Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Safety and Clinical Activity in Patients With Advanced Chondrosarcoma

Abstract

Purpose: Surgery is the primary therapy for localized chondrosarcoma; for locally advanced and/or metastatic disease, no known effective systemic therapy exists. Mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) enzymes occur in up to 65% of chondrosarcomas, resulting in accumulation of the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (AG-120) is a selective inhibitor of mutant IDH1 approved in the United States for specific cases of acute myeloid leukemia. We report outcomes of patients with advanced chondrosarcoma in an ongoing study exploring ivosidenib treatment.

Patients and methods: This phase I multicenter open-label dose-escalation and expansion study of ivosidenib monotherapy enrolled patients with mutant IDH1 advanced solid tumors, including chondrosarcoma. Ivosidenib was administered orally (100 mg twice daily to 1,200 mg once daily) in continuous 28-day cycles. Responses were assessed every other cycle using RECIST (version 1.1).

Results: Twenty-one patients (escalation, n = 12; expansion, n = 9) with advanced chondrosarcoma received ivosidenib (women, n = 8; median age, 55 years; range, 30-88 years; 11 had received prior systemic therapy). Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. Twelve patients experienced grade ≥ 3 AEs; only one event was judged treatment related (hypophosphatemia, n = 1). Plasma 2-HG levels decreased substantially in all patients (range, 14%-94.2%), to levels seen in healthy individuals. Median progression-free survival (PFS) was 5.6 months (95% CI, 1.9 to 7.4 months); the PFS rate at 6 months was 39.5%. Eleven (52%) of 21 patients experienced stable disease.

Conclusion: In patients with chondrosarcoma, ivosidenib showed minimal toxicity, substantial 2-HG reduction, and durable disease control. Future studies of ivosidenib monotherapy or rational combination approaches should be considered in patients with advanced mutant IDH1 chondrosarcoma.

Trial registration: ClinicalTrials.gov NCT02073994.

FIG 1.

Duration of treatment and best overall response (full analysis set; patients classified according to assigned dose level). Patients could continue to receive therapy beyond disease progression (PD) if they were experiencing clinical benefit in the investigator’s opinion. (*) Administered twice daily. (†) One patient with PD had an IDH2 mutation that was erroneously captured as IDH1. SD, stable disease.

FIG 2.

Best percentage change in the sum of the longest diameter (SLD) of the target lesions (full analysis set; patients classified according to assigned dose level). Dashed lines represent RECIST thresholds for progressive disease (PD; 20% increase) and partial response (30% decrease). Postbaseline assessments were not available for three patients; also excluded is the patient with an IDH2 mutation that was erroneously captured as IDH1. SD, stable disease. (*) Patients with dedifferentiated disease. (†) Patient had one postbaseline assessment of target lesion; per RECIST, this was designated unknown because it occurred < 6 weeks after first dose. (‡) Administered twice daily.

FIG 3.

Cooccurring mutations (n = 13). The heatmap shows the allelic fraction of known or likely oncogenic mutations that were detected at baseline, with patients ordered by progression-free survival (PFS). Only genes present in both FoundationOne and Personalis panels are included. D, dedifferentiated histology at baseline; NA, not assessed; PD, progressive disease; RTK, receptor tyrosine kinase; SD, stable disease. (*) Denotes censoring.