e14586 Background: Epithelial growth factor receptor (EGFR) inhibitors are not effective in KRAS mutant colorectal tumors. In these tumors the k-ras protein is activated by post-translational modification by binding farnesyl (C15) and geranylgeranyl (C17) moieties. Both are products of the mevalonate pathway, as is cholesterol. Statins (HMG-CoA-reductase inhibitors) not only inhibit synthesis of cholesterol, but also of C15 and C17 and thus may reduce post-translational activation of ras proteins. Therefore, statins may inhibit the expression of the mutant KRAS phenotype and normalize the phenotype into KRAS wild type. In a phase II study we investigated whether simvastatin treatment renders KRAS mutant colorectal tumors sensitive to cetuximab. Methods: Major eligibility criteria were metastatic colorectal cancer failing 5-FU, oxaliplatin and irinotecan containing regimens, with a mutation in codon 12, 13 or 61 of KRAS gene in a tumor sample. Patients were treated with simvastatin 80mg once daily and cetuximab 250mg/m2 weekly (after a starting dose of 400mg/m2). Primary objective was to investigate the percentage of patients free from progression and alive 12.5 weeks after the first administration of cetuximab, similar to the results of the KRAS wild type population of the phase III study. This phase II study was performed in a Simon two stage design, performing an interim analysis after enrolment of 15 patients. If at least 6 of these patients (i.e. 40%) were to be alive and free from progression at 12.5 weeks after the start of cetuximab, another 31 patients would be included during stage II. Results: Fifteen evaluable patients were enrolled at 3 study sites. Four patients (i.e. 27%) were free from progression at time of the primary endpoint. Three patients experienced serious adverse events; an allergic reaction during cetuximab infusion, rhabdomyolysis and intracranial haemorrhage due to cerebral metastases. Conclusions: Though 4 patients experienced stable disease at 12.5 weeks, the predefined efficacy boundary was not met in order to continue enrolment to stage II. Simvastatin 80mg once daily does not induce sensitivity to cetuximab in colorectal cancer patients with a mutation in the KRAS gene. Clinical trial information: NCT01190462.
UCGI 28 Panirinox: A randomized phase II study assessing Panitumumab + FOLFIRINOX or mFOLFOX6 in RAS and BRAF wild type metastatic colorectal cancer patients (mCRC) selected from circulating DNA analysis
