Anti-EGFR-based maintenance versus stop and go in patients with left-sided, non-MSI-H, RAS/BRAF-wt metastatic colorectal cancer: individual patient data pooled analysis

BACKGROUND: Doublet chemotherapy plus an anti- epidermal growth factor receptor (EGFR) agent is a standard of care in patients with left-sided, microsatellite stable, RAS/BRAF wild-type (wt) mCRC. No conclusive evidence is available to guide treatment de-escalation, but several randomized clinical trials investigated either maintenance or intermittent treatment schedules (stop and go). PATIENTS AND METHODS: We performed an individual patient data pooled analysis of four multicenter, randomized phase II trials (PanaMa, Valentino, PRODIGE-28 TIME, IMPROVE). Only patients with left-sided, non-microsatellite instability-high, RAS/BRAFV600E-wt who started the protocol-planned post-induction treatment were included and stratified into three treatment groups: maintenance with 5-fluorouracil/leucovorin (5-FU/LV) plus anti-EGFR, maintenance with anti-EGFR alone, or stop and go. The primary endpoint was overall survival (OS) with stop and go versus 5-FU/LV plus anti-EGFR maintenance. Secondary endpoints were progression-free survival (PFS) and time to failure of strategy (TFS) with stop and go versus 5-FU/LV plus anti-EGFR; and OS, PFS, and TFS with stop and go versus anti-EGFR alone. RESULTS: A total of 378 molecularly selected left-sided patients were included. Overall, 166, 109, and 103 patients received maintenance with 5-FU/LV plus anti-EGFR, anti-EGFR alone, or stop and go, respectively. No significant differences in OS were reported between stop and go versus 5-FU/LV plus anti-EGFR maintenance [median 26.3 versus 29.7 months, hazard ratio (HR) 1.24, P = 0.530], or stop and go compared with anti-EGFR alone (median 26.3 versus 30.1 months, HR 1.39, P = 0.165). PFS was significantly shorter with stop and go, while TFS was comparable between stop and go compared with both maintenance schedules. CONCLUSIONS: This pooled analysis of candidates considered optimal for initial anti-EGFR-based therapy supports both stop and go and maintenance as de-intensification strategies to consider in shared decision making. Adequately powered phase III studies are advocated to compare the two strategies.