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Effect of simvastatin plus cetuximab/irinotecan for KRAS mutant colorectal cancer and predictive value of the RAS signature for treatment response to cetuximab

  • PHASE II STUDIES
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An Erratum to this article was published on 20 September 2014

Summary

Purpose Preclinical data has demonstrated the potential of simvastatin to overcome cetuximab resistance in KRAS mutant CRC patients. Therefore, we designed a study using simvastatin/cetuximab/irinotecan for KRAS mutant CRC patients who are refractory to irinotecan and oxaliplatin-based chemotherapy. Patients and methods In this phase II study, patients received 500 mg/m2 cetuximab, 150–180 mg/m2 (day 1), and 80 mg simvastatin (once daily, days 1–14, every 2 weeks). The primary endpoint was the objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), the disease control rate (DCR), and safety. We also analyzed the relationship between the RAS gene expression signature score and treatment response to simvastatin/cetuximab/irinotecan. Results Fifty-two KRAS mutant CRC patients were enrolled. The ORR (complete response [CR], 0; partial response [PR], 1) was 1.9 % (95 % confidence interval [CI], −1.8–5.6). The DCR (CR, 0; PR, 1; stable disease, 33) was 65.4 % (95 % CI, 52.5–78.3). The median PFS and OS from the time of study drug administration were 7·6 months (95 % CI, 4.4–10.8) and 12.8 months (95 % CI, 9.5–16.2), respectively. The most common grade 3/4 adverse events were anemia (28.8 %), neutropenia (13.5 %), and diarrhea (7.7 %). The RAS signature score was significantly correlated with the maximal change in target lesions from baseline (r = 0.57, P = 0.014). Conclusion The simvastatin/cetuximab/irinotecan regimen showed promising efficacy and safety in KRAS mutant CRC patients who failed irinotecan and oxaliplatin-based chemotherapy. The RAS signature may be a novel predictor of treatment response to cetuximab-combined chemotherapy in CRC patients.

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Funding

This work was supported by grants from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A102166).

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The authors have declared no conflicts of interest.

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Correspondence to Won Ki Kang.

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Jeeyun Lee, Yong Sang Hong and Jung Yong Hong contributed equally to this paper.

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Lee, J., Hong, Y.S., Hong, J.Y. et al. Effect of simvastatin plus cetuximab/irinotecan for KRAS mutant colorectal cancer and predictive value of the RAS signature for treatment response to cetuximab. Invest New Drugs 32, 535–541 (2014). https://doi.org/10.1007/s10637-014-0065-x

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  • DOI: https://doi.org/10.1007/s10637-014-0065-x

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