Erschienen in:
01.06.2014 | PHASE II STUDIES
Effect of simvastatin plus cetuximab/irinotecan for KRAS mutant colorectal cancer and predictive value of the RAS signature for treatment response to cetuximab
verfasst von:
Jeeyun Lee, Yong Sang Hong, Jung Yong Hong, Se Won Han, Tae Won Kim, Hye Jin Kang, Tae You Kim, Kyu-pyo Kim, Suk Hyung Kim, In-Gu Do, Kyoung-Mee Kim, Insuk Sohn, Se Hoon Park, Joon Oh Park, Ho Yeong Lim, Yong Beom Cho, Woo Yong Lee, Seong Hyeon Yun, Hee Cheol Kim, Young Suk Park, Won Ki Kang
Erschienen in:
Investigational New Drugs
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Ausgabe 3/2014
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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.