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

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.

Cyanine Dye Conjugation Enhances Crizotinib Localization to Intracranial Tumors, Attenuating NF-κB-Inducing Kinase Activity and Glioma Progression

“…Crizotinib, a potent inhibitor of the receptor tyrosine kinase MET and anaplastic lymphoma kinase (ALK), , has demonstrable antitumor efficacy in mouse xenografts and shows great promise in clinical trials of patients with cancers harboring ALK rearrangements. In GBM patients, Crizotinib has exhibited potential as an adjuvant therapy in addition to radiation and temozolomide in newly diagnosed GBM patients but has limited efficacy on its own, likely due to its poor BBB permeability. A recent report demonstrated that the conjugation of Crizotinib to the infrared cyanine dye 786 (referred to as IR-Criz) resulted in increased cellular uptake and inhibition of cell viability in vitro in U87 GBM cells .…”

The Spectrum of Molecular Pathways in Gliomas—An Up-to-Date Review

“…These studies include those investigating new therapeutics that act against targets that have been studied multiple times in the past, such as the epidermal growth factor receptor EGFR [ 180 ]. Most of these recent studies are still at the phase I or II stage, but in several studies, there is already evidence of an objective clinical response with prolonged overall survival or even partial or complete remissions in some patients [ 181 , 182 , 183 ]. Another promising finding is that in two studies, molecular combination therapies against more than one target were well tolerated by patients, indicating a realistic perspective on using molecular combination therapies in patients with gliomas [ 179 , 182 ].…”

“…Another promising finding is that in two studies, molecular combination therapies against more than one target were well tolerated by patients, indicating a realistic perspective on using molecular combination therapies in patients with gliomas [ 179 , 182 ]. Therefore, all these recent studies show that continued molecular and clinical research is worthwhile to arrive at clinically applicable forms of targeted therapy [ 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 ] ( Table 2 ). In summary, the review of the spectrum of molecular pathways in gliomas provides insight into two recent aspects that should be highlighted, namely, the increasing evidence of distinct pathway interconnectivity and even the finding of a prominent role of noncoding RNAs (ncRNAs) in the regulation of all molecular pathways that have a direct impact on the biological behavior of gliomas in vitro and in vivo.…”

Small Molecule Tyrosine Kinase Inhibitors (TKIs) for Glioblastoma Treatment

“…Recently, crizotinib in combination with TMZ and standard radiotherapy showed a tolerable safety profile and promising efficacy as a first-line therapy for GBM patients [37].…”