SO-1 A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH1 and IDH2, as monotherapy and in combination with cisplatin and gemcitabine in advanced IDH-mutant cholangiocarcinoma

IDH1 and 2 (IDH1/2) are mutated in 10-15% of intrahepatic cholangiocarcinoma (CCA). The reversible inhibitor ivosidenib is approved 2L IDH1-mutant CCA. Cisplatin gemcitabine (CISGEM) the standard 1L chemotherapy backbone for advanced Addition PD1/PDL1 inhibitors have demonstrated modest improvement OS (median 12.8 months), highlighting ongoing unmet need. LY3410738 an oral, potent, selective, dual IDH1/2 mutations (IDH1/2m). binds covalently at a novel binding site, enabling continued potency preclinical models setting second site IDH resistance mutations. Here, we present translational vivo findings data from phase 1 study as monotherapy with CISGEM IDH1/2m CCA (NCT04521686). In study, dose escalation (3+3 design) evaluated relapsed/refractory (R/R) other solid tumors. Dose expansion combination treatment naïve patients. Objectives included determining RP2D, safety, PK/PD, antitumor activity. IDH1m PDX model, single agent (10-30 mpk, QD) >60% tumor growth inhibition. (30 plus (3/60 Q7Dx3, 3/40mpk, Q7Dx3) 6 weeks followed by 15 maintenance led to 85% inhibition, while alone achieved only 47% inhibition (p < 0.001). cohorts, November 01, 2022, 45 patients R/R received (25 - 600 mg QD or 150 300 BID) (1). Median number prior lines therapy was (range, 1-7). ORR 4.5% PR 23 SD. mPFS 3.5 months (95% CI, 1.9-5.1). PFS rate 32.5% CI 18.8-47.0). cohort, 13 (300 BID 400 CISGEM. median age 64 years 51-77). time on 5.95 2.3-9.1). No DLTs were observed. TEAE ≥30% regardless attribution anemia (54%), platelet count decreased nausea (46%), appetite (39%), neutrophil constipation (31%). Most frequent grade ≥3 ≥25% 7 (54%) reported related AEs which 3. 46% PR/uPR (pending confirmation ongoing) not reached, 83.3% 27.3-97.5). PK/PD profiles consistent this favorable safety profile preliminary efficacy locally metastatic RP2D evaluation ongoing. Reference: 1. Rodon J. et al. To be presented AACR 2023, Apr 14-19.