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 Mutations.
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Harding James J, Oh Do-Youn, Mercade Teresa Macarulla, Goyal Lipika, Varkaris Andreas, Palmieri Lola Jade, Ikeda Masafumi, Kondo Shunsuke, Bai Li-Yuan, Ueno Makoto, 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-Khoueiry Anthony, 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
Аннотация
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.