Safety and Efficacy of Crizotinib in Combination with Temozolomide and Radiotherapy in Patients with Newly Diagnosed Glioblastoma: Phase Ib GEINO 1402 Trial

Cancers

Elena Tovar Ambel¹  Guillermo Velasco¹  Israel López-Valero¹  Juan Manuel Sepúlveda-Sánchez²  Mari Cruz Martín-Soberón²  Álvaro Taus³  María Martínez-García³  Montserrat Arumi⁴  Miguel Gil-Gil⁴  Aurelio Hernández-Laín⁵  Francesc Alameda⁶  Palmira Foro⁷  Jaume Capellades⁸  Estela Pineda⁹ 

[1] Biochemistry and Molecular Biology Department, School of Biology, Complutense University, 28040 Madrid, Spain;Medical Oncology Department, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain;Medical Oncology Department, Hospital del Mar, 08003 Barcelona, Spain;Medical Oncology Department, Institut Català d’Oncologia L’Hospitalet, 08908 L’Hospitalet de Llobregat, Spain;Pathology Department (Neuropathology), Hospital 12 de Octubre Research Institute (imas12), 28041 Madrid, Spain;Pathology Department, Hospital del Mar, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain;Radiation Oncology Department, Hospital del Mar, 08003 Barcelona, Spain;Radiology Department, Hospital del Mar, 08003 Barcelona, Spain;Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Medical Oncology Department, Hospital Clínic, 08036 Barcelona, Spain;

关键词: glioblastoma;    crizotinib;    temozolomide;    radiotherapy;    midkine;   

DOI  :  10.3390/cancers14102393

来源: DOAJ

【 摘 要 】

Background: MET-signaling and midkine (ALK ligand) promote glioma cell maintenance and resistance against anticancer therapies. ALK and c-MET inhibition with crizotinib have a preclinical therapeutic rationale to be tested in newly diagnosed GBM. Methods: Eligible patients received crizotinib with standard radiotherapy (RT)/temozolomide (TMZ) followed by maintenance with crizotinib. The primary objective was to determine the recommended phase 2 dose (RP2D) in a 3 + 3 dose escalation (DE) strategy and safety evaluation in the expansion cohort (EC). Secondary objectives included progression-free (PFS) and overall survival (OS) and exploratory biomarker analysis. Results: The study enrolled 38 patients. The median age was 52 years (33–76), 44% were male, 44% were MGMT methylated, and three patients had IDH1/2 mutation. In DE, DLTs were reported in 1/6 in the second cohort (250 mg/QD), declaring 250 mg/QD of crizotinib as the RP2D for the EC. In the EC, 9/25 patients (32%) presented grade ≥3 adverse events. The median follow up was 18.7 months (m) and the median PFS was 10.7 m (95% CI, 7.7–13.8), with a 6 m PFS and 12 m PFS of 71.5% and 38.8%, respectively. At the time of this analysis, 1 died without progression and 24 had progressed. The median OS was 22.6 m (95% CI, 14.1–31.1) with a 24 m OS of 44.5%. Molecular biomarkers showed no correlation with efficacy. Conclusions: The addition of crizotinib to standard RT and TMZ for newly diagnosed GBM was safe and the efficacy was encouraging, warranting prospective validation in an adequately powered, randomized controlled study.

【 授权许可】

Unknown