Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial

Autor: Andrew B Lassman, Stephanie L Pugh, Tony J C Wang, Kenneth Aldape, Hui K Gan, Matthias Preusser, Michael A Vogelbaum, Erik P Sulman, Minhee Won, Peixin Zhang, Golnaz Moazami, Marian S Macsai, Mark R Gilbert, Earle E Bain, Vincent Blot, Peter J Ansell, Suvajit Samanta, Madan G Kundu, Terri S Armstrong, Jeffrey S Wefel, Clemens Seidel, Filip Y de Vos, Sigmund Hsu, Andrés F Cardona, Giuseppe Lombardi, Dmitry Bentsion, Richard A Peterson, Craig Gedye, Véronique Bourg, Antje Wick, Walter J Curran, Minesh P Mehta
Rok vydání: 2022
Předmět:
Zdroj: Neuro-Oncology. 25:339-350
ISSN: 1523-5866
1522-8517
Popis: Background Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene amplification (EGFR-amp). Preclinical and early-phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody–drug conjugate 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 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 overall survival (OS) at a 2.5% 1-sided significance level (ie traditional two-sided p ≤ 0.05) by log-rank testing. Results There were 639 randomized patients (median age 60, range 22–84; 62% men). Prespecified 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, 1-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% confidence interval [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, 1-sided p = 0.002) or MGMT unmethylated (HR 0.77, 95% CI 0.61–0.97; 1-sided p = 0.012) tumors but without an OS improvement. Corneal epitheliopathy 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.
Databáze: OpenAIRE
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