KRAS Mutations First Line Chemo And...

VOLUME
30
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29
OCTOBER
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2012
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Association of KRAS G13D Tumor Mutations With Outcome in Patients With Metastatic Colorectal Cancer Treated With First-Line Chemotherapy With or Without Cetuximab
Sabine Tejpar, Ilhan Celik, Michael Schlichting, Ute Sartorius, Carsten Bokemeyer, and Eric Van Cutsem Processed as a Rapid Communication manuscript. See accompanying editorial on page 3565; listen to the podcast by Dr Messersmith at www.jco.org/podcasts
Sabine Tejpar and Eric Van Cutsem, University Hospital Gasthuisberg, Leuven, Belgium; Ilhan Celik, Michael Schlichting, and Ute Sartorius, Merck KGaA, Darmstadt; and Carsten Bokemeyer, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Submitted February 16, 2012; accepted May 8, 2012; published online ahead of print at www.jco.org on June 25, 2012. Supported by Merck KGaA (Darmstadt, Germany). S.T. and E.V.C. are senior investigators of the Fund for Scientic ResearchFlanders (Fonds Wetenschappelijk OnderzoekVlaanderen). S.T. is also sponsored by the National Kankerplan Belgium. *C.B. and E.V.C. contributed equally to this work. Presented in part at the 47th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 3-7, 2011, and the 13th World Congress on Gastrointestinal Cancer, Barcelona, Spain, June 22-25, 2011. Authors disclosures of potential conicts of interest and author contributions are found at the end of this article. Corresponding author: Sabine Tejpar, MD, PhD, Digestive Oncology Unit, University Hospital Gasthuisberg, Herestraat 49, Leuven, Belgium B-3000; e-mail: sabine.tejpar@ uz.kuleuven.ac.be. 2012 by American Society of Clinical Oncology 0732-183X/12/3029-3570/$20.00 DOI: 10.1200/JCO.2012.42.2592
Purpose We investigated in the rst-line setting our previous nding that patients with chemorefractory KRAS G13Dmutated metastatic colorectal cancer (mCRC) benet from cetuximab treatment. Methods Associations between tumor KRAS mutation status (wild-type, G13D, G12V, or other mutations) and progression-free survival (PFS), survival, and response were investigated in pooled data from 1,378 evaluable patients from the CRYSTAL and OPUS studies. Multivariate analysis correcting for differences in baseline prognostic factors was performed. Results Of 533 patients (39%) with KRAS-mutant tumors, 83 (16%) had G13D, 125 (23%) had G12V, and 325 (61%) had other mutations. Signicant variations in treatment effects were found for tumor response (P .005) and PFS (P .046) in patients with G13D-mutant tumors versus all other mutations (including G12V). Within KRAS mutation subgroups, cetuximab plus chemotherapy versus chemotherapy alone signicantly improved PFS (median, 7.4 v 6.0 months; hazard ratio [HR], 0.47; P .039) and tumor response (40.5% v 22.0%; odds ratio, 3.38; P .042) but not survival (median, 15.4 v 14.7 months; HR, 0.89; P .68) in patients with G13D-mutant tumors. Patients with G12V and other mutations did not benet from this treatment combination. Patients with KRAS G13Dmutated tumors receiving chemotherapy alone experienced worse outcomes (response, 22.0% v 43.2%; odds ratio, 0.40; P .032) than those with other mutations. Effects were similar in the separate CRYSTAL and OPUS studies. Conclusion The addition of cetuximab to rst-line chemotherapy seems to benet patients with KRAS G13Dmutant tumors. Relative treatment effects were similar to those in patients with KRAS wild-type tumors but with lower absolute values. J Clin Oncol 30:3570-3577. 2012 by American Society of Clinical Oncology
INTRODUCTION
Epidermal growth factor receptor (EGFR) monoclonal antibodies were initially approved for the treatment of EGFR-expressing metastatic colorectal cancer (mCRC). However, since 2006, retrospective analyses of mCRC trials have consistently reported that patients with KRAS-mutated tumors do not benet from treatment with the EGFR monoclonal antibodies cetuximab (Erbitux; Merck Serono, Geneva, Switzerland; Bristol-Myers Squibb, New York, NY; Imclone Systems, New York, NY) and panitumumab (Vectibix; Amgen, Thousand Oaks, CA),1-7 and currently, patients with KRAS codon
12 or 13mutated mCRC are not treated with these agents.8,9 The KRAS gene is mutated in approximately 40% of CRCs, the most frequent mutations occurring at codons 12 (G12D, 13%; G12V, 9%) or 13 (G13D, 8%).10 Previous comparisons between patients with KRAS wild-type tumors and those with KRAS mutations have not differentiated between the mutational subtypes. Increasing evidence from different diseases suggests that not all KRAS mutations are alike in terms of their biology, and individual genotypes should be considered separately. However, reliable interpretation requires large data sets. In CRC, analysis of the RASCAL (Kirsten Ras in-Colorectal-Cancer
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KRAS G13D Mutations and Outcome in mCRC Treated With Cetuximab
Collaborative Group) database of 2,721 patients with different stages of disease revealed that those with KRAS G12Vmutated tumors (8.6%) were the only patient group to be signicantly associated with poor prognosis.11 The distribution of KRAS mutations differs between tumor types. Although pancreatic and nonsmall-cell lung cancers generally contain KRAS codon 12 mutations, both codon 12 and 13 mutations are found in CRCs.12 Furthermore, KRAS codon 13 mutations have been found to occur predominantly in a subset of CRCs defective in DNA repair genes.13,14 Finally, data from in vitro studies have suggested that KRAS codon 12mutated alleles have stronger transforming activity than KRAS codon 13mutant alleles.15-19 Several studies have shown that a minority of patients with KRAS-mutated CRC respond to EGFR-targeted therapy and that KRAS codon 13mutated tumors are over-represented in this group compared with other KRAS mutations.20-22 An in vitro study recently
demonstrated that CRC cell lines and xenografts with KRAS G12V mutant alleles were insensitive to cetuximab, whereas those with KRAS G13D or wild-type alleles were sensitive.23 In that study, the inuence of KRAS G13D mutations on outcome was further investigated in a pooled analysis of 579 patients with chemorefractory CRC treated with cetuximab from the CO.17 (National Cancer Institute of Canada Clinical Trials Group/Australasian Gastro-Intestinal Trials Group CO.17), BOND (Bowel Oncology with Cetuximab Antibody), MABEL (Monoclonal Antibody Erbitux in a European Pre-License Study), EMR202600, EVEREST (Evaluation of Various Erbitux Regimens by Means of Skin and Tumor Biopsies), BABEL, and SALVAGE clinical trials.23 Patients with KRAS G13Dmutant tumors treated with cetuximab had prolonged overall survival (OS; hazard ratio [HR], 0.50; 95% CI, 0.31 to 0.81; P .05) and progression-free survival (PFS; HR, 0.51; 95% CI, 0.32 to 0.81; P .004) compared with
Table 1. Baseline Characteristics in Patients by Tumor KRAS Mutation Status Tumor KRAS Mutation Status KRAS Wild Type CT Characteristic No. of patients Sex Male Female Age, years Median Range 65 65 ECOG PS 0-1 2 No. of metastatic sites 2 2 Liver metastasis only Yes No Leukocytes, L 10,000 10,000 Alkaline phosphatase, U/L 300 300 LDH ULN ULN No. 447 266 181 60 40 % CT Cetuximab No. 398 238 160 60 40 % No. 41 21 20 51 49 CT % KRAS G13D CT Cetuximab No. 42 26 16 62 38 % No. 53 31 22 58 42 CT % KRAS G12V CT Cetuximab No. 72 42 30 58 42 % No. 148 85 63 57 43 Other KRAS Mutations CT % CT Cetuximab No. 177 103 74 58 42 %
59 19-84 297 66 150 34 423 24 71 370 95 352 360 76 95 5 16 83 21 79 81 17
61 24-79 246 62 152 38 379 19 48 344 93 305 322 64 95 5 12 86 23 77 81 16
63 37-80 24 59 17 41 36 5 9 31 9 32 34 7 88 12 22 76 22 78 83 17
63 35-82 22 52 20 48 41 1 9 33 11 31 31 10 98 2 21 79 26 74 74 24
65 41-80 26 49 27 51 50 3 7 46 16 37 34 16 94 6 13 87 30 70 64 30
61 33-77 47 65 24 33 67 5 13 58 11 61 55 17 93 7 18 81 15 85 76 24
61 30-83 91 61 57 39 145 3 22 125 40 108 112 35 98 2 15 84 27 73 76 24
62 22-80 106 60 71 40 313 12 24 152 86 239 140 31 96 4 14 86 26 74 79 18
61 369 183 216
14 83 41 48
43 338 178 178
11 85 45 45
6 33 21 14
15 80 51 34
4 37 18 21
10 88 43 50
9 42 30 17
17 79 57 32
13 56 30 37
18 78 42 51
22 116 59 72
15 78 40 49
34 138 81 75
19 78 46 42
Abbreviations: CT, chemotherapy (infusional uorouracil, leucovorin, and irinotecan for CRYSTAL; infusional uorouracil, leucovorin, and oxaliplatin for OPUS); ECOG PS; Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; ULN, upper limit of normal. Data missing for one patient with KRAS G12V mutations (CT cetuximab). Data missing for 12 patients with KRAS wild-type tumors (six in each treatment arm), one patient with KRAS G13D mutation (CT arm), one patient with KRAS G12V mutation (CT cetuximab), and two patients with other KRAS mutations (one CT; one CT cetuximab). Data missing for 23 patients with KRAS wild-type tumors (11 CT; 12 CT cetuximab), one patient with KRAS G13D mutation (CT cetuximab), three patients with KRAS G12V mutations (CT), and seven patients with other KRAS mutations (one CT; six CT cetuximab). Data missing for 34 patients with KRAS wild-type tumors (17 in each treatment arm), three with KRAS G13D mutations (two CT; one CT cetuximab), ve with KRAS G12V mutations (two CT; three CT cetuximab), 15 patients with other KRAS mutations (10 CT; ve CT cetuximab). Data missing for 90 patients with KRAS wild-type tumors (48 CT; 42 CT cetuximab), nine patients with KRAS G13D mutations (six CT; three CT cetuximab), 11 patients with KRAS G12V mutations (six CT; ve CT cetuximab), 38 patients with other KRAS mutations (17 CT; 21 CT cetuximab).
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patients with tumors harboring other KRAS mutations. A signicant interaction was found between KRAS mutation status (KRAS G13D v other KRAS mutations) and OS benet with cetuximab treatment (adjusted HR, 0.30; 95% CI, 0.14 to 0.67; P .003). Worse prognosis was observed for patients with KRAS G13Dmutant tumors (n 13) in the best supportive care arm of the CO.17 trial. The poor prognosis observed for untreated patients with KRAS G13Dmutant tumors, coupled with the benet derived from receiving cetuximab, led to important treatment effects in this patient subgroup. To validate these ndings in an independent series, we further investigated the updated data sets from the CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Chemotherapy for Metastatic Colorectal Cancer) and OPUS (Oxaliplatin and Cetuximab in First-Line Treatment in Metastatic Colorectal Cancer) studies.2,4 In these randomized studies, the addition of cetuximab to rst-line infusional uorouracil, leucovorin, and irinotecan (FOLFIRI) or infusional uorouracil, leucovorin, and oxaliplatin (FOLFOX4), respectively, signicantly improved treatment outcome in patients with KRAS wild-type mCRC. In contrast, these combinations seemed to provide no treatment benet over chemotherapy alone in patients harboring KRAS-mutant tumors, and in the case of FOLFOX4, the combination may be considered detrimental.3,4 The present retrospective analysis was performed on a pooled data set from the CRYSTAL and OPUS studies, including all previously reported patient and outcome data. Patients with KRAS-mutant tumors were divided into those with KRAS G13D mutations, G12V mutations, and other KRAS mutations. KRAS G12Vmutant tumors were considered separately in this new analysis to explore their potential association with poor prognosis, as reported in the RASCAL study.11
METHODS
Patients and Study Designs of the CRYSTAL and OPUS Studies All patients had previously untreated mCRC; study designs and key eligibility and exclusion criteria have previously been described in detail.1,3 All patients provided written informed consent, and the studies were carried out in accordance with the Declaration of Helsinki under good clinical practice and full ethics committee approval. The CRYSTAL study was an open-label, randomized, multicenter, phase III study comparing FOLFIRI plus cetuximab with FOLFIRI alone. The OPUS study was an open-label, randomized, multicenter, phase II study comparing FOLFOX4 plus cetuximab with FOLFOX4 alone. In both studies, patients were treated until disease progression or the occurrence of unacceptable toxicity. Radiologic response was carried out every 8 weeks until disease progression or withdrawal. The primary end point for the CRYSTAL study was PFS as determined by anindependentreviewcommitteeperformingapreplannedblindedreview(based on modied WHO criteria) of radiologic assessments. Secondary end points included OS, best overall response, and safety. The primary end point of the OPUS study was best overall response rate as evaluated by an independent review committee according to modied WHO criteria. Secondary end points included PFS and OS. In both studies, after an increase in the ascertainment rate for KRAS mutation status, updated analyses were carried out with new cutoff dates for OS of May 31, 2009 (CRYSTAL),2 and November 30, 2008 (OPUS).4 KRAS Mutation Analyses DNA was extracted from formalin-xed parafn-embedded tumor tissue and from tissue recovered from stained slides previously used to evaluate EGFR expression. KRAS mutations were detected using a polymerase chain reaction clamping and melting curve technique, as described previously.2,4 Statistical Considerations The objectives of this retrospective study were, rst, to examine interactions between treatment effect and KRAS mutation status and, second, to
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investigate the treatment effect of adding cetuximab to standard chemotherapy on clinical outcome (response, PFS, OS) in different KRAS subgroups. Clinical outcome was compared among different patient subgroups based on tumor KRAS mutation status: KRAS wild type, G13D mutant, G12V mutant, and other KRAS codon 12 mutations (excluding G12V). Finally, we assessed whether tumor KRAS mutation status affected outcome in the standard chemotherapy-alone arm (FOLFOX4 or FOLFIRI). For the purpose of this analysis, individual patient data previously reported from the CRYSTAL and OPUS studies were pooled. PFS and survival times of the patient subgroups were analyzed using the Kaplan-Meier method. Cox proportional hazards model for survival and PFS and a logistic regression model for best overall response were stratied by study and Eastern Cooperative Oncology Group (ECOG) performance status (PS). Likelihood-ratio tests were performed to test treatment by KRAS mutation status interactions. Treatment effects were tested by score tests and main effects in a multivariate regression model adjusted for baseline covariates (sex, age, ECOG PS, number of metastases, liver-only metastases, leukocytes, alkaline phosphatase, and lactate dehydrogenase [LDH]) using the Wald test. Multiplicity adjustments were not performed because of the exploratory nature of the analyses.
RESULTS
Patients Of the 1,535 randomly assigned and treated patients from the CRYSTAL and OPUS studies, 1,378 (689 in each treatment arm) were evaluable for tumor KRAS mutation analysis. Of these, 845 patients (61%) had KRAS wild-type tumors, and 533 patients (39%) had KRAS-mutant tumors. The reported efcacy data2,4 for patients with KRAS wild-type and KRAS-mutant tumors from the individual studies are listed in the Data Supplement. In the pooled analyses, patients with KRAS-mutant tumors comprised: 83 (16%) with G13D, 125 (23%) with G12V, and 325 (61%) with other KRAS mutations. Small, and likely not relevant, differences were found in baseline characteristics: by treatment group in patients with KRAS G12Vmutant tumors for age, occurrence of liver-only metastases, leukocytes, and LDH status; in patients with KRAS G13Dmutant tumors for ECOG PS, sex, leukocytes, and LDH status; and across tumor KRAS mutation subsets within the chemotherapy control arm (Table 1).
Table 2. Treatment Interaction by KRAS Mutation Status in the Pooled Analysis Efcacy End Point Overall: wild-type v G13D v G12V v other mutations PFS OS Objective response Overall: wild-type v G13D v other mutations PFS OS Objective response Among mutation types: G13D v other mutations PFS OS Objective response Abbreviations: OS, overall survival; PFS, progression-free survival. P values were derived from likelihood-ratio test. Adjusted for differences in baseline characteristics. Other codon 12 mutations including G12V. P .001 .013 .001 .001 .022 .001 .046 .16 .005
Treatment Effect on Clinical Outcome in Patients Grouped by Tumor KRAS Mutation Status The pooled data sets from the CRYSTAL and OPUS studies were interrogated in a fashion similar to our analysis in chemorefractory mCRC.23 Treatment interaction tests by KRAS mutation status are shown in Table 2. An overall interaction test was performed to exam-
ine treatment effects over patients grouped by type of tumor KRAS mutation. As expected, a signicant variation in treatment effects across the four tumor KRAS mutation groups for all end points was found: tumor response (P .001), PFS (P .001), and OS (P .013). Comparing patients with KRAS G13Dmutant tumors with those with all other KRAS codon 12 mutations (including G12V) revealed
Study KRAS mutation status Pooled analysis wt (n = 845) mt G13D (n = 83) mt G12V (n = 125) mt other (n = 325) CRYSTAL wt (n = 666) mt G13D (n = 60) mt G12V (n = 91) mt other (n = 246) OPUS wt (n = 179) mt G13D (n = 23) mt G12V (n = 34) mt other (n = 79)
CT + cetuximab v CT alone Median PFS (months) 9.6 v 7.6 7.4 v 6.0 5.6 v 8.8 6.7 v 8.1 9.9 v 8.4 7.5 v 7.4 6.7 v 8.2 7.1 v 7.7 8.3 v 7.2 5.7 v 5.6 4.4 v 9.4 5.5 v 8.6 0.1 0.5 1.0 Benefit under CT + cetuximab
HR 0.66 0.60 1.55 1.37 0.69 0.72 1.43 1.19 0.57 0.40 1.89 2.06 2.0 Benefit under CT alone
95% CI 0.55 to 0.80 0.32 to 1.12 0.94 to 2.56 1.02 to 1.84 0.56 to 0.86 0.33 to 1.57 0.79 to 2.59 0.84 to 1.68 0.37 to 0.86 0.13 to 1.21 0.73 to 4.86 1.12 to 3.76
CT + cetuximab v CT alone Median OS (months) 23.5 v 19.5 15.4 v 14.7 15.9 v 17.8 15.4 v 17.7 23.5 v 20.0 16.8 v 15.8 17.1 v 18.0 15.7 v 16.3 22.8 v 18.5 13.4 v 14.1 15.5 v 17.8 13.3 v 23.6 0.5 1.0 Benefit under CT + cetuximab
HR 0.81 0.80 1.10 1.16 0.80 0.84 1.03 1.10 0.85 0.70 1.39 1.40 2.0 Benefit under CT alone Odds Ratio 2. 17 2. 41 0. 54 0. 58 2. 08 2. 38 0. 77 0. 63 2. 53 2. 47 0. 20 0. 44
Fig 1. Forest plots to demonstrate the treatment effect of KRAS mutation (mt) status by study (A) hazard ratios (HRs) for progression-free survival (PFS), (B) HRs for overall survival (OS), and (C) odds ratios for tumor response. Data presented are unadjusted for differences in baseline characteristics. CRYSTAL, Cetuximab Combined With Irinotecan in First-Line Chemotherapy for Metastatic Colorectal Cancer; CT, chemotherapy; OPUS, Oxaliplatin and Cetuximab in First-Line Treatment in Metastatic Colorectal Cancer; wt, wild type.
CT + cetuximab v CT alone Tumor Response Rate (%) 57.3 v 38.5 40.5 v 22.0 30.6 v 45.3 30.5 v 43.2 57.3 v 39.7 35.5 v 17.2 33.3 v 40.0 29.5 v 39.5 57.3 v 34.0 54.5 v 33.3 23.8 v 61.5 33.3 v 55.9
0.1 0.5 1.0 2.0 10.0 20.0 Benefit under CT alone Benefit under CT + cetuximab
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signicant variations in treatment effects for tumor response (P .005) and PFS (P .046). Pooling the CRYSTAL and OPUS studies did not seem to inuence the treatment effects observed in patient groups by KRAS mutation status, with no signicant studyby-treatment interactions found for any of the efcacy end points (Data Supplement). The treatment effects of adding cetuximab to standard chemotherapy within different patient subgroups are presented in forest plots in Figures 1A to 1C. In the pooled analysis, a heterogeneous treatment effect was observed according to KRAS mutation status across all efcacy end points investigated. For each outcome parameter, patients with KRAS G13Dmutant tumors seemed to benet more from receiving chemotherapy plus cetuximab than chemotherapy alone; adjusting for differences in baseline variables, signicant improvements were found for PFS (median, 7.4 v 6.0 months; HR, 0.47; P .039) and tumor response (40.5% v 22.0%; odds ratio, 3.38; P .042) but not survival (median, 15.4 v 14.7 months; HR, 0.89; P .68). The opposite was found for patients with KRAS G12V or
other KRAS tumor mutations. These treatment benets are in part because of the worse prognosis of the G13D mutants in the control arm. The relative treatment effects were similar for patients with KRAS G13Dmutant tumors and KRAS wild-type tumors but at a lower absolute effect level in patients with KRAS G13D mutations. Thus, within the chemotherapy plus cetuximab arm, the PFS times of patients with KRAS G13Dmutated tumors were only marginally better than those with tumors harboring G12V mutations or other KRAS mutations (Figs 1A and 2A). OS times were similar across the different tumor KRAS mutation subgroups and markedly lower than those for patients with KRAS wild-type tumors (Figs 1B and 2B). Similar results were found in the individual CRYSTAL and OPUS studies (Figs 1A to 1C). Prognostic Effect of Tumor KRAS Mutation Status in Patients Grouped by Treatment Received Having assessed the relative treatment effects, we next assessed the outcomes of each patient subgroup in the specic treatment arms
A
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
PFS (probability)
wt mt G13D mt G12V mt other
OS (probability)
wt mt G13D mt G12V mt other (n = 398) (n = 42) (n = 72) (n = 177) No. of events 184 24 40 109 Median PFS, months 9.6 7.4 5.6 6.7 95% CI 8.9 to 11.3 7.3 to 8.2 5.0 to 11.0 5.6 to 7.7
B
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 6
wt mt G13D mt G12V mt other (n = 398) (n = 42) (n = 72) (n = 177) 152 No. of events 297 36 61 15.4 Median OS, months 23.5 15.4 15.9 95% CI 20.7 to 25.7 12.4 to 20.4 14.5 to 20.1 13.5 to 17.5
12
16
20
12
18
24
30
36
42
48
54
60
Time (months)
No. at risk wt 398 mt G13D 42 mt G12V 72 mt other 177 286 28 40 98 154 7 14 45 46 4 3 8 9 0 0 3 1 0 0 0 No. at risk wt 398 mt G13D 42 mt G12V 72 mt other 177 356 37 65 141 296 30 49 110 246 18 28 70
Time (months)
177 9 18 46 128 8 13 31 83 6 10 17 65 5 6 13 21 2 3 5 4 1 0 1 0 0 0 0
C
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
wt mt G13D mt G12V mt other (n = 447) (n = 41) (n = 53) (n = 148) No. of events 251 21 28 77 Median PFS, months 7.6 6.0 8.8 8.1 95% CI 7.4 to 8.4 5.4 to 7.8 7.2 to 9.5 7.2 to 9.4
D
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 6
wt mt G13D mt G12V mt other (n = 447) (n = 41) (n = 53) (n = 148) No. of events 359 33 48 120 Median OS, months 19.5 14.7 17.8 17.7 95% CI 17.8 to 21.1 12.4 to 19.4 15.5 to 21.7 15.3 to 20.5
PFS (probability)
OS (probability)
12
16
20
12
18
24
30
36
42
48
54
60
Time (months)
No. at risk wt 447 mt G13D 41 mt G12V 53 mt other 148 298 21 38 107 128 4 18 42 24 1 2 9 4 0 1 2 0 0 1 0 No. at risk wt 447 mt G13D 41 mt G12V 53 mt other 148 395 34 51 133 313 23 40 105 227 13 26 63
Time (months)
159 7 16 46 112 3 12 35 67 2 8 18 48 1 5 11 18 0 0 2 2 0 0 1
Fig 2. Kaplan-Meier plots showing outcome according to tumor KRAS mutation (mt) status in a pooled analysis of patients receiving chemotherapy with or without cetuximab. (A) Progression-free survival (PFS) in patients treated with chemotherapy plus cetuximab, (B) overall survival (OS) in patients treated with chemotherapy plus cetuximab, (C) PFS in patients treated with chemotherapy only, and (D) OS in patients treated with chemotherapy only. wt, wild type. 3574
Table 3. KRAS Mutation Effect by Treatment Groups in the Pooled Analysis Chemotherapy Efcacy End Point Other mutations v wild type PFS OS Objective response G13D v other mutations PFS OS Objective response G13D v wild type PFS OS Objective response G12V v other mutations PFS OS Objective response G12V v wild type PFS OS Objective response G13D v G12V PFS OS Objective response HR/Odds Ratio 0.92 1.11 1.23 1.49 1.25 0.40 1.37 1.39 0.50 0.77 1.00 1.05 0.71 1.11 1.29 1.92 1.26 0.39 95% CI 0.71 to 1.20 0.90 to 1.37 0.83 to 1.81 0.90 to 2.44 0.84 to 1.86 0.18 to 0.92 0.87 to 2.16 0.96 to 2.00 0.23 to 1.09 0.49 to 1.23 0.70 to 1.41 0.55 to 2.02 0.47 to 1.08 0.81 to 1.51 0.71 to 2.34 1.06 to 3.47 0.80 to 1.98 0.15 to 0.99 P .53 .34 .30 .12 .26 .032 .18 .079 .080 .27 .99 .89 .11 .53 .40 .031 .33 .047 Chemotherapy HR/Odds Ratio 1.78 1.65 0.32 0.78 0.98 1.55 1.39 1.61 0.50 0.96 0.92 1.11 1.71 1.51 0.35 0.81 1.06 1.40 Cetuximab P .001 .001 .001 .29 .90 .23 .14 .0085 .040 .83 .59 .75 .003 .0043 .001 .44 .78 .42
95% CI 1.40 to 2.27 1.35 to 2.01 0.22 to 0.47 0.49 to 1.23 0.67 to 1.42 0.76 to 3.17 0.90 to 2.16 1.13 to 2.29 0.26 to 0.97 0.66 to 1.40 0.68 to 1.25 0.60 to 2.04 1.20 to 2.44 1.14 to 2.01 0.20 to 0.62 0.48 to 1.37 0.70 to 1.62 0.62 to 3.18
NOTE. Analyses shown were adjusted for differences in baseline characteritics. Abbreviations: HR, hazard ratio; OS, overall survival; PFS, progression-free survival. HRs are given for PFS and OS; odds ratios are given for objective response. HRs and odds ratios were derived from models stratied by Eastern Cooperative Oncology Group performance status and study. P values were derived from the Wald test.
(summarized in Table 3). In the pooled analysis, for patients receiving standard chemotherapy alone, those with KRAS G13Dmutant tumors tended to have worse PFS (HR, 1.49; P .12) and survival (HR, 1.25; P .26; Figs 2C and 2D) and signicantly worse tumor response (odds ratio, 0.40; P .032) than patients with other KRAS mutations. These differences were also observed in the individual studies, with a more pronounced separation of the curves in the KRAS mutation subgroups in the OPUS study (Data Supplement). In the pooled analysis, patients with KRAS G12Vmutant tumors receiving standard chemotherapy alone did not demonstrate worse PFS (HR, 0.77; P .27), OS (HR, 1; P not signicant; Fig 2C and 2D), or response (HR, 1.05; P .89) than those with other KRAS mutations (Table 3).
DISCUSSION
This study aimed to validate, in an independent series and in the rst-line setting, our previously reported nding of improved clinical outcome for patients with KRAS G13Dmutant tumors receiving cetuximab for chemorefractory mCRC.23 We investigated a pooled population of patients evaluated for tumor KRAS mutation status from the rst-line randomized CRYSTAL and OPUS studies.2,4 Pooling of the data was performed to increase the statistical power of the analysis, because KRAS G13D mutations remain a relatively rare event (8% in unselected CRC). No study effect was found in our analysis, and similar effects were seen separately in both trials, providing validation for this approach.
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The results from the pooled analysis were comparable to those observed in chemorefractory patients.23 In both studies, patients with KRAS G13D tumor mutations seemed to respond differently from those with other KRAS mutations when receiving cetuximab. Patients with tumors harboring KRAS G13D mutations fared worse in the control arm but better in the cetuximab-containing arm. This led to a high relative treatment effect, which was comparable to that observed for patients with KRAS wild-type tumors. It is important to emphasize, however, that the positive treatment effect observed for patients with KRAS G13Dmutant tumors was a consequence of a combination of the poor prognosis observed for these patients under standard chemotherapy alone, or best supportive care in chemorefractory patients,23 and the improved outcome under treatment with cetuximab. Therefore, for absolute values, the response rate, PFS, and OS obtained in patients with KRAS G13Dmutant tumors were still well below those observed for patients with KRAS wild-type tumors. Patients with tumors harboring KRAS G12V and other mutations were associated with worse outcome when receiving chemotherapy plus cetuximab (particularly tumor response with oxaliplatin-based chemotherapy), compared with chemotherapy alone, whereas those with KRAS G13Dmutant tumors beneted from this combination, further highlighting the potential differences in tumor biology of different KRAS mutations when treated with EGFR-targeted agents in combination with standard chemotherapy regimens. In the present study, no marked associations were found between patients with tumor KRAS G12V mutations and worse outcome
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compared with patients with tumors containing other KRAS mutations. This was in contrast to the ndings from the RASCAL study (in patients with tumors of differing Dukes stages), in which tumor KRAS G12V mutation was considered the only signicant biomarker of poor outcome.11 More recently, in patients with mCRC treated in the rst-line setting in the FOCUS (Fluorouracil, Oxaliplatin and Irinotecan: Use and Sequencing) and COIN (Continuous or Intermittent) trials, tumor KRAS mutation was found to be signicantly associated with poor prognosis, although correlations between outcome and different KRAS mutation types were not reported.24,25 An analysis of a series of studies in patients with mCRC treated with panitumumaborcontroltherapyinrst-orsecond-linechemorefractory settings,6,26,27 in which the inuence of KRAS G13D mutations on clinical outcome was investigated, was recently presented at the 2011 European Multidisciplinary Cancer Congress28 and American Society of Clinical Oncology Gastrointestinal Symposium.29 Across the studies, no consistent associations were found between tumors with specic KRAS mutations and patient outcome (PFS or OS). In comparison with our data, the authors reported opposite ndings for the effect of KRAS G13D tumor mutations on PFS and OS when panitumumab was combined with rstline oxaliplatin, whereas similar data (same magnitude and direction of effect but not statistically signicant) were reported for the effect of KRAS G13D tumor mutations on PFS and OS when panitumumab was combined with second-line FOLFIRI. These recent observations highlight the need for additional studies with different anti-EGFR agents in different lines of therapy and chemotherapy backbones in this setting. Our ndings generally support the increasing body of evidence from CRC and other diseases that not all KRAS mutations have the same effects on tumor biology and patient outcome. Thus, recent analysis of data from the BATTLE-1 (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) clinical trial in patients with advanced chemorefractory nonsmall-cell lung cancer demonstrated that KRAS mutation status was predictive of outcome in patients treated with erlotinib, vandetanib, or sorafenib.30 However, it is clear from emerging new data that that KRAS mutation type alone is not sufcient to fully describe the clear heterogeneity underlying CRC biology. We recently reported that one third of KRAS-mutant CRCs display gene expression proles similar to those found in BRAF-mutant tumors; thus, the biologic difference of this tumor subgroup is not captured by tumor KRAS mutation status alone.31 Similarly, Hinoue et al32 identied four CRC groups based on different tumor DNA methylation patterns; one of these groups comprised all tumors with BRAF mutations and also 20% of KRAS-mutant tumors. There seem to be some similarities between the biology of tumors harboring KRAS G13D and BRAF mutations, with patients with advanced CRC containing these mutation types exhibiting poor prognosis.33 These observations suggest that in the future, multiple molecular parameters (gene expression proles, DNA mutations, and DNA methylation patterns) together with information on tumor histologic subtype
REFERENCES
1. Van Cutsem E, Kohne CH, Hitre E, et al: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408-1417, 2009 2. Van Cutsem E, Kohne CH, Lang I, et al: Cetuximab plus irinotecan, uorouracil, and leuco3576
will be needed to identify specic phenotypes of tumor biology and thus may provide predictors for response to treatment. Currently, although mostclinicaltrialswillhaveaccesstotumorgenemutationdata,astepwise process will be required for the integration of more complex biologic signatures into drug response assessment. In summary, in this analysis of pooled individual patient data from two randomized trials investigating rst-line chemotherapy with or without cetuximab, signicant heterogeneous treatment effects were observed in patients with different tumor KRAS mutation subgroups. The data suggest that KRAS G13D mutations are associated with improved clinical outcome when cetuximab is added to rst-line chemotherapy. These ndings support those previously reported in chemorefractory patients. The data from many randomized studies of cetuximab in combination with chemotherapy will become available for further validation of these ndings. Meanwhile, preclinical efforts are ongoing to improve understanding of the mechanisms underlying differential responses. Data from preplanned prospective randomized clinical trials are needed before such ndings should be considered in clinical decision making. Currently, the value of KRAS testing is unprecedented, with tumor KRAS status as the only clinically validated biomarker for the efcacy of treatment with cetuximab.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) and/or an authors immediate family member(s) indicated a nancial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a U are those for which no compensation was received; those relationships marked with a C were compensated. For a detailed description of the disclosure categories, or for more information about ASCOs conict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conicts of Interest section in Information for Contributors. Employment or Leadership Position: Ilhan Celik, Merck KGaA (C); Michael Schlichting, Merck KGaA (C); Ute Sartorius, Merck KGaA (C) Consultant or Advisory Role: Sabine Tejpar, Merck Serono (C); Carsten Bokemeyer, Merck Serono (C); Eric Van Cutsem, Merck Serono (C) Stock Ownership: None Honoraria: Sabine Tejpar, Merck Serono; Carsten Bokemeyer, Merck Serono Research Funding: Sabine Tejpar, Merck Serono; Carsten Bokemeyer, Merck Serono; Eric Van Cutsem, Amgen, Merck Serono Expert Testimony: None Other Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Sabine Tejpar, Ilhan Celik, Eric Van Cutsem Provision of study materials or patients: Sabine Tejpar, Carsten Bokemeyer, Eric Van Cutsem Collection and assembly of data: Sabine Tejpar, Ilhan Celik, Eric Van Cutsem Data analysis and interpretation: All authors Manuscript writing: All authors Final approval of manuscript: All authors
4. Bokemeyer C, Bondarenko I, Hartmann JT, et al: Efcacy according to biomarker status of cetuximab plus FOLFOX-4 as rst-line treatment for metastatic colorectal cancer: The OPUS study. Ann Oncol 22:1535-1546, 2011 5. Karapetis CS, Khambata-Ford S, Jonker DJ, et al: K-ras mutations and benet from cetuximab in advanced colorectal cancer. N Engl J Med 359:17571765, 2008
vorin as rst-line treatment for metastatic colorectal cancer: Updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 29:2011-2019, 2011 3. Bokemeyer C, Bondarenko I, Makhson A, et al: Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the rst-line treatment of metastatic colorectal cancer. J Clin Oncol 27:663671, 2009
6. Douillard JY, Siena S, Cassidy J, et al: Randomized, phase III trial of panitumumab with infusional uorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as rst-line treatment in patients with previously untreated metastatic colorectal cancer: The PRIME study. J Clin Oncol 28:4697-4705, 2010 7. Allegra CJ, Jessup JM, Somereld MR, et al: American Society of Clinical Oncology provisional clinical opinion: Testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 27:2091-2096, 2009 8. European Medicines Agency: Questions and answers on the marketing authorisation of Vectibix. http://www.emea.europa.eu/pdfs/human/opinion/ 40511307 9. US Food and Drug Administration: About FDA: Cetuximab (Erbitux) and Panitumumab (Vectibix). http:// www.fda.gov/AboutFDA/CentersOfces/Ofceof MedicalProductsandTobacco/CDER/ucm172905.htm 10. Normanno N, Tejpar S, Morgillo F, et al: Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol 6:519-527, 2009 11. Andreyev HJ, Norman AR, Cunningham D, et al: Kirsten ras mutations in patients with colorectal cancer: The RASCAL II study. Br J Cancer 85:692696, 2001 12. Wellcome Trust Sanger Institute: Catalogue of somatic mutations in cancer. http://www.sanger .ac.uk/genetics/CGP/cosmic/ 13. Zlobec I, Kovac M, Erzberger P, et al: Combined analysis of specic KRAS mutation, BRAF and microsatellite instability identies prognostic subgroups of sporadic and hereditary colorectal cancer. Int J Cancer 127:2569-2575, 2010 14. Oliveira C, Westra JL, Arango D, et al: Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status. Hum Mol Genet 13:2303-2311, 2004 15. Guerrero S, Casanova I, Farre L, et al: K-ras codon 12 mutation induces higher level of resistance to apoptosis and predisposition to anchorageindependent growth than codon 13 mutation or
proto-oncogene overexpression. Cancer Res 60: 6750-6756, 2000 16. Horsch M, Recktenwald CV, Schadler S, et al: Overexpressed vs mutated Kras in murine broblasts: A molecular phenotyping study. Br J Cancer 100:656-662, 2009 17. Smith G, Bounds R, Wolf H, et al: Activating K-Ras mutations outwith hotspot codons in sporadic colorectal tumours: Implications for personalised cancer medicine. Br J Cancer 102:693-703, 2010 18. Recktenwald CV, Mendler S, Lichtenfels R, et al: Inuence of Ki-ras-driven oncogenic transformation on the protein network of murine broblasts. Proteomics 7:385-398, 2007 19. Muegge I, Schweins T, Langen R, et al: Electrostatic control of GTP and GDP binding in the oncoprotein p21ras. Structure 4:475-489, 1996 20. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al: Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 67: 2643-2648, 2007 21. Frattini M, Saletti P, Romagnani E, et al: PTEN loss of expression predicts cetuximab efcacy in metastatic colorectal cancer patients. Br J Cancer 97:1139-1145, 2007 22. Moroni M, Veronese S, Benvenuti S, et al: Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: A cohort study. Lancet Oncol 6:279-286, 2005 23. De Roock W, Jonker DJ, Di Nicolantonio F, et al: Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 304:1812-1820, 2010 24. Richman SD, Seymour MT, Chambers P, et al: KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benet from oxaliplatin or irinotecan: Results from the MRC FOCUS trial. J Clin Oncol 27:5931-5937, 2009 25. Maughan TS, Adams RA, Smith CG, et al: Addition of cetuximab to oxaliplatin-based rst-line combination chemotherapy for treatment of ad
vanced colorectal cancer: Results of the randomised phase 3 MRC COIN trial. Lancet 377:2103-2114, 2011 26. Amado RG, Wolf M, Peeters M, et al: Wildtype KRAS is required for panitumumab efcacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626-1634, 2008 27. Peeters M, Price TJ, Cervantes A, et al: Randomized phase III study of panitumumab with uorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 28:4706-4713, 2010 28. Peeters M, Douillard JY, Van Cutsem E, et al: Evaluation of individual codon 12 and 13 mutant (mt) KRAS alleles as prognostic and predictive biomarkers of response to panitumumab (pmab) in patients with metastatic colorectal cancer (mCRC). Eur J Cancer 47:16, 2011 (suppl 2; abstr LBA33) 29. Peeters M, Douillard JY, Van Cutsem E, et al: Mutant (MT) KRAS codon 12 and 13 alleles in patients (pts) with metastatic colorectal cancer (mCRC): Assessment as prognostic and predictive biomarkers of response to panitumumab (pmab). J Clin Oncol 30, 2012 (suppl; abstr 383) 30. Ihle NT, Herbst RS, Kim ES, et al: Specic forms of mutant KRAS predict patient benet from targeted therapy in the BATTLE-1 clinical trial in advanced non-small cell lung cancer. Presented at the 102nd Annual Meeting of the American Association for Cancer Research, Orlando, FL, April 2-6, 2011 (abstr 955) 31. Tejpar S, Popovici V, Delorenzi M, et al: Mutant KRAS and BRAF gene expression proles in colorectal cancer: Results of the translational study on the PETACC 3-EORTC 40993-SAKK 60-00 trial. J Clin Oncol 28:262s, 2010 (suppl; abstr 3505) 32. Hinoue T, Weisenberger DJ, Lange CP, et al: Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res 22:271-282, 2012 33. Yokota T, Ura T, Shibata N, et al: BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer. Br J Cancer 104: 856-862, 2011
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JOURNAL OF CLINICAL ONCOLOGY

2012 by American Society of Clinical Oncology

KRAS G13D Mutations and Outcome in mCRC Treated With Cetuximab

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61 24-79 246 62 152 38 379 19 48 344 93 305 322 64 95 5 12 86 23 77 81 16

61 30-83 91 61 57 39 145 3 22 125 40 108 112 35 98 2 15 84 27 73 76 24

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2012 by American Society of Clinical Oncology

JOURNAL OF CLINICAL ONCOLOGY

KRAS G13D Mutations and Outcome in mCRC Treated With Cetuximab

2012 by American Society of Clinical Oncology

wt mt G13D mt G12V mt other

wt mt G13D mt G12V mt other

wt mt G13D mt G12V mt other

wt mt G13D mt G12V mt other

2012 by American Society of Clinical Oncology

KRAS G13D Mutations and Outcome in mCRC Treated With Cetuximab

2012 by American Society of Clinical Oncology

KRAS G13D Mutations and Outcome in mCRC Treated With Cetuximab

2012 by American Society of Clinical Oncology

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