ACTR-46. AG-120, A FIRST-IN-class MUTANT IDH1 INHIBITOR IN PATIENTS WITH RECURRENT OR PROGRESSIVE IDH1 MUTANT GLIOMA: UPDATED RESULTS FROM THE PHASE 1 NON-ENHANCING GLIOMA POPULATION

Abstract

INTRODUCTION: Isocitrate dehydrogenase 1/2 (IDH1/2) mutations occur in >70% of low-grade gliomas (LGG) and lead to an altered metabolic state associated with production of D-2-hydroxyglutarate (2-HG), resulting in genetic/epigenetic dysregulation and oncogenesis. AG-120 is a potent oral inhibitor of mutant IDH1 (mIDH1) under clinical evaluation in an ongoing phase 1 study that treated 66 pretreated (median 2 prior systemic therapies) glioma patients in dose escalation and expansion cohorts. Safety and preliminary results were presented previously (SNO2016). We present updated results from the non-enhancing glioma patient population. METHODS: Key eligibility: mIDH1 recurrent or progressive disease, ECOG 0-1, no surgery/ radiation within 6 months. MRI response was assessed every 8 weeks using RANO and LGG-RANO criteria by local and independent central review. Exploratory analyses: change in tumor growth rate (FLAIR tumor volume, non-enhancing glioma expansion cohort) and pharmacodynamic evaluations of tissue and serum. RESULTS: As of 10March2017, 35 patients with non-enhancing glioma were enrolled in dose escalation (n=11) and expansion (n=24), and 51% (n=18) remain on AG-120. M/F 23/12, median age 38 years, 1p19q intact in 54% (n=19) of patients, 74% reported anticonvulsant use. Frequent (≥5 patients) adverse events (AEs) grade 1-2: diarrhea (26%), headache (26%), nausea (20%), anemia (17%), neutrophil decrease (17%), and vomiting (17%). 7 (20%) patients experienced a grade 3-4 AE (hypophosphatemia most frequent, n=2, unrelated), with no dose reduction due to AEs. 73% and 88% of patients achieved stable disease as best response in the dose escalation (RANO) and expansion (LGG-RANO) cohorts, respectively. Median duration on AG-120 was 14.7 months (range 1.4-25.0); 63% remained on AG-120 for ≥1 year. Updated safety, response, and exploratory imaging analyses will be presented. CONCLUSIONS: AG-120 monotherapy is associated with a favorable safety profile and prolonged stable disease in a previously treated non-enhancing mIDH1 glioma patient population, and warrants further clinical evaluation.