Triplet chemotherapy combined with anti Epidermal Growth Factor Receptor treatment in RAS wild-type colorectal cancer: a network metanalysis

BACKGROUND The optimal first-line treatment for RASwild-type metastatic colorectal cancer remains undetermined. Several studies have compared the efficacy of different first-line regimens, including doublet- or triplet-chemotherapy(CT) alone or in combination with targeted therapies (anti-EGFR/anti-VEGF), without conclusive results.

METHODS We conducted a systematic review and meta-analysis of phase II/III randomized clinical trials(RCT) comparing triplet-CT+anti-EGFRs with alternative first-line regimens in RASwild-type patients. Pairwise- and network-meta-analyses were performed to assess ORR. Furthermore, we evaluated PFS and OS with pairwise-metanalyses.

RESULTS A total of 1,283 patients across seven RCT were included. Four treatment arms were analyzed: Arm A (triplet-CT+anti-EGFR), Arm B (doublet-CT+anti-EGFR), Arm C (triplet alone), and Arm D (triplet+anti-VEGF). Arms A, B e D demonstrated higher ORR compared to Arm C, while no significant differences were found among Arms A, B, and D (OR 1.05, 95% CI 0.73-1.49; p = 0.804, for Arm B in comparison to Arm A; OR 0.80, 95% CI 0.52-1.25; p = 0.328, for Arm D in comparison to Arm A). Pairwise-meta-analysis revealed significantly lower ORR for Arm C compared to Arm A (OR 4.23,95% CI 2.06-8.68, p = 0.002). P-scores ranked Arm B highest for effectiveness (0.808), followed by Arm A (0.746), then Arm D (0.444) and lastly Arm C (0.002) The pooled HR for OS demonstrated a superiority for arm A (0.82, 95% CI 0.70-0.97, p = 0.022).

CONCLUSIONS Triplet-CT+anti-EGFR demonstrated no clear ORR advantage over other targeted regimens but was superior to triplet-CT alone. Preliminary data indicate a potential OS benefit. Due to increased toxicity, routine use of triplet-CT+anti-EGFR should be carefully evaluated.