(P 66) PHASE I STUDY OF THE MUTANT IDH1 INHIBITOR IVOSIDENIB: LONG-TERM SAFETY AND CLINICAL ACTIVITY IN PATIENTS WITH CONVENTIONAL CHONDROSARCOMA

Objective: Chondrosarcomas are rare primary bone malignancies for which there are no approved systemic therapies. 85% of chondrosarcomas are the conventional subtype. Mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in ~50% of conventional chondrosarcomas. In a phase 1 study in patients with IDH1-mutated advanced solid tumors, ivosidenib, an oral potent inhibitor of mutant IDH1, demonstrated manageable toxicity (without dose-limiting toxicities), suppression of the oncometabolite 2-hydroxyglutarate at dose levels ≥300 mg/day, and disease control in patients with conventional chondrosarcoma. We report long-term safety, tolerability and efficacy of ivosidenib in patients with conventional chondrosarcoma.

Methods: In this phase I multicenter open-label dose-escalation and expansion study, ivosidenib was administered orally (100 mg twice/day [BID] to 1200 mg once/day [QD]) in continuous 28-day cycles. Primary outcome was safety and tolerability; secondary outcomes included clinical activity (objective response rates [ORR, defined as complete response (CR) + partial response (PR)], stable disease [SD] and progression-free survival [PFS]). Adverse events (AEs) were assessed every visit and reported per the Common Terminology Criteria for Adverse Events (CTCAE version 4.03). Responses were assessed every other cycle using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).

Results: 13 patients with advanced conventional chondrosarcoma were included in this analysis (data cut off 15 September 2022; women, n=4; median age 54.0; AJCC tumor grade I [n=2], II [n=8], III [n=1], unknown [n=2]; 6 had received prior systemic therapy; received 100 mg ivosidenib BID [n=1], 400 mg QD [n=1], 500 mg QD [n=7], 800 mg QD [n=2], and 1200 mg QD [n=2]). Median treatment duration was 11.3 months (range: 0.5-92.6 months). Four patients (30.8%) have continued therapy for >6 years (two of which were treated for >7 years). Median relative dose intensity was 100%. The most frequent treatment emergent AEs (in >4 pts; mostly grade 1/2) were diarrhea (n=5) and nausea (n=5). Six patients experienced grade ≥3 AEs. Three patients experienced serious AEs (none considered related to treatment). There were no discontinuations, dose reductions or deaths due to AEs. The ORR was 23.1%. Median duration of response was 42.5 months (range: 25.8-51.8 months). One patient with a base of the skull lesion achieved a CR (1200 mg IVO QD); two achieved PR (one 500 mg and one 1200 mg IVO QD); seven had SD (five received ≥500 mg IVO QD) and two had PD (both received ≥500 mg IVO QD). All responses occurred after >2 years on treatment. Median PFS was 7.4 months (95% CI: 2.0-61.3).

Conclusion: In patients with IDH1 mutated advanced conventional chondrosarcoma, ivosidenib demonstrates manageable toxicity and durable disease control including long-term responses, extending several years for a proportion of patients. Future studies are warranted to better understand the efficacy of ivosidenib in patients with advanced conventional chondrosarcoma.