Bender, Mark H
Mayo Clinic
Eli Lilly and Company, Indianapolis, Indiana.
Citations 1
Final Results from a First-in-Human Phase I Study of the Dual Isocitrate Dehydrogenase (IDH) 1/2 Inhibitor, LY3410738, in Advanced Solid Tumors Harboring IDH1 or IDH2
Harding, James J. , Oh, Do‐Youn , Macarulla, Teresa , Goyal, Lipika , Varkaris, Andreas , Palmieri, Lola‐Jade , Ikeda, Masafumi , Kondo, Shunsuke , Bai, Li‐Yuan , Ueno, Makoto , Papadopoulos, Kyriakos P. , Shroff, Rachna T. , Kizilbash, Sani H. , Liao, Chih‐Yi , Azad, Nilofer S. , Jaeckle, Kurt A. , Bender, Mark H. , Varughese, Sunoj Chacko , Sachdeva, Deepa , Radtke, David B. , Gueorguieva, Ivelina , Chen, Hsiao-Rong , Liu, Hui , Xu, Xiangyuan , Macarulla, Teresa , Chen, Li-Tzong , Papadopoulos, Kyriakos P , Shroff, Rachna T , Kizilbash, Sani H , Hollebecque, Antoine , Adeva, Jorge , Cosman, Rasha , Yokota, Tomoya , Park, Joon Oh , Turk, Anita , Liao, Chih-Yi , Satoh, Taroh , Borad, Mitesh J , El-Khouiery, Anthony B , Azad, Nilofer , Jaeckle, Kurt A , Loong, Herbert H , Yong, Wei-Peng , Bender, Mark H , Varughese, Sunoj Chacko , Sachdeva, Deepa , Radtke, David B , Gueorguieva, Ivelina , Szpurka, Anna M , Chen, Hsiao-Rong , Liu, Hui , Xu, Xiaojian , Rodon, Jordi , Ikeda, Masafumi , Goyal, Lipika , Harding, James J , Chen, Li‐Tzong , Adeva, Jorge , Yokota, Tomoya , Borad, Mitesh J. , El-Khoueiry, Anthony B. , Loong, Herbert H. , Yong, Wei Peng
Clinical Cancer Research | September 30, 2025 | Volume: 31 | Issue: 23 | Pages: 4920-4932
Abstract Purpose: Isocitrate dehydrogenase (IDH) 1/2–isoform inhibitors have clinical efficacy in IDH1/IDH2-mutated neoplasms. However, primary resistance and secondary resistance limit their therapeutic potential. LY3410738, an oral, brain-penetrant, dual IDH1/IDH2-mutated isoform-selective inhibitor, was designed to overcome resistance. Patients and Methods: This global, multicenter, open-label, phase I study of patients with IDH-mutant solid tumors evaluated LY3410738 as monotherapy (dose escalation) for advanced solid tumors in combination with cisplatin–gemcitabine (CISGEM) for newly diagnosed cholangiocarcinoma or with durvalumab for relapsed/refractory cholangiocarcinoma (dose expansion; NCT04521686). Primary objectives were the maximum tolerated dose, recommended phase II dose, and preliminary antitumor activity. Safety, pharmacokinetics, inhibition of D-2-hydroxyglutarate, and ctDNA were assessed. Results: Overall, 119 patients received LY3410738 alone (N = 94) or in combination with CISGEM (N = 19) or durvalumab (N = 6). No dose-limiting toxicities were observed; the maximum tolerated dose was not determined. Common adverse events included nausea, vomiting, and decreased appetite. Overall response rates of 5.2% and 11.1% and disease control rates of 56.9% and 63.0% were observed for patients with relapsed/refractory IDH1- or IDH2-mutant cholangiocarcinoma or IDH1-mutant glioma, respectively. D-2-hydroxyglutarate normalization was rapid and durable. In dose-expansion cohorts, combination treatments were tolerable, with one dose-limiting toxicity in the durvalumab cohort. LY3410738 plus CISGEM demonstrated a response rate of 42.1%, a median duration of response of 8.1 months, and a median progression-free survival of 10.2 months for patients with newly diagnosed IDH-mutant cholangiocarcinoma. Conclusions: LY3410738 demonstrated largely cytostatic antitumor activity in IDH1- or IDH2-mutated cholangiocarcinoma and IDH1-mutated gliomas. LY3410738 plus CISGEM exhibited favorable antitumor activity in patients with treatment-naïve IDH-mutated cholangiocarcinoma, warranting further exploration as a treatment strategy.