"P3.12D.11 Phase 1/2, Dose-expansion Study of AMG 193, an MTA-cooperati" by A. Sacher, A. Addeo et al.
 

P3.12D.11 Phase 1/2, Dose-expansion Study of AMG 193, an MTA-cooperative PRMT5 Inhibitor, In MTAP-deleted NSCLC

Document Type

Conference Proceeding

Publication Date

10-1-2024

Publication Title

J Thorac Oncol

Abstract

Introduction: AMG 193 is an oral S-methyl-5’-thioadenosine (MTA)-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor being evaluated for the treatment of methylthioadenosine phosphorylase (MTAP)-deleted cancers. MTAP deletion occurs in 16-20% of squamous and 12-16% of non-squamous non-small cell lung cancer (NSCLC). Deletion of MTAP leads to the accumulation of MTA, which binds to and inhibits PRMT5, an enzyme responsible for methylation and gene silencing of cell-essential proteins. Thus, in the context of MTAP-deleted cancers, MTA accumulation creates an additional vulnerability to further inhibit PRMT5 activity. AMG 193 preferentially targets and inhibits the MTA-bound state of PRMT5. In preclinical models, AMG 193 demonstrated selective antitumor activity in in vitro and in vivo MTAP-deleted compared to MTAP-wild type NSCLC cell line assays and NSCLC cell line-derived xenograft mouse models (Belmontes, 2023 AACR-NCI-EORTC). AMG 193 also demonstrated central nervous system penetrance with pharmacokinetic models. In the ongoing first-in-human (FIH) study with AMG 193 monotherapy, RECIST responses have been observed in a variety of MTAP-deleted tumors without dose-limiting myelosuppression and a favorable safety profile (Rodon, 2023 AACR-NCI-EORTC), demonstrating differentiated safety from the first generation indiscriminate PRMT5 inhibitors. This study will enroll up to 40 previously treated NSCLC patients in dose expansion (Part 1c), currently open for enrolment. Methods: This is a FIH, open-label, phase 1/2, dose escalation and expansion study of AMG 193 administered continuously in 28-day cycles in patients with advanced MTAP-deleted tumors (FIGURE). Up to 40 previously treated patients with NSCLC (squamous and non-squamous histology) will be enrolled in Part 1c. Central prescreening NGS will be offered to all participating sites. One interim futility will be conducted by using Simon’s minimax two-stage design. The primary objectives are safety and tolerability; secondary objectives include antitumor activity by investigator-assessed RECIST, pharmacokinetics, and pharmacodynamics. Key eligibility criteria for patients with NSCLC (Part 1c) include adult patients (≥ 18 years of age) with MTAP-deleted advanced tumors (determined by NGS or evidence of MTAP depletion determined by IHC); treatment with 1-3 prior lines of systemic therapy in the advanced/metastatic setting including platinum-based chemotherapy. Additionally, patients without actionable mutations must have received treatment with a PD(L)-1 inhibitor (unless contraindicated or PD-L1 < 1%), and patients whose tumors harbor actionable genomic aberrations (i.e. EGFR, ALK, MET, RET, ROS1, KRASG12C) should have disease progression on approved systemic therapies for these aberrations. [Formula presented] Keywords: AMG 193, MTA-cooperative PRMT5 inhibitor, MTAP-deleted NSCLC

Volume

19

Issue

10

First Page

S350

Last Page

S351

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