Correlation of KRAS status (wild type [wt] vs. mutant [mt]) with efficacy to first-line cetuximab in a study of cetuximab single agent followed by cetuximab + FOLFIRI in patients (pts) with metastatic colorectal cancer (mCRC).

4129 Background: KRAS mutation status predicts sensitivity to anti-epidermal growth factor receptor (EGFR) agents in pts with refractory mCRC. In order to assess the efficacy of cetuximab alone and in combination with chemotherapy in the first-line setting, we have analyzed the KRAS mutation status in EGFR-expressing mCRC pts participating in a clinical trial comparing weekly versus bi-weekly administration of cetuximab (Tabernero et al. Proc ASCO 2006). Cetuximab was administered as a first-line single agent for 6 weeks, pts were assessed for response and then FOLFIRI chemotherapy was added to all pts. KRAS mutation status was determined in archived tumor material and its correlation with efficacy parameters evaluated.,Blocks of archived tumor material from 50 pts and paraffin- embedded slide sets from 2 pts were assessed for KRAS mutation analysis eligibility. Genomic DNA was isolated from slides with no prior macrodissection. The KRAS mutation status of codons 12/13 was determined by a highly sensitive quantitative polymerase chain reaction- based assay. Independent histopathologic evaluation revealed that 48/52 samples contained tumor tissue. All 48 pts were fully evaluable for efficacy. Response rate (RR) at end of monotherapy, overall RR during the combination phase (cetuximab + FOLFIRI), and progression-free survival (PFS) time for the 48 pts were determined and correlated with the KRAS status of these pts.,KRAS mutations were detected in 19 samples (40%) from the KRAS evaluable population. At the end of the monotherapy phase, RR was 27.6% for the KRAS wt population and 0% for the KRAS mt population (p=0.015). During the combination phase this RR increased to 55.2% vs 31.6%, respectively (p=0.144). PFS for cetuximab + FOLFIRI was significantly improved (hazard ratio: 0.47, p=0.0475) for KRAS wt pts vs KRAS mt pts.,KRAS mutation status determines efficacy to cetuximab in the first-line setting of pts with mCRC either alone or when subsequently combined with FOLFIRI. Our findings support that KRAS mutation status should be considered in the choice of therapy in the first- line setting of pts with mCRC. [Table: see text].