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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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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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