Maintenance strategies after anti–EGFR-based induction in RAS wild-type (wt) metastatic colorectal cancer (mCRC): A systematic review and Bayesian network meta-analysis.
Authors: Mastrantoni Luca , Beccia Viria , Caira Giulia , Trovato Giovanni , Calegari Maria Alessandra , Basso Michele , Salvatore Lisa , Tortora Giampaolo , Bria Emilio , Orlandi Armando 
Published: January 2023

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Background: In RAS wt mCRC the use of maintenance therapy after induction with fluoropyrimidine (FP)-based cytotoxic therapy (CT) plus anti-EGFR agents is controversial. Herein, we conducted a systematic review and network meta-analysis to compare different maintenance strategies. Methods: PubMed, CENTRAL, Embase and oncological meeting websites were screened to identify eligible studies. Phase II-III randomized trials which enrolled patients with previously untreated RAS wt mCRC, who switched to a maintenance strategy after an induction of CT combined with an anti-EGFR agent were included. Maintenance strategies considered were: observation, single agent anti-EGFR or FP, FP + anti-EGFR, doublet CT + anti-EGFR. Outcomes were progression-free survival (PFS), overall survival (OS) and safety (grade 3-4 adverse events). Subgroup analyses were performed in BRAF wt patients and left sided tumors. The meta-analysis was conducted using a random-effects model. A Markov Chain Monte Carlo simulation was used to estimate the posterior distributions. Strategies were ranked using the surface under the cumulative ranking (SUCRA) probabilities. Risk of bias was assessed with Cochrane Risk of Bias Tool. Results: Overall, 4207 records were screened and 10 trials were included in the analysis. Cumulative risk of bias was low-moderate. Maintenance therapy with FP + anti-EGFR (HR 0.56, 95% CrI 0.36-0.88) and doublet CT + anti-EGFR (HR 0.68, 95% CrI 0.46-1.01), showed the greatest PFS benefit compared to observation. On SUCRA analysis, FU + anti-EGFR had the highest likelihood of improving PFS (96.3%), compared to doublet CT + anti-EGFR (73.5%) or EGFR monotherapy (48.0%). In terms of OS, compared to observation, maintenance therapy with doublet CT + anti-EGFR (HR 0.51, 95% CrI 0.19-1.28), FU + anti-EGFR (HR 0.59, 95% CrI 0.19-1.68) or anti-EGFR monotherapy (HR 0.56, 95% CrI 0.24-1.34) yielded similar results. On SUCRA analysis probabilities were 78.3% with doublet CT + anti-EGFR, 64.5% with FP + anti-EGFR and 63.4% with anti-EGFR monotherapy. FP + anti-EGFR confirmed to be the best option in terms of PFS in BRAF wt patients (SUCRA: 96.3%) and left sided tumors (SUCRA: 89.6%). OS results in BRAF wt patients were consistent with the primary analysis. In left sided tumors, the OS benefit of adding CT seems limited compared to EGFR monotherapy. The addition of CT to anti-EGFR agents resulted in an increase of toxicity while FP monotherapy plus anti-EGFR showed a favourable safety profile compared to doublet CT + anti-EGFR. Conclusions: FP + anti-EGFR should be considered the best maintenance option in RAS wt mCRC in terms of PFS. Taking into account the similar OS performance of the different strategies, EGFR monotherapy could be considered, especially in left-sided tumors. Doublet CT + anti-EGFR, despite being effective, is limited by toxicities.