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

Abstract

2 Background: Efficacy analyses of the randomized phase III CRYSTAL trial have shown a significant improvement in progression-free survival (PFS), overall response, and curative surgery rate when adding cetuximab to FOLFIRI in the first-line treatment of mCRC. Furthermore, KRAS mutation status has recently been shown to relate to outcome in mCRC patients (pts) treated with cetuximab as a single agent or in combination with irinotecan. Efficacy analyses have been repeated to evaluate the influence of KRAS mutation status in first-line pts treated with FOLFIRI with or without cetuximab under controlled study conditions. Methods: Blocks from archived tumor material were available from 587 of 1198 of the total pt population. Isolation of genomic DNA was performed directly from slides (3×10 μm). Determination was done by qPCR-based KRAS mutation analysis of codons 12/13. The KRAS-evaluable pts (n=540) were analyzed statistically to evaluate treatment effect stratified by KRAS mutation status (wild-type [wt] or mutation [mt]) and the given randomization strata using Cox regression for PFS time (primary IRC evaluation) and the CMH test for best overall response. Results: The population with available tissue for KRAS analysis was representative of the overall ITT population. KRAS mt were detected in 35.6% (192/540) of pts with evaluable samples. A statistically significant difference in favor of cetuximab was seen in KRAS wt pts for PFS (p=0.0167; hazard ratio [HR] estimate 0.68 [95% CI: 0.051–0.934]) and best overall response (59.3% [cetuximab + FOLFIRI] vs 43.2% [FOLFIRI], p=0.0025). Subgroup analyses by KRAS mt status for cetuximab + FOLFIRI vs FOLFIRI showed no significant differences between treatment groups for PFS (p=0.75; HR estimate 1.07 [95% CI: 0.71–1.61]) or best overall response (p=0.46). Conclusions: This large analysis shows the predictive value of KRAS mutation status for treatment with cetuximab plus FOLFIRI in the first-line treatment of mCRC. The data demonstrate that treatment effect of cetuximab in pts with KRAS wt is significantly enhanced compared with standard chemotherapy alone, whereas pts with KRAS mt could not be shown to benefit from cetuximab treatment. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck Merck Merck Merck