title: Safety and efficacy of the addition of simvastatin to panitumumab in previously treated KRAS mutant metastatic colorectal cancer patients.
abstract: Panitumumab has proven efficacy in patients with metastatic or locally advanced colorectal cancer patients, provided that they have no activating KRAS mutation in their tumour. Simvastatin blocks the mevalonate pathway and thereby interferes with the post-translational modification of KRAS. We hypothesize that the activity of the RAS-induced pathway in patients with a KRAS mutation might be inhibited by simvastatin. This would theoretically result in increased sensitivity to panitumumab, potentially comparable with tumours with wild-type KRAS. A Simon two-stage design single-arm, phase II study was designed to test the safety and efficacy of the addition of simvastatin to panitumumab in colorectal cancer patients with a KRAS mutation after failing fluoropyrimidine-based, oxaliplatin-based and irinotecan-based therapy. The primary endpoint of this study was the proportion of patients alive and free from progression 11 weeks after the first administration of panitumumab, aiming for at least 40%, which is comparable with, although slightly lower than, that in KRAS wild-type patients in this setting. If this 40% was reached, then the study would continue into the second step up to 46 patients. Explorative correlative analysis for mutations in the KRAS and related pathways was carried out. One of 14 patients was free from progression at the primary endpoint time. The median progression-free survival was 8.4 weeks and the median overall survival status was 19.6 weeks. We conclude that the concept of mutant KRAS phenotype expression modulation with simvastatin was not applicable in the clinic.
authors.affiliation: Departments of aClinical Oncology bClinical Pharmacy and Toxicology cPathology, Leiden University Medical Center dDepartment of Internal Medicine, Diaconessenhuis Leiden, Leiden eDepartment of Internal Medicine, Reinier de Graaf Hospital, Delft fDepartment of Internal Medicine and Clinical Oncology, Haga Hospital, The Hague, The Netherlands.
authors.forename: Jara M
authors.initials: JM
authors.lastname: Baas
authors.forename: Lisanne L
authors.initials: LL
authors.lastname: Krens
authors.forename: Monique M
authors.initials: MM
authors.lastname: Bos
authors.forename: Johanneke E A
authors.initials: JE
authors.lastname: Portielje
authors.forename: Erdogan
authors.initials: E
authors.lastname: Batman
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D000077544:Panitumumab; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D019821:Simvastatin / Q000008:administration & dosage; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D000077544:Panitumumab; D019821:Simvastatin; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins