Combination of oral fluoropyrimidines and EGFR-directed antibodies in frail patients with metastatic colorectal cancer: a systematic review

Background Evidence of treatment strategies in frail patients (i.e. not fit for combination therapies) with unresectable metastatic colorectal cancer (mCRC) is limited to dose-reduced doublet regimens or oral fluoropyrimidines (FP) with bevacizumab. We conducted a systematic review analyzing evidence for oral FPs with epidermal growth factor receptor (EGFR)-directed monoclonal antibodies for patients with RAS wild-type (WT) mCRC across treatment lines. Methods We searched PubMed and Cochrane Library for phase II and phase III studies evaluating oral FPs (capecitabine, S-1 or trifluridine/tipiracil (FTD/TPI)) plus EGFR-directed monoclonal antibody (panitumumab or cetuximab) in mCRC. Outcomes included efficacy and safety. Results Seven publications met inclusion criteria (n = 262 patients). First-line data was limited to elderly cohorts receiving capecitabine plus cetuximab or panitumumab with a median progression-free survival (PFS)/median overall survival (OS) of 7.2/17.1 months (cetuximab) and 7.5/23.7 months (panitumumab), respectively. In third-line and beyond, median PFS for the combination of FTD/TPI plus cetuximab or panitumumab ranged from 2.4 (cetuximab) to 5.8 months (panitumumab), and OS from 9.8 (cetuximab) to 14.2 months (panitumumab). S-1 plus cetuximab was associated with a median PFS of 5.5 months and OS of 13.6 months. Conclusion While capecitabine should not be used together with anti-EGFR antibodies, FTD/TPI in combination with an EGFR-directed antibody appears feasible, shows promising activity and manageable toxicity profile in RAS WT mCRC potentially offering an alternative for frail patients; prospective trials are needed.