Article: Safety and Efficacy of Crizotinib in Combination with Temozolomide and Radiotherapy in Patients with Newly Diagnosed Glioblastoma: Phase Ib GEINO 1402 Trial.
2022 Volume 14, Issue 10
Abstract: 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.: ... ...
| Abstract | 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. |
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| Language | English |
| Publishing date | 2022-05-12 |
| Publishing country | Switzerland |
| Document type | Journal Article |
| ZDB-ID | 2527080-1 |
| ISSN | 2072-6694 |
| ISSN | 2072-6694 |
| DOI | 10.3390/cancers14102393 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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