Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2015 Dec;33(6):1242-7.
doi: 10.1007/s10637-015-0285-8. Epub 2015 Sep 19.

Safety and Efficacy of the Addition of Simvastatin to Cetuximab in Previously Treated KRAS Mutant Metastatic Colorectal Cancer Patients

Affiliations
Free PMC article
Clinical Trial

Safety and Efficacy of the Addition of Simvastatin to Cetuximab in Previously Treated KRAS Mutant Metastatic Colorectal Cancer Patients

J M Baas et al. Invest New Drugs. .
Free PMC article

Abstract

Introduction: Cetuximab is registered for use in colorectal cancer (CRC) patients with RAS wild-type tumours only. Simvastatin blocks the mevalonate pathway and thereby interferes with the post-translational modification (prenylation) of KRAS. We hypothesize that the activated KRAS pathway in KRAS mutant tumors can be inhibited by simvastatin rendering these tumors sensitive to the EGFR inhibitor cetuximab.

Methods: A Simon two-stage, single-arm, phase II study was performed to test the efficacy and safety of the addition of simvastatin to cetuximab in patients with a KRAS mutation in their CRC tumour who were previously treated with fluoropyrimidine, oxaliplatin and irinotecan based regimens. The primary endpoint was to test the percentage of patients alive and free from progression 12.5 weeks after the first administration of cetuximab. Our hypothesis was that at least 40% was free from progression, comparable to, though slightly lower than in KRAS wild-type patients.

Results: Four of 18 included patients (22.2%) were free from progression at the primary endpoint time. The time to progression in these 4 patients ranged from 20.3 to 47 weeks.

Conclusion: Based on the current study we conclude that the theoretical concept of KRAS modulation with simvastatin was not applicable in the clinic, as we were not able to restore sensitivity to cetuximab in CRC patients harbouring a somatic KRAS mutation.

Keywords: Cetuximab; Colorectal cancer; KRAS; Statin.

Figures

Fig. 1
Fig. 1
a Progression free survival in weeks for the addition of simvastatin to cetuximab in CRC patients failing standard therapy. b Overall survival in weeks for the addition of simvastatin to cetuximab in CRC patients failing standard therapy

Similar articles

See all similar articles

Cited by 7 articles

See all "Cited by" articles

References

    1. Denters MJ, Deutekom M, Fockens P, Bossuyt PM, Dekker E. Implementation of population screening for colorectal cancer by repeated fecal occult blood test in the Netherlands. BMC Gastroenterol. 2009;9:28. doi: 10.1186/1471-230X-9-28. - DOI - PMC - PubMed
    1. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–1765. doi: 10.1056/NEJMoa0804385. - DOI - PubMed
    1. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626–1634. doi: 10.1200/JCO.2007.14.7116. - DOI - PubMed
    1. Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. 2014;26:13–21. doi: 10.1093/annonc/mdu378. - DOI - PubMed
    1. Krens LL, Baas JM, Gelderblom H, Guchelaar HJ. Therapeutic modulation of k-ras signaling in colorectal cancer. Drug Discov Today. 2010;15:502–516. doi: 10.1016/j.drudis.2010.05.012. - DOI - PubMed

Publication types

Feedback