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.

MR-detectable metabolic biomarkers of response to mutant IDH inhibition in low-grade glioma

“…Additionally, studies have also shown that glutamate levels are lower in mutant IDH tumors compared to normal brain 61 . When assessing the effect of mutant IDH inhibitors in our cells, we observed that IDH1mut inhibition led to the expected decrease in steady-state 2-HG, in line with prior in vitro , in vivo , and ex vivo studies with AG-120 and AG-881 9 - 11 , 48 , 49 , 55 , 62 - 64 . Furthermore, and consistent with our hypothesis that the IDH1mut biomarkers would be reversed with treatment, we also observed a significant increase in steady-state glutamate in both NHAIDH1mut and U87IDH1mut cells.…”

“…Clinical trials with AG-120 have shown substantial 2-HG reduction and disease control in patients with advanced tumors including acute myeloid leukemia (AML) and chondrosarcoma (e.g. clinicaltrials.gov NCT02073994 and NCT02074839) 11 , 55 , and AG-120 continues to be investigated either alone or in combination with traditional chemotherapies (e.g. clinicaltrials.gov NCT03245424 and NCT03173248).…”

Metabolism of Amino Acids in Cancer

“…For patients with IDH (WT)/TET2 (WT) myeloid leukemia, a high level of BCAT1 is a strong predictor of worse survival outcomes, and the BCAT1 level significantly increases on disease relapse (Raffel et al, 2017 ). In recent years, IDH inhibitors targeting IDH mutants, including ivosidenib and enasidenib ( Table 1 ), have been approved by the Food and Drug Administration to be used in patients with IDH1 or IDH2 mutant recurrent or refractory AML, respectively (Kim, 2017 ; Dhillon, 2018 ), while trials of IDH inhibitors for other tumors such as cholangiocarcinoma, chondrosarcoma, and myelodysplastic syndrome are still underway (Abou-Alfa et al, 2020 ; Stein et al, 2020 ; Tap et al, 2020 ). Unlike α-KG, abnormal accumulation of succinate and fumarate in tumor tissues represses PHD, thus reducing HIF1 α hydrolysis, suppressing demethylation of DNA and histones, and promoting the occurrence and development of tumors (Cavalli and Heard, 2019 ).…”

Chondrosarcoma-from Molecular Pathology to Novel Therapies

“…Mutations in IDH1 and IDH2 genes have been described in several malignancies, including gliomas [ 68 ], acute myeloid leukemia (AML) [ 69 , 70 ], and myelodysplastic disorders [ 71 ]. IDH1 / 2 mutations are also documented in cartilaginous neoplasms, including approximately 50% of patients with CHS (65% of conventional CHSs and up to 57% of dedifferentiated CHSs) [ 60 , 72 , 73 , 74 ]. However, these mutations were not found in the clear cell [ 37 ] and mesenchymal CHS [ 60 ].…”