First-in-human study of AMG 193, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP-deleted solid tumors: results from phase I dose exploration

• Published in: Annals of oncology Vol. 35; no. 12; pp. 1138 - 1147
• Main Authors: Rodon, J., Prenen, H., Sacher, A., Villalona-Calero, M., Penel, N., El Helali, A., Rottey, S., Yamamoto, N., Ghiringhelli, F., Goebeler, M.E., Doi, T., Postel-Vinay, S., Lin, C.-C., Liu, C., Chuang, C.-H., Keyvanjah, K., Eggert, T., O’Neil, B.H.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2024
• Subjects: Adult; Aged; Dose-Response Relationship, Drug; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - therapeutic use; Female; Gene Deletion; Humans; Male; Maximum Tolerated Dose; methylthioadenosine phosphorylase; Middle Aged; MTAP; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; non-small-cell lung cancer; pancreas cancer; PRMT5; protein arginine methyltransferase 5, synthetic lethality; Protein-Arginine N-Methyltransferases - antagonists & inhibitors; Protein-Arginine N-Methyltransferases - genetics; Purine-Nucleoside Phosphorylase - antagonists & inhibitors; Purine-Nucleoside Phosphorylase - genetics; Pyrazoles; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Pyrimidines - pharmacokinetics; Pyrimidinones; methylthioadenosine phosphorylase; PRMT5; MTAP; pancreas cancer; protein arginine methyltransferase 5, synthetic lethality; non-small-cell lung cancer
• ISSN: 0923-7534; 1569-8041; 1569-8041
• DOI: 10.1016/j.annonc.2024.08.2339

Homozygous 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.