IDH1 Inhibition Emerging as Viable Option for Glioma

IDH1-mutated glioma across a variety of doses, in a phase I study presented at the 2016 Society for Neuro-Oncology (SNO) Annual Meeting.

Across all efficacy-evaluable patients withIDH1-mutant glioma treated in the open-label study (n = 65), 2 had a minor response (3%; 95% CI, 0.4-10.7), 41 had stable disease (63%), and 20 had progressive disease (31%).

“AG-120 is well tolerated and 42% of patients remained on AG-120 as of data cut-off,” said presenter Ingo K. Mellinghoff, MD, Vice Chair for Research in the Department of Neurology and Evnin Family Chair in Neuro-Oncology at the Memorial Sloan Kettering Cancer Center in New York, New York. “AG-120 has the potential to help a large number of patients withIDH1mutations.”

About 80% of WHO grade II/III gliomas and up to 5% of glioblastomas have mutations inIDH1.These mutations result in an altered metabolic state, in which production of 2-hydroxyglutarte (2-HG) is increased. This increased 2-HG production dysregulates genetic and epigenetic processes, leading to oncogenesis. Inhibition of IDH1 reduces 2-HG in preclinical models and tumor growth in the xenograft TS603 glioma model.

In the dose-escalation arm of the phase I study, AG-120 was administered orally once daily over a 28-day cycle at doses ranging from 200 mg to 1200 mg. The dose escalation cohort enrolled 20 patients withIDH1-mutant glioma that had recurred, progressed, or did not respond to standard therapy. A steady-state plasma concentration of AG-120 was achieved in the first cycle of treatment, and plasma exposure above 500 mg daily dosing was not proportional. Based on observed clinical activity, safety, and pharmacokinetic/pharmacodynamic data, 500 mg of AG-120 daily was selected for the expansion.

An additional 46 patients were enrolled into the expansion cohort. In cohort 1 of the expansion arm, patients had non-enhancingIDH1-mutant glioma (n = 24) and had not received tumor resection or radiotherapy within 6 months of enrollment. These patients had 3 or more prior full sets of scan and had progressed within 12 months of enrollment. In cohort 2, labeled a basket cohort, patients had enhancing glioma (n = 22) that was progressive andIDH1-mutant but did not meet other criteria for cohort 1.

The median age across all enrolled patients (N = 66) was 41 years (range, 21-71). Patients had astrocytoma (29%), oligoastrocytoma (18%), glioblastoma (18%), oligodendroglioma (15%). Co-deletion of 1p19q occurred in 17 patients (31% of those tested), and the ATRX mutation was present in 24 patients (92% of those tested). The enrolled patients had received a median of 2 prior systemic therapies (range, 1-6), primarily temozolomide (71%). Prior radiotherapy was received by 49 patients (74%).

In 23 efficacy-evaluable patients with non-enhancing glioma treated at the recommended phase II dose of the AG-120, 2 had minor responses (9%; 95% CI, 1.1-28.0), 19 had stable disease (83%), and 2 had progressive disease (9%). The median duration of treatment was 8.1 months (range, 1.4-17.8). Response data were not yet available for the enhancing cohort. At the time of the analysis, the median duration of treatment was just 1.9 months (range, 0.4-10.4).

Across the full study, baseline plasma levels of 2-HG were not elevated above those of healthy volunteers. After treatment with AG-120, levels of 2-HG were decreased by 95% in 2 patients at day 15 of cycle 1 (P<.01 vs baseline) and 25 patients had this reduction after day 1 of cycle 2 (P<.001 vs baseline).

Exploratory imaging to measure the effects of AG-120 on tumor growth rates was explored in the non-enhancing glioma expansion cohort. A total of 174 MRI scans were examined, including 63 historical scans (2 of the 24 patients lacked historical scans) and 111 MRIs done on protocol. Tumor slope was determined to be stable or decreased by volumetric analysis in 14 of 22 patients (64%) and by bidimensional analysis in 12 of 22 (55%). Mellinghoff commented that volumetric analysis requires further development as a response evaluation tool.

&ldquo;The SNO presentation is the first look at data for AG-120 in a defined cohort of glioma patients, where we evaluated the potential for volumetric analyses to improve our understanding of the response patterns beyond the conventional bi-dimensional methods,&rdquo; Mellinghoff said. &ldquo;This methodology could be instrumental in developing more effective, targeted therapies for patients with this disease.&rdquo;

As of August 1, 2016, 28 of 66 patients (42%) remained on treatment. The reasons for the 38 discontinuations were progressive disease (n = 34), physician decision (n = 3), and adverse events (n = 1). No dose-limiting toxicities were observed and no on-treatment deaths occurred.

The maximum tolerated dose was not reached. At least 1 serious treatment-emergent adverse event was experienced by 11 of the 66 patients (17%), and all were deemed unrelated to treatment. Adverse events of any grade were experienced by 62 patients (94%), and grade 3 or higher adverse events were experienced by 14 patients (21%).

Further evaluation of inhibitors of IDH in glioma is warranted, based on these results. Mellinghoff stated that the brain-penetrant pan-IDH inhibitor AG-881 is under phase I investigation in patients with gliomas or other solid tumors with mutatedIDH1or&nbsp;IDH2. The primary endpoint of this study is focused on safety and tolerability (NCT02481154).

Mellinghoff IK, Tauat M, Maher E, et al. AG120, a first-in-class mutant IDH1 inhibitor in patients with recurrent or progressive IDH1 mutant glioma: results from the phase 1 glioma expansion cohorts.Neuro-Oncology. 2016; 18: abstract ACTR-46.