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Background: 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 dose escalation study of oral LY3410738 in patients (pts) with R/R IDH1/2m hematologic cancers. Methods: Dose escalation (3+3 design) evaluated LY3410738 monotherapy in IDH1/2m R/R AML (NCT04603001). 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, 114 pts including 108 R/R AML pts received LY3410738 dosed at 5-600 mg QD or 40-300 mg BID. Pts were median 73 years of age (range, 22-92) with a median of 2 prior therapies (range, 1-10); 29% received a prior IDH inhibitor and 58% a prior BCL2 inhibitor. Median time on treatment was 2.3 months (range, 0.1-15). No DLTs or treatment related deaths were observed. Treatment emergent adverse events ≥20% were diarrhea (22%), fatigue (21%), and anemia (20%). Differentiation syndrome was reported in 11 pts (10%); 4 grade 1/2 (4%), 7 grade 3 (6%). 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. Responses were observed in both IDH1m and IDH2m AML (Table). Higher doses were required for IDH2m AML, especially IDH2 R140m pts. Efficacy appears higher in venetoclax naïve pts and limited in IDH inhibitor pre-treated pts. Conclusions: LY3410738 demonstrated a favorable safety profile with potent and sustained D-2-HG inhibition in pts with IDH1m R132, IDH2m R172, and IDH2m R140 mutations. Preliminary efficacy was also seen in all genotypes, in a dose dependent manner. RP2D evaluation is ongoing. Table: Response in R/R AML IDH Inhibitor Naive (N=68) IDH1 R132 IDH2 R172 IDH2 R140 No prior Venetoclax (n=13) Prior Venetoclax (n=19) Total (N=32) Low Dosesa (n=5) (High Dosesb) Total (N=13) Low Dosesa (n=9) (High Dosesb) Total (N=23) No prior Venetoclax (n=3) Prior Venetoclax (n=5) No prior Venetoclax (n=6) Prior Venetoclax (n=8) CR+CRh, n (%) 5 (38%) 2 (11%) 7 (22%) - 3 (100%) 2 (40%) 5 (38%) - 2 (33%) - 2 (9%) CR, n (%) 3 (23%) 2 (11%) 5 (16%) - 2 (67%) 2 (40%) 4 (31%) - 2 (33%) - 2 (9%) CRh, n (%) 2 (15%) - 2 (6%) - 1 (33%) - 1 (8%) - - - - CRc (CR+CRh+CRi/CRp), n (%) 6 (46%) 6 (32%) 12 (38%) - 3 (100%) 3 (60%) 6 (46%) - 2 (33%) - 2 (9%) MFLS, n (%) 1 (8%) 3 (16%) 4 (13%) 2 (40%) - - 2 (15%) 1 (11%) - - 1 (4%) IDH Inhibitor Pre-Treated (N=33) IDH1 R132 IDH2 R172 IDH2 R140 No prior Venetoclax (n=2) Prior Venetoclax (n=8) Total (N=10) Low Dosesa (n=6) (High Dosesb) Total (N=8) Low Dosesa (n=4) (High Dosesb) Total (N=15) No prior Venetoclax (n=1) Prior Venetoclax (n=1) No prior Venetoclax (n=3) Prior Venetoclax (n=8) CR+CRh, n (%) - - - - - - - - - 1 (13%) 1 (7%) CR, n (%) - - - - - - - - - - - CRh, n (%) - - - - - - - - - 1 (13%) 1 (7%) CRc (CR+CRh+CRi/CRp), n (%) - - - - - - - 1 (25%) - 1 (13%) 1 (7%) MLFS, n (%) - - - - - - - - - - - Among the 108 treated R/R AML pts, 101 were efficacy evaluable (42 IDH1 R132, 21 IDH2 R172, 38 IDH2 R140); 68 pts were IDH inhibitor naïve and 33 had received a prior IDH inhibitor treatment. Efficacy evaluable pts are those who had completed the first bone marrow assessment or had discontinued treatment prior to first bone marrow assessment aTotal daily low doses: ≤75 mg Arm A, ≤30 mg Arm B bTotal daily high doses: ≥150 mg Arm A, ≥60 mg Arm B Arm A: not requiring a strong CYP3A4 inhibitor Arm B: requiring a strong CYP3A4 inhibitor Citation Format: Courtney D. DiNardo, Pau Montesinos, Lina Benajiba, Ana Triguero, Christian Recher, Andre C. Schuh, Maël Heiblig, Ashish Bajel, Arnaud Pigneux, Juan M. Alonso-Domiguez, Amir T. Fathi, Carolyn Grove, Hsin-An Hou, Michael Heuser, Sarit Assouline, Shaun Fleming, Dong-Yeop Shin, Kendra Sweet, Olatoyosi Odenike, Jessica Altman, Melissa Gaik Ming Ooi, Lao Zhentang, Nobert Vey, Joshua Zeidner, Amandeep Salhotra, Eunice Wang, Gary Schiller, Kimmo Porkka, Tsila Zuckerman, Violaine Havelange, Brian A. Jonas, Sujaatha Narayanan, Jun Ho Jang, Je-Hwan Lee, Anna M. Szpurka, Dana Heirich, Hsiao Rong Chen, Violet Hanft, Junjie Zhao, Ivelina Gueorguieva, Yin Zhang, Eytan M. Stein. A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH, in advanced myeloid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT026.