Mutations in Patients Mutations in Patients With Metastatic Colorectal Cancer With Metastatic Colorectal Cancer Receiving Panitumumab Monotherapy Receiving Panitumumab Monotherapy Abstract 0007: Abstract 0007: Wild-type Wild-type KRAS KRAS is Required for is Required for Panitumumab Efficacy in Patients With Metastatic Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer: Results From a Randomized, Controlled Colorectal Cancer: Results From a Randomized, Controlled Trial 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 Chang Eric Van Cutsem, Salvatore Siena, Sid Suggs, Scott Patterson, David Chang Abstract 3014 Abstract 3014 : Association of Somatic : Association of Somatic KRAS KRAS Gene Gene Mutations and Clinical Outcome in Patients With Metastatic Mutations and Clinical Outcome in Patients With Metastatic Colorectal Cancer Receiving Panitumumab Monotherapy Colorectal Cancer Receiving 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 Peeters Rafael G. Amado, Marc Peeters
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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
• 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.
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
Progression-Free Survival for Panitumumab-Progression-Free Survival for Panitumumab-Treated Patients by Treated Patients by KRASKRAS Status Status
_Median (95% CI) in Weeks
Mutant: 7.4 (7.1–8.0)
-- Wild-type: 16.2 (8.3–23.7)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
po
rtio
n w
ith
PF
S
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
Sp < 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
Maximum Percent Decrease in Target Lesions Maximum Percent Decrease in Target Lesions Final Analysis, Final Analysis, KRASKRAS Evaluable Group Evaluable Group
16014012010080604020%
Cha
nge
-20-40-60-80
0
PR (0%) SD (12%) PD (70%)
Mutant
Patient
Pmab+ BSC
16014012010080604020%
Cha
nge
-20-40-60-80
0
PR (17%) SD (34%) PD (36%)
Wild-Type
Patient
16014012010080604020
% C
hang
e
-20-40-60-80
0
PR (0%) SD (8%) PD (60%)
Patient
BSCAlone
16014012010080604020
% 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
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 We also thank all investigators and study personnelpersonnel
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.