Bokemeyer C, Bondarenko I, Hartmann JT, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study

Department of Oncology, Hematology, BMT with Section Pneumology, University Hospital, Hamburg-Eppendorf, Germany.
Annals of Oncology (Impact Factor: 7.04). 06/2011; 22(7):1535-46. DOI: 10.1093/annonc/mdq632
Source: PubMed


The randomized phase II OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer) study showed that tumor KRAS mutation status was predictive for outcome in patients receiving cetuximab plus FOLFOX-4 (oxaliplatin/5-fluorouracil/folinic acid) as first-line therapy for metastatic colorectal cancer (mCRC).
The biomarker analysis was extended through the use of additional DNA samples extracted from stained tissue sections. KRAS and BRAF tumor mutation status was determined for new (and for BRAF, existing) samples using a PCR technique. Clinical outcome was reassessed according to mutation status. Overall survival data are presented.
Of 315 KRAS evaluable patient samples (93%), 179 tumors (57%) were KRAS wild type. Eleven of 309 (4%) KRAS/BRAF evaluable tumors (all KRAS wild type) carried BRAF mutations. The addition of cetuximab to FOLFOX-4 significantly improved progression-free survival (hazard ratio 0.567, P = 0.0064) and response (odds ratio 2.551, P = 0.0027) in patients with KRAS wild-type tumors. A favorable effect on survival was also observed.
These results confirm the efficacy of cetuximab plus FOLFOX-4 in the first-line treatment of patients with KRAS wild-type mCRC and confirm KRAS mutation status as an effective predictive biomarker. The small number of tumors with BRAF mutations precluded the drawing of definitive conclusions concerning the predictive or prognostic utility of this biomarker.

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    • "There were no severe adverse events related to the study medications occurred in our patients. The toxicity profile was in line with the reported incidence in those large scale studies: CRYSTAL,[10] OPUS[9] and COIN[12] study, reflecting that this biweekly regimen is safe when used in combination with chemotherapy. "
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    ABSTRACT: Background: The efficacy and safety of using combination chemotherapy with cetuximab as first-line treatment in patients with K-ras wild-type colorectal cancers has been well established. In general, weekly cetuximab was given with biweekly chemotherapy FOLFOX-4 or FOLFIRI, synchronizing them would be appealed to both patients and health care professionals. Materials and Methods: This Phase II, prospective study investigated the efficacy and safety of using biweekly cetuximab 500 mg/m2 with chemotherapy FOLFOX-4 or FOLFIRI as first-line treatment for Chinese patients with K-ras wild-type metastatic colorectal cancer. The study endpoints included overall objective response (OR), progression-free survival (PFS), overall survival (OS) and safety. Results: Total 15 Chinese patients (male: 10 [67%]; median age: 60 [range 41-80]) were enrolled. Patients received median 12 cycles (range 2-12) of chemotherapy + cetuximab (FOLFOX-4 + cetuximab: 9 [60%]; FOLFIRI + cetuximab: 6 [40%]). Six patients (40%) with non-progressive disease after 12 cycles of chemotherapy + cetuximab carried on maintenance cetuximab. Median duration of follow-up (FU) was 23.7 months. The OR was 40% (complete response: 0%; partial response: 40%) for a disease control rate of 87%. Median PFS and OS were 7.8 months and 17.9 months respectively. For maintenance cetuximab phase, median PFS since the start of maintenance cetuximab was 6.8 months and median OS was 17.0 months. The only grade 3-4 toxicities were neutropenia (26.7%) in chemotherapy phase and acneiform rashes (16.7%) in maintenance phase. Conclusions: Biweekly cetuximab with combination chemotherapy was effective and safe as weekly dose. Further studies are warranted for the role of maintenance cetuximab.
    South Asian Journal of Cancer 07/2014; 3(3):175-8. DOI:10.4103/2278-330X.136802
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    • "Specifically, BRAF is responsible for resistance when patients received anti-EGFR therapy in a second or subsequent round of treatment, as shown in several retrospective studies [10, 25, 27, 28]. In contrast, the predictive value of BRAF mutations in first line treatment has not been fully demonstrated [18, 29, 30]. A recent study conducted by Saridaki et al. showed lower PFS and OS in BRAF V600E mutated patients compared with wild-type (4.2 "
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    ABSTRACT: Targeting epidermal growth factor receptor (EGFR) has been one of the most effective colorectal cancer strategies. Anti-EGFR antibodies function by binding to the extracellular domain of EGFR, preventing its activation, and ultimately providing clinical benefit. KRAS mutations in codons 12 and 13 are recognized prognostic and predictive biomarkers that should be analyzed at the clinic prior to the administration of anti-EGFR therapy. However, still an important fraction of KRAS wild-type patients do not respond to the treatment. The identification of additional genetic determinants of primary or secondary resistance to EGFR targeted therapy for further improving the selection of patients is urgent. Herein, we review the latest published literature highlighting the most important genes that may predict resistance to anti-EGFR monoclonal antibodies in colorectal cancer patients. According to the available findings, the evaluation of BRAF, NRAS, PIK3CA, and PTEN status could be the right strategy to select patients who are likely to respond to anti-EGFR therapies. In the future, the combination of those biomarkers will help establish consensus that can be introduced into clinical practice.
    BioMed Research International 06/2014; 2014:591867. DOI:10.1155/2014/591867 · 2.71 Impact Factor
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    • "The idea of personalized medicine was introduced to the treatment of metastatic colorectal cancer (mCRC) when KRAS codon 12/13 mutations were identified as negative predictors of anti-EGFR-antibody (EGFR-mAB) treatment. Consequently, only patients with KRAS codon 12/13 wild-type tumors were subjected to cetuximab or panitumumab treatment (Douillard et al. 2013; Huang et al. 2012; Modest et al. 2012; Douillard et al. 2010; Bokemeyer et al. 2011; Amado et al. 2008). This KRAS codon 12/13 wild-type population already excluded about 40 % of all patients and was associated with improved response rates (objective response rates, ORRs), progression-free survival (PFS) and overall survival (OS) in patients receiving EGFR-mABs. "
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    ABSTRACT: AIO KRK-0104 investigated first-line therapy of metastatic colorectal cancer (mCRC) with cetuximab, capecitabine and irinotecan versus cetuximab, capecitabine and oxaliplatin. This analysis investigated the impact of primary tumor location on outcome of patients. Left-sided primary tumors were defined as tumors from rectum to left flexure, while tumors in the remaining colon were regarded right sided. Overall survival (OS), progression-free survival (PFS) and response rate were correlated with primary tumor location. A Cox regression model was used to evaluate interaction between primary tumor location and KRAS mutation. Of 146 patients of the AIO KRK-0104 trial, 100 patients presented left-sided (of those 68 KRAS codon 12/13 wild-type) and 46 patients right-sided primary tumors (of those 27 KRAS codon 12/13 wild-type). Left-sided tumors were associated with significantly longer OS (p = 0.016, HR = 0.63) and PFS (p = 0.02, HR = 0.67) as compared to right-sided tumors. These effects were present in the KRAS codon 12/13 wild-type population (HR OS: 0.42; HR PFS: 0.54), while no impact of primary tumor location was evident in patients with KRAS codon 12/13 mutant tumors (HR OS: 1.3; HR PFS: 1.01). A significant interaction of KRAS status and primary tumor location concerning OS and PFS was observed. Our findings suggest that primary tumor location and KRAS codon 12/13 mutational status interact on the outcome of patients with mCRC receiving cetuximab-based first-line therapy. Left-sided primary tumor location might be a predictor of cetuximab efficacy.
    Journal of Cancer Research and Clinical Oncology 05/2014; 140(9). DOI:10.1007/s00432-014-1678-3 · 3.08 Impact Factor
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