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Cetuximab Maintenance Treatment Versus Continuation After Induction Therapy in mCRC

ABSTRACT: This study is try to evaluate the effect of cetuximab monotherapy as maintenance treatment, versus continuation after 8 courses of induction therapy with cetuximab plus standard chemotherapy regimen (FOLFIRI or mFOLFOX6）in metastatic colorectal cancer (mCRC) patients. The maintenance treatments are continued until disease progression or untolerated toxicity. The aim of this study is to demonstrate that cetuximab monotherapy is non-inferior to continuation treatment, in those mCRC patients who responded to induction therapy(SD, PR, or CR), and carry biomarker-panels (KRAS, NRAS, BRAF, and PIK3CA) favor EGFR antibody.

DISEASE(S): Colorectal Cancer,Colorectal Neoplasms

PROVIDER: 2228220 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Novel predictive markers are required to further improve the selection of patients for this treatment. Here, we assessed the influence of modification of KRAS by gene copy number aberration (CNA) and microRNAs (miRNAs) in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab. Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n=17) or poor (n=17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR. Good response was associated with 12p12.1 copy number loss, even in patients with a KRAS mutation, while copy number gain in wild-type KRAS patients was correlated with a poor response. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good response. In wild-type KRAS patients, miRNA expression did not predict response in a multivariate model. Thus, assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of patients eligible for anti-EGFR therapy. Copy number detection was performed using NimbleScan and Nexus software Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 metastisized colorectal cancer patients in a phase III trial (CKTO 2005-02; ClinTrials.gov NCT00208546) of the Dutch Colorectal Cancer Group (DCCG), who were selected based upon their good (n=17) or poor (n=17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab.

Project description:Colorectal Cancer ranks third among the most frequent malignancies representing a leading cause of cancer-related death worldwide. The constant improvement in the "continuum of care" of metastatic colorectal cancer (mCRC) patients led to a median overall survival of about 30-36 months. Due to the cumulative toxicities of first-line combinations of chemotherapy and biological agents, discontinuation or intermittent chemotherapy or maintenance strategies have been investigated in clinical trials. After a 4 to 6-month induction treatment with bevacizumab plus doublet or triplet regimens, a fluoropyrimidine plus bevacizumab is regarded as the optimal maintenance regimen. Little evidence is available on the role of maintenance with anti-EGFR agents. A recent systematic review and network meta-analysis of 12 relevant randomized clinical trials comprising 5540 patients with mCRC showed that a maintenance strategy with a fluoropyrimidine, with or without the addition of bevacizumab, is preferred. However, given the lack of a clear overall survival benefit, shared decision-making should include observation as an acceptable alternative. Poly(ADP)-ribose polymerase (PARP) inhibitors are now approved for breast, ovarian and pancreatic cancers. Evidence suggests that PARP inhibitors are more effective in tumors harboring homologous recombination DNA damage repair (HRR) deficiency and platinum sensitivity may be used a surrogate marker of HRD and therefore of PARP-inhibitors efficacy. An extensive Next Generation Sequencing analysis revealed that 15% of mCRC samples harbors mutations in genes involved in the HRR pathway. Several clinical trials are ongoing to test PARP inhibitors either alone or in combination in mCRC patients. The originality of this trial is to investigate PARPi in the maintenance setting. Pre-clinical evidence showed that PARP blockade after initial oxaliplatin response delayed disease progression in mCRC carrying Kirsten Rat Sarcoma and BRAF mutations, suggesting that maintenance treatment with PARP inhibitors warrants further clinical investigation in mCRC patients who respond to oxaliplatin-containing induction treatment. The main objective of this trial is to investigate the efficacy of anti-PARP inhibition as maintenance treatment in mCRC patients who obtained a complete or partial response after 4-month induction treatment with oxaliplatin-based double or triplet plus biologic agents.

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Cetuximab Maintenance Treatment Versus Continuation After Induction Therapy in mCRC

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