Interim results from a Phase 1 trial expansion cohort (NCT04794699) presented at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics indicate that the MAT2A inhibitor IDE397 exhibits antitumor activity and a manageable safety profile in patients with MTAP-deletion urothelial cancer and non-small cell lung cancer (NSCLC). The study suggests potential for IDE397 as a monotherapy and in combination treatments.
In the monotherapy cohort, a confirmed overall response rate (ORR) of 33% was achieved among evaluable patients (n = 27) receiving the 30 mg recommended phase 2 dose (RP2D) of IDE397. This included 1 complete response and 8 partial responses (PRs). Tumor type-specific ORRs were 38% in squamous NSCLC (n = 8), 22% in non-small cell adenocarcinoma (n = 9), and 40% in urothelial carcinoma (n = 10). The disease control rate (DCR) was 93%.
As of the data cutoff date of August 22, 2024, fifteen patients remained on treatment, including 7 responders. The median duration of treatment exceeded 6.2 months, with a median time to response of approximately 2.7 months. Duration of response (DOR) and progression-free survival (PFS) data were still immature at the time of analysis.
ctDNA Reduction
Circulating tumor DNA (ctDNA) reduction was observed in patients with evaluable samples (n = 21), with a ctDNA molecular response rate (MMR) of 81%. Notably, 17 patients experienced a 50% or greater ctDNA reduction, and 33% achieved a 90% or greater reduction. All molecular responses were reported at the first ctDNA evaluation.
Safety Profile
No treatment-related discontinuations or serious adverse events (AEs) were observed with IDE397 in the safety population (n = 28). Long-term tolerability was reported among several patients treated with at least 6 cycles of the agent. Any-grade treatment-related AEs (TRAEs) were observed in 54% of patients, with 18% being grade 3 or higher. Common any-grade treatment-emergent AEs (TEAEs) and TRAEs included fatigue, peripheral neuropathy, decreased appetite, constipation, blood creatinine increase, nausea, and asthenia.
Mechanism of Action and Study Design
IDE397 is a selective allosteric MAT2A inhibitor that exploits the synthetic lethal relationship between MTAP and MAT2A. Loss of MTAP leads to dependence on MAT2A, resulting in MTA accumulation, PRMT5 inhibition, and SAM reduction, ultimately causing pre-mRNA splicing defects and impaired DNA replication and repair.
The open-label, multicenter, multiple-dose, Phase 1 dose-escalation study evaluated IDE397 in patients with NSCLC or urothelial cancer harboring MTAP homozygous deletion. Patients were required to have measurable disease, an ECOG performance status of 0 or 1, and adequate organ function. NSCLC patients must have progressed on prior anti-PD-(L)1 and/or targeted therapy, while urothelial cancer patients required prior exposure to cytotoxic and anti-PD-(L)1 therapy.
The study's primary endpoints were dose-limiting toxicities and identification of the maximum tolerated dose and/or RP2D. Secondary endpoints included pharmacokinetics, pharmacodynamics, and initial antitumor activity.
Combination Therapy
Preliminary data from a clinical case study of IDE397 and sacituzumab govitecan-hziy (Trodelvy) in MTAP-deletion urothelial cancer showed one patient with both a MTAP-deletion and a FGFR3-TACC3 fusion achieving a PR at 12 weeks. Two patients with MTAP-deletion urothelial cancer reported a greater than 95% reduction in ctDNA at their first molecular response evaluation.
Based on these findings, investigators plan to initiate a Phase 1 combination expansion cohort evaluating IDE397 plus sacituzumab govitecan in MTAP-deletion urothelial carcinoma, in addition to an ongoing Phase 1/2 combination study (NCT05975073) assessing AMG 193 plus IDE397 in MTAP-deletion solid tumors.
