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Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR-amplified, recurrent glioblastoma: results from an international phase I multicenter trial

BACKGROUND: Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody–drug conjugate depatuxizu...

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Detalles Bibliográficos
Autores principales: Lassman, Andrew B, van den Bent, Martin J, Gan, Hui K, Reardon, David A, Kumthekar, Priya, Butowski, Nicholas, Lwin, Zarnie, Mikkelsen, Tom, Nabors, Louis B, Papadopoulos, Kyriakos P, Penas-Prado, Marta, Simes, John, Wheeler, Helen, Walbert, Tobias, Scott, Andrew M, Gomez, Erica, Lee, Ho-Jin, Roberts-Rapp, Lisa, Xiong, Hao, Ansell, Peter J, Bain, Earle, Holen, Kyle D, Maag, David, Merrell, Ryan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303422/
https://www.ncbi.nlm.nih.gov/pubmed/29982805
http://dx.doi.org/10.1093/neuonc/noy091
Descripción
Sumario:BACKGROUND: Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody–drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM. METHODS: M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5–1.5 mg/kg) on days 1 and 15, and TMZ (150–200 mg/m(2)) on days 1–5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve. RESULTS: There were 60 patients, median age 56 years (range, 20–79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%. CONCLUSIONS: Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).