KRAS Status and Efficacy in the First –Line Treatment of Patients with Metastatic Colorectal Cancer (mCRC) Treated with FOLFIRI with or without Cetuximab: The Crystal Experience
Cetuximab is a targeted therapy agent that blocks epidermal growth factor receptor (EGFR) and that is used in the treatment of colon cancers. EGFR has several targets, including one called k-ras. K-ras is a protein that is activated when bound to GTP. GTP can then convert to GDP, which turns off k-ras. However, if k-ras is mutated, it can remain constantly active. So, if the k-ras is mutated, it no longer relies on EGFR to work, and therefore may be less likely to be affected by a therapy that blocks EGFR (i.e. cetuximab). Researchers refer to unmutated k-ras as "wild type", and feel that this wild type may be more responsive to cetuximab.
The CRYSTAL trial (Van Custem E., et al., ASCO Annual Meeting , 2007) was a large, randomized, phase III trial which investigated the use of FOLFIRI (Arm A) versus FOLFIRI plus cetuximab (Arm B) as first-line treatment in EGFR-expressing advanced colorectal cancers. Results demonstrated an increase in both response rate (RR), median progression-free survival (PFS), and curative surgery rates in the arm with cetuximab. This presentation was an analysis of patients in whom k-ras status was available (about half of the original study participants).
Mutated k-ras (MT) was present in 35.6% of these patients and wild type (WT) in 64.4%. Patients with WT k-ras improved with the addition of cetuximab: median* survival was 9.9 months for patients in arm B versus 8.7 months for patients in arm A. Outcomes for patients with mutant k-ras were not affected by the addition of cetuximab: median survival was 7.6 months for arm B versus 8.1 months for arm A.
Response to FOLFIRI was similar for patients with WT and mutant k-ras. The duration of treatment was longer in patients with WT k-ras, likely reflecting their better outcome and longer survival. There was no difference in toxicity seen between patients with WT and those with mutant k-ras. In the original CRYSTAL study, there was more grade 3 or greater toxicity in the cetuximab arm. This held true for patients with WT and mutant k-ras in the present study (both groups had more grade 3 or higher toxicity with cetuximab).
Based on these data, k-ras status should be assayed in patients who are candidates for cetuximab or panitumumab therapy, as it appears that only those with WT k-ras will benefit. This will spare k-ras mutant patients unnecessary toxicity. It is also important to tell patients with k-ras mutation that traditional chemotherapies remain effective. Further development of an easily accessible, reliable assay to determine k-ras status is still necessary to implement these findings on a wide-spread basis.
* The median is the "middle of the pack", where half of the patients have had more years since treatment and half have less. For instance, if the patients were 2, 4, 6, 10.8, 12, 12 and 14 years since treatment, 10.8 is the mid point, or the median. It is different from the mean, which would be the average time since treatment.