PROSPECTIVE TRIAL OF CETUXIMAB PLUS IRINOTECAN FOR OXALIPLATIN AND IRINOTECAN-BASED CHEMOTHERAPY-REFRACTORY PATIENTS ADVANCED AND/OR METASTATIC COLORECTAL CANCER, EVALUATION OF THE EFFICACY AND SAFETY BASED ON MUTATION STATUS OF THE EGFR RELATED GENES

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Abstract

Background

Activating mutation of the KRAS gene is a predictive biomarker for the loss of efficacy to Anti-EGFR antibody therapy. However, this was mainly established by the evidences of Caucasian studies. Then, this prospective study investigated the role of KRAS and other EGFR-related gene mutations on efficacy and safety to cetuximab plus irinotecan in Japanese patients with metastatic colorectal cancer (mCRC).

Method

We conducted a prospective study to analyze objective response to cetuximab plus irinotecan in molecularly defined KRAS wild-type (WT) or mutant subgroups of chemotherapy–refractory mCRC. KRAS mutations were detected by direct sequence on DNA from formalin-fixed, paraffin-embedded tissue of patients treated in 11 centers in Japan. Additional EGFR-related genes such as BRAF, PIK3CA, NRAS and AKT1 were examined.

Results

Forty-three patients were enrolled. KRAS mutations were found in 31.7% of 41 eligible patients. Response rate (RR) to cetuximab plus irinotecan, the primary end point of the study, was 17.9% and 0% for the WT KRAS patients and mutant KRAS patients, respectively. Progression-free survivals were 3.7 months versus 1.6 months (P = 0.0039); overall survivals were 7.7 months versus 4.4 months (P = 0.0005) for the WT KRAS patients and mutant KRAS patients, respectively. No significant differences in toxicity were observed between the WT and mutant KRAS groups. The combination of five genes analysis made the difference of clinical outcomes wider between all WT group and any mutant group.

Conclusion

We confirmed that the KRAS status is a useful predictive maker for the efficacy to cetuximab plus irinotecan therapy in Japanese mCRC patients, even though the response rate in the KRAS WT group was lower than expected. The combination of analysis in EGFR-related genes possibly contributes to the better prediction of the response.

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