Relevance of liver‐limited disease in metastatic colorectal cancer: Subgroup findings of the FIRE‐3/AIO KRK0306 trial

In metastatic colorectal cancer (mCRC), liver-limited disease (LLD) is associated with a higher chance of metastectomy leading to long-term survival. However, limited data describes the prognostic and predictive relevance of initially unresectable LLD with regard to targeted first-line therapy. The present analysis investigated the relevance of initially unresectable LLD in mCRC patients treated with targeted therapyagainst either the epidermal growth factor receptor (EGFR) or vascular epithelial growth factor (VEGF). The analysis was performed based on FIRE-3, a randomized phase III trial comparing first-line chemotherapy with FOLFIRIplus either cetuximab(anti-EGFR) or bevacizumab(anti-VEGF) in RAS wild-type (WT) mCRC. Of 400 patients, 133 (33.3%) had LLD and 267 (66.8%) had non-LLD. Median overall survival (OS) was significantly longer in LLD compared to non-LLD patients (36.0 vs. 25.4 months; hazard ratio HR = 0.66; 95{\%} confidence interval CI: 0.51-0.87; p = 0.002). In a multivariate analysis also including secondary hepatic resection as time-dependent variable, LLD status was independently prognostic for OS (HR = 0.67; 95{\%} CI: 0.50-0.91; p = 0.01). As assessed by interaction tests, treatment benefit from FOLFIRIplus cetuximabcompared to FOLFIRIplus bevacizumabwas independent of LLD status with regard to objective response rate (ORR), early tumour shrinkage ≥20{\%} (ETS), depth of response (DpR) and OS (all p > 0.05). In conclusion, LLD could be identified as a prognostic factor in RAS-WT mCRC, which was independent of hepatic resection in patients treated with targeted therapy. LLD had no predictive relevance since benefit from FOLFIRIplus cetuximabover bevacizumabwas independent of LLD status.