Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I Trial

Abstract

Purpose: Lower-grade gliomas (LGGs) are malignant tumors in young adults. Current therapy is associated with short-and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1/IDH2).Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes. Experimental Design:We conducted a multicenter, open-label, phase I, dose escalation study of vorasidenib in 93 patients with mutant IDH1/2 (mIDH1/2) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154.Results: Vorasidenib showed a favorable safety profile in the glioma cohort. Doselimiting toxicities of elevated transaminases occurred at doses >100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG (RANO-LGG) in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2-40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients.Research.

Precision Oncology in Lower-Grade Gliomas: Promises and Pitfalls of Therapeutic Strategies Targeting IDH-Mutations

“…Though MTD/RP2D was not reached according to the Bayesian model adopted, the clinical team recommended no further escalation beyond 300 mg and thus to proceed with doses <100 mg in glioma patients [41]. All-grade TRAEs were reported in 38 (73.1%) patients with glioma, including 4 of grade ≥3; 2 (3.8%) patients discontinued treatment due to AEs, and 7 (13.5%) required a dose reduction due to AEs [41]. In the non-enhancing glioma group (n = 22), the overall response rate (ORR) was 18% (1 PR, three minor responses), while 17 (72.7%) patients had SD as the best response [41].…”

Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer

“…The IDH1 and IDH2 dual inhibitor AG-881 has also been shown to cross the blood-brain barrier. Recently, the results of a phase I clinical trial (NCT02481154) (Table 2) of AG-881 for low-grade gliomas demonstrated that it is safe and can shrink tumors in many non-enhanced glioma patients (Mellinghoff et al, 2021).…”

IDH1/2 Mutations in Cancer Stem Cells and Their Implications for Differentiation Therapy

“…Vorasidenib inhibits both mtIDH1 and mtIDH2 at nanomolar concentrations 80 and is currently under investigation for IDH1/2mt glioma. 32 Its dual mtIDH1/2 inhibition will likely reduce the possibility for IDH1/2mt cells to escape mtIDH1/2 inhibition via isoform switching. In addition, a novel type of inhibitor that is in preclinical testing does not target the allosteric site, but instead binds the active site of mtIDH1, 81 thereby decreasing the possibility for IDH1/2mt to restore their D-2-HG production via a second-site mutation at the allosteric site.…”

“…23 These small-molecule inhibitors effectively reduce the production of D-2-HG by mtIDH1/2 and are also known as sidenibs. 24,25 Examples include the mtIDH1 inhibitor ivosidenib, which is Food and Drug Administration (FDA)approved for the treatment of IDH1mt newly diagnosed (ND), refractory or relapsed (R/R) AML and IDH1mt previously treated, locally advanced, or metastatic cholangiocarcinoma [26][27][28][29] ; the mtIDH2 inhibitor enasidenib, which is FDA-approved for the treatment of IDH2mt R/R AML 30,31 ; the dual mtIDH1/2 inhibitor vorasidenib, which is being investigated for IDH1/2mt recurrent or progressive glioma 32 ; and various other mtIDH1/2 inhibitors that are still in clinical trials. 33 In addition to the aforementioned indications, ivosidenib is currently being investigated for the treatment of IDH1mt glioma and chondrosarcoma in early-phase clinical trials 34,35 and enasidenib is studied in IDH2mt MDS.…”