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.

Autor:	Rodon J; MD Anderson Cancer Center, Houston, USA. Electronic address: jrodon@mdanderson.org., Prenen H; University Hospital Antwerp, Edegem, Belgium., Sacher A; Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada., Villalona-Calero M; Department of Medical Oncology and Therapeutics Research, University of California, Irvine, USA., Penel N; Centre Oscar Lambret, Lille, France., El Helali A; Centre of Cancer Medicine, University of Hong Kong, Hong Kong, China., Rottey S; Ghent University Hospital, Ghent, Belgium., Yamamoto N; National Cancer Center Hospital, Tokyo, Japan., Ghiringhelli F; INSERM U866, Cancer Center Georges Francois Leclerc, Dijon, France., Goebeler ME; Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany., Doi T; National Cancer Center Hospital East, Chiba, Japan., Postel-Vinay S; Institut Gustave Roussy, Villejuif, France; University College London Cancer Institute, London, UK., Lin CC; National Taiwan University Hospital, Taipei, Taiwan., Liu C; Amgen Inc., Thousand Oaks., Chuang CH; Amgen Inc., Thousand Oaks., Keyvanjah K; Amgen Inc., Thousand Oaks., Eggert T; Amgen Inc., Thousand Oaks., O'Neil BH; Community-Health Network, Indianapolis, USA.
Jazyk:	angličtina
Zdroj:	Annals of oncology : official journal of the European Society for Medical Oncology [Ann Oncol] 2024 Dec; Vol. 35 (12), pp. 1138-1147. Date of Electronic Publication: 2024 Sep 16.
DOI:	10.1016/j.annonc.2024.08.2339
Abstrakt:	Background: 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. Patients and Methods: 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. Results: 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. Conclusions: 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. (Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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