Abstract
Background
Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor
EGFR gene amplification (
EGFR-amp). Preclinical and early phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody drug conjugate (ADC) comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule-inhibitor toxin in
EGFR-amp GBMs.
Methods
In this phase III trial, adults with centrally confirmed,
EGFR-amp, newly diagnosed GBM were randomized 1:1 to radiotherapy, temozolomide, and depatux-m/placebo. Corneal epitheliopathy (CE) was treated with a combination of protocol-specified prophylactic and supportive measures. There was 85% power to detect a Hazard Ratio (HR) ≤0.75 for survival (OS) at a 2.5% one-sided significance level (i.e., traditional two-sided p ≤0.05) by log-rank testing.
Results
There were 639 randomized patients (median age 60, range 22-84; 62% men). Pre-specified interim analysis found no improvement in OS for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.02, 95% CI 0.82-1.26, one-sided p= 0.63). Progression-free survival was longer for depatux-m than placebo (median 8.0 vs. 6.3 months; HR 0.84, 95% CI 0.70-1.01, p=0.029), particularly among those with
EGFRvIII mutant (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56-0.93, p=0.002 one sided) or
MGMT unmethylated (HR 0.77, 95% CI 0.61-0.97; p=0.012 one-sided) tumors but without an OS improvement. CE occurred in 94% of depatux-m treated patients (61% grade 3-4), causing 12% to discontinue.
Conclusions
Interim analysis demonstrated no OS benefit for depatux-m in treating
EGFR-amp newly diagnosed GBM. No new important safety risks were identified.
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