Phase I study of the mutant IDH1 inhibitor ivosidenib: long-term safety and clinical activity in patients with conventional chondrosarcoma

Abstract Purpose: A phase I study demonstrated that ivosidenib, a mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, showed manageable toxicity and durable disease control in patients with mIDH1 conventional chondrosarcoma (CS). Here we present long-term follow-up data on the safety and clinical activity of ivosidenib in patients with mIDH1 conventional CS from this phase I study. Patients and Methods: This phase I open-label dose-escalation and expansion study assessed ivosidenib monotherapy in patients with advanced mIDH1 solid tumors, including CS. An ivosidenib dose of 500 mg/day was identified in the dose-escalation phase and used for the expansion phase. The primary outcome was safety and tolerability. Secondary outcomes included objective response rate (ORR) and progression-free survival (PFS). The database lock date for this analysis was 18 March 2024. Results: Of 168 patients with advanced mIDH1 solid tumors receiving ivosidenib in this study, 21 patients had CS, of which 13 had conventional histology. Six (46.2%), 4 (30.8%) and 3 (23.1%) patients with conventional CS continued ivosidenib treatment for >1 year, >6 years and >7 years, respectively. Of the 21 patients with CS, 71.4% and 28.6% had treatment-related and serious adverse events (SAEs), respectively, but no SAEs were considered related to ivosidenib. The ORR for patients with conventional CS was 23.1% and median duration of response was 53.5 months. The median PFS of patients with conventional CS treated with ivosidenib was 7.4 months. Conclusions: Ivosidenib demonstrated long-term disease control and manageable toxicity for some patients with mIDH1 conventional CS and is under further investigation (NCT06127407).