Phase II trial of cetuximab (Cmab) plus irinotecan (CPT-11) for chemorefractory Japanese patients with advanced and/or metastatic colorectal cancer (mCRC), to evaluate the efficacy and safety based on KRAS, BRAF, PIK3CA, NRAS, and AKT1 mutation status (T-CORE0801).

Abstract

e14597 Background: Mutations in the KRAS gene have been identified as negative predictors of response to anti-epidermal growth factor receptor (EGFR) antibody (mAb) therapy among patients with mCRC based on Caucasian studies. To date, few studies have examined the relationship between KRAS status and response to Cmab therapy in Asian populations. Therefore, this prospective study investigated the relationship between the mutation status of KRAS and other EGFR-related genes along with clinical outcomes in response to Cmab + CPT-11 therapy in Japanese patients with mCRC. Methods: Samples that had been collected from 43 chemo-refractory patients with mCRC, who had undergone Cmab + CPT-11 therapy at 11 medical centers in Japan, were subjected to direct DNA sequencing to determine their KRAS, BRAF, PIK3CA, NRAS, and AKT1 status. The response rate (RR) was the primary endpoint along with safety, median progression free survival (mPFS), and median overall survival (mOS) as secondary endpoints. Results: The clinical outcomes in response to Cmab + CPT-11 therapy was observed to be better in the wild-type (WT) KRAS subgroup than in the mutant (MT) KRAS subgroup (RR: 17.9% vs. 0%; mPFS: 3.7 vs. 1.6 months (M) ; mOS: 10.3 vs. 7.5 M). The differences in clinical outcomes were more remarkable between patients with both WT KRAS and BRAFand those with MT of either of these genes (RR: 19.2% vs. 0%; mPFS: 5.2 vs. 1.6 M; mOS: 11.8 vs. 7.4 M), as well as between patients with all 5 WT genes and those with MT of either of these genes (RR: 26.3% vs. 0%; mPFS: 5.2 vs. 1.8 M; mOS: 11.8 vs. 7.4 M). Conclusions: Despite identification of a lower than expected RR to treatment among the WT KRAS subgroup, KRAS mutation status appeared to be a useful predictive marker of response to Cmab + CPT-11 therapy in Japanese patients with mCRC . Combined analysis of KRAS and BRAF improved both the sensitivity and specificity of the predictive biomarker. However, the combined analysis of all 5 genes did not result in any considerable improvement compared with that achieved with the KRAS and BRAF analysis alone. Clinical trial information: UMIN000001668.