Our preliminary findings in experiments with RAD-001 indicate that cotreatment with mTOR inhibitors and either Let or ICI reverses the Akt-mediated resistance and restores responsiveness to antiestrogens. Concurrent ER and mTOR inhibition is therefore an effective strategy to overcome growth factor-induced resistance and bears significant implications for optimal clinical development of these agents in breast cancer treatment.

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.

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Introduction: Somatic mutations in the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and 2 occur in a spectrum of solid and hematologic malignancies. Mutant IDH1/2 in cancer cells results in the neomorphic production of the oncometabolite, D-2-hydroxyglutarate (2-HG), which impairs cellular differentiation via an epigenetic mechanism. AG-120 is a first-in-class, oral, potent, reversible and selective inhibitor of mutated IDH1 protein. We report preliminary results from the ongoing, first-in-human, phase 1, open-label, single-arm study of AG-120 (NCT02073994). Aims: Key objectives are to evaluate the safety, tolerability, and maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity. Key exploratory objectives include an analysis of tumor tissue samples in non-glioma subjects and magnetic resonance imagining/spectroscopy (MRI/MRS) in glioma subjects, pre and on AG-120 treatment. Methods: Patients with advanced, IDH1-mutant solid tumors, including glioma, who have recurred or progressed following standard therapy, or who have not responded to standard therapy, are eligible to receive continuous, single-agent, oral AG-120 dosed daily in 28-day cycles. Informed consent is obtained prior to entry. Sequential dose cohorts are being enrolled, with expansion cohorts planned. Blood and tumor biopsies are collected for PK/PD assessment. Objective responses are investigator assessed using either RECIST or RANO criteria for subjects with solid tumors and gliomas, respectively. Results: As of 1 July 2015, 55 patients (glioma: 20, non-glioma: 35) were treated with AG-120. Median age was 54 years (range, 23-88) and median number of prior systemic regimens 3 (range, 1-6). Doses administered were 100 mg BID (n = 4), 300 mg QD (n = 9), 400 mg QD (n = 5), 500 mg QD (n = 17), 600 mg QD (n = 5), 800 mg QD (n = 6), 900 mg QD (n = 4), and 1200 mg QD (n = 5). Median treatment duration was 1.9 months (range, 0.1-12.5). The MTD was not reached. PK analyses showed high plasma exposure and drug accumulation following oral administration and a mean half-life of 73.1 ± 66.6 hr. Overall, treatment was well tolerated: 49 patients experienced treatment-emergent adverse events (AEs), regardless of causality. Most frequently occurring AEs (%) were nausea (21.8), diarrhea (16.4), vomiting (14.5), anemia (12.7), and abdominal pain (10.9). There were no treatment-related serious AEs. Summary/Conclusion: AG-120 is a first-in-class, oral, potent, selective inhibitor of mutant IDH1 in development for solid and liquid tumors. Updated safety and clinical activity, as well as exploratory PD analyses will be presented. Future development plans for AG-120 in solid tumors will also be highlighted. Citation Format: Howard Burris, Ingo Mellinghoff, Elizabeth Maher, Patrick Wen, Murali Beeram, Mehdi Touat, Jason Faris, Nilofer Azad, Timothy Cloughesy, Lia Gore, Jonathan Trent, Daniel Von Hoff, Meredith Goldwasser, Bin Fan, Sam Agresta. The first reported results of AG-120, a first-in-class, potent inhibitor of the IDH1 mutant protein, in a Phase I study of patients with advanced IDH1-mutant solid tumors, including gliomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL04-05.