Efficacy and safety of depatuxizumab mafodotin (ABT-414) in EGFR-amplified glioblastoma: A systematic review and Bayesian network meta-analysis.

Abstract

2060 Background: Glioblastoma (GBM) is a highly aggressive brain tumor with a poor prognosis, typically resulting in a median survival of 12–15 months. Epidermal growth factor receptor (EGFR) alterations, present in half of GBM cases, are key therapeutic targets. Depatuxizumab mafodotin (Depatux-M, ABT-414), an EGFR-targeting antibody-drug conjugate, represents a novel therapeutic option. This Bayesian network meta-analysis assessed the efficacy and safety of Depatux-M in EGFR-amplified GBM. Methods: Eight randomized controlled trials (RCTs) involving 1,183 patients were analyzed. Trials evaluating Depatux-M as monotherapy or combined with temozolomide (TMZ) and/or radiotherapy (RT) were included. Outcomes included overall survival (OS), progression-free survival (PFS), and safety (grade 3/4 adverse events and keratitis). Bayesian models estimated mean differences (MDs) and relative risks (RRs) with 95% credible intervals (CrI), while SUCRA values ranked treatments. Results: Depatux-M plus TMZ showed modest OS improvement over TMZ alone (MD: 0.91 months; 95% CrI: -11.83 to 13.86; SUCRA: 62.09%). Depatux-M monotherapy showed minimal OS benefit (MD: 0.07 months; 95% CrI: -12.69 to 12.95; SUCRA: 51.2%), and the combination of Depatux-M, TMZ, and RT had the lowest OS benefit (MD: -2.17 months; 95% CrI: -19.83 to 15.74; SUCRA: 35.48%). For PFS, Depatux-M monotherapy performed best (MD: 1.46 months; 95% CrI: -4.92 to 7.78; SUCRA: 81.00%), while Depatux-M plus TMZ (MD: -0.45 months; 95% CrI: -6.85 to 5.89; SUCRA: 40.03%) and Depatux-M, TMZ, and RT (MD: -1.54 months; 95% CrI: -10.34 to 7.24; SUCRA: 28.32%) were less effective. Depatux-M monotherapy had a lower RR for grade 3/4 adverse events (RR: 1.38; 95% CrI: 0.23 to 8.07) and keratitis (RR: 2.62; 95% CrI: 0.43 to 15.63) compared to combination regimens, with the highest keratitis risks observed in Depatux-M, TMZ, and RT. Conclusions: Depatuxizumab mafodotin offers limited survival benefits in EGFR-amplified GBM, with monotherapy showing the most favorable PFS. However, significant safety concerns, particularly keratitis, warrant further research to optimize its therapeutic potential and identify more tolerable regimens. Efficacy and safety outcomes of depatuxizumab mafodotin in EGFR-amplified glioblastoma. Regimen Overall Survival (OS) Progression-Free Survival (PFS) Grade 3/4 Adverse Events (RR) Keratitis (RR) Depatux-M + TMZ 0.91 (-11.83 to 13.86); SUCRA 62.09 -0.45 (-6.85 to 5.89); SUCRA 40.03 1.54 (0.20 to 13.53); SUCRA 41.75 4.40 (0.51 to 31.10); SUCRA 33.07 Depatux-M 0.07 (-12.69 to 12.95); SUCRA 51.20 1.46 (-4.92 to 7.78); SUCRA 81.00 1.38 (0.23 to 8.07); SUCRA 49.06 2.62 (0.43 to 15.63); SUCRA 62.34 Depatux-M + TMZ + RT -2.17 (-19.83 to 15.74); SUCRA 35.48 -1.54 (-10.34 to 7.24); SUCRA 28.32 0.98 (0.09 to 9.65); SUCRA 68.37 6.63 (0.62 to 66.40); SUCRA 12.73