Rodon, JJRodonPrenen, HHPrenenSacher, AASacherVillalona-Calero, MMVillalona-CaleroPenel, NNPenelEl Helali, AAEl HelaliRottey, SSRotteyYamamoto, NNYamamotoGhiringhelli, FFGhiringhelliGoebeler, M EM EGoebelerDoi, TTDoiPostel-Vinay, SSPostel-VinayCHIA-CHI LINLiu, CCLiuChuang, C-HC-HChuangKeyvanjah, KKKeyvanjahEggert, TTEggertO'Neil, B HB HO'Neil2025-08-112025-08-112024-12https://scholars.lib.ntu.edu.tw/handle/123456789/731217Homozygous deletion of methylthioadenosine phosphorylase (MTAP) occurs in ∼10%-15% of solid tumors. AMG 193, a CNS-penetrant methylthioadenosine-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor, selectively induces synthetic lethality in MTAP-deleted tumor cells. Here, we report results of the completed monotherapy dose exploration evaluating AMG 193 in patients with MTAP-deleted solid tumors. In this first-in-human, multicenter, open-label, phase I study, patients with advanced CDKN2A-deleted and/or MTAP-deleted solid tumors received AMG 193 orally [once (o.d.) or twice (b.i.d.) daily] continuously in 28-day cycles. Primary objectives were safety and tolerability assessed by dose-limiting toxicities and determination of the maximum tolerated dose; secondary objectives included pharmacokinetics and preliminary antitumor activity measured by RECIST v1.1. As of 23 May 2024, 80 patients in dose exploration received AMG 193 at doses 40-1600 mg o.d. or 600 mg b.i.d. The most common treatment-related adverse events were nausea (48.8%), fatigue (31.3%), and vomiting (30.0%). Dose-limiting toxicities were reported in eight patients at doses ≥240 mg, including nausea, vomiting, fatigue, hypersensitivity reaction, and hypokalemia. The maximum tolerated dose was determined to be 1200 mg o.d. Mean exposure of AMG 193 increased in a dose-proportional manner from 40 mg to 1200 mg. Among the efficacy-assessable patients treated at the active and tolerable doses of 800 mg o.d., 1200 mg o.d., or 600 mg b.i.d. (n = 42), objective response rate was 21.4% (95% confidence interval 10.3% to 36.8%). Responses were observed across eight different tumor types, including squamous/non-squamous non-small-cell lung cancer, pancreatic adenocarcinoma, and biliary tract cancer. At doses ≥480 mg, complete intratumoral PRMT5 inhibition was confirmed in paired MTAP-deleted tumor biopsies, and molecular responses (circulating tumor DNA clearance) were observed. AMG 193 demonstrated a favorable safety profile without clinically significant myelosuppression. Encouraging antitumor activity across a variety of MTAP-deleted solid tumors was observed based on objective response rate and circulating tumor DNA clearance.enMTAPPRMT5methylthioadenosine phosphorylasenon-small-cell lung cancerpancreas cancerprotein arginine methyltransferase 5, synthetic lethality[SDGs]SDG3journal article10.1016/j.annonc.2024.08.233939293516