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Ref Type Abstract
PMID
Authors Jordi Rodon; Lipika Goyal; Teresa Macarulla Mercade; Masafumi Ikeda; Shunsuke Kondo; Do-Youn Oh; Li-Yuan Bai; Makoto Ueno; Antoine Italiano; Kyriakos Papadopoulos; David Spigel; Sani H. Kizilbash; Rasha Cosman; Joon Oh Park; Li-Tzong Chen; Tomoya Yokota; Anita A. Turk; Chih-Yi Liao; Rachna Shroff; Anthony El-Khoueiry; Taroh Satoh; Antoine Hollebecque; Mitesh J. Borad; Nilofer Azad; Kurt A. Jaeckle; Herbert H. Loong; Jorge Adeva; Wei Peng Yong; Junjie Zhao; Hui Liu; Anna M. Szpurka; Ivelina Gueorguieva; Kamnesh R. Pradhan; Xiaojian Xu; James J. Harding
Title Abstract CT098: A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH, in advanced IDH-mutant cholangiocarcinoma and other solid tumors
Journal Vol Issue Date Pages Journal Short Title
Cancer Research 83 8_Supplement April 15, 2023
URL https://aacrjournals.org/cancerres/article/83/8_Supplement/CT098/725320/Abstract-CT098-A-first-in-human-phase-1-study-of
Abstract Text Background: Isocitrate dehydrogenase 1/2 (IDH1/2) is mutated in a subset of cholangiocarcinoma (CCA), gliomas, and other solid tumors. LY3410738 is a potent, selective, covalent, dual inhibitor of IDH1/2 mutations (IDH1/2m). LY3410738 binds covalently at a novel binding site, enabling continued potency in preclinical models in the setting of second site IDH resistance mutations. We present initial results from the first-in-human phase 1 study of oral LY3410738 in patients (pts) with IDH1/2m CCA, and IDH1m glioma or other solid tumors. Methods: Dose escalation (3+3 design) evaluated LY3410738 monotherapy in advanced IDHm CCA and other solid tumors (NCT04521686). Key objectives included determining the RP2D, safety, PK, PD (inhibition of plasma D-2-HG), and preliminary antitumor activity. Results: As of 28 July 2022, 80 pts including 42 with CCA (33 IDH1m, 9 IDH2m), 27 with glioma (IDH1m), and 11 other tumor types (IDH1m) received LY3410738 dosed at 25-600 mg QD or 300 mg BID. Pts were median 52 years of age (range, 23-80) with a median of 2 prior therapies (range, 1-7). 19% of CCA pts had received prior IDH1 inhibitor. Median time on treatment was 3.7 months (range, 0.1-19). No DLTs or treatment related deaths were observed; the MTD was not reached. Treatment emergent adverse events (TEAEs) ≥15% included nausea (35%), vomiting (21%), and decreased appetite (19%) and were mostly grade 1-2. Most frequent grade ≥3 TEAEs >2% were anemia (4%), cholangitis (3%), headache (3%), decreased lymphocyte count (3%), and hyponatremia (3%). LY3410738 exposure was dose proportional. In pts with IDH1m cancers, LY3410738 achieved sustained D-2-HG inhibition at all dose levels, including in pts who received prior IDH1 inhibitor. In pts with IDH2m cancers, a higher dose (≥150 mg daily dose) was required for D-2-HG inhibition. Among the 42 pts with R/R CCA, the best response included 1 PR and 22 SD. Of the 22 glioma pts with contrast enhancing tumors, best response included 3 PR and 9 SD. Conclusions: LY3410738 demonstrated a favorable safety profile with potent and sustained D-2-HG inhibition in pts with IDH1/2m advanced solid tumors. Consistent with the expectations for IDH inhibitor monotherapy in this setting, CCA and glioma pts exhibited prolonged stable disease. RP2D evaluation is ongoing. Updated data on LY3410738 monotherapy will be presented at the meeting.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
IDH1 act mut cholangiocarcinoma predicted - sensitive LY3410738 Phase I Actionable In a Phase I trial, LY3410738 treatment demonstrated safety and resulted in D-2-HG inhibition in patients with IDH-mutant advanced solid tumors, and led to partial response in 1 and stable disease in 22 of 42 patients with relapsed or refractory cholangiocarcinoma and partial response in 3 and stable disease in 9 of 22 patients with glioma (Cancer Res (2023) 83 (8_Supplement): CT098; NCT04521686). detail...
IDH2 act mut cholangiocarcinoma predicted - sensitive LY3410738 Phase I Actionable In a Phase I trial, LY3410738 treatment demonstrated safety and resulted in D-2-HG inhibition in patients with IDH-mutant advanced solid tumors, and led to partial response in 1 and stable disease in 22 of 42 patients with relapsed or refractory cholangiocarcinoma and partial response in 3 and stable disease in 9 of 22 patients with glioma (Cancer Res (2023) 83 (8_Supplement): CT098; NCT04521686). detail...
IDH2 act mut brain glioma predicted - sensitive LY3410738 Phase I Actionable In a Phase I trial, LY3410738 treatment demonstrated safety and resulted in D-2-HG inhibition in patients with IDH-mutant advanced solid tumors, and led to partial response in 1 and stable disease in 22 of 42 patients with relapsed or refractory cholangiocarcinoma and partial response in 3 and stable disease in 9 of 22 patients with glioma (Cancer Res (2023) 83 (8_Supplement): CT098; NCT04521686). detail...
IDH1 act mut brain glioma predicted - sensitive LY3410738 Phase I Actionable In a Phase I trial, LY3410738 treatment demonstrated safety and resulted in D-2-HG inhibition in patients with IDH-mutant advanced solid tumors, and led to partial response in 1 and stable disease in 22 of 42 patients with relapsed or refractory cholangiocarcinoma and partial response in 3 and stable disease in 9 of 22 patients with glioma (Cancer Res (2023) 83 (8_Supplement): CT098; NCT04521686). detail...