Phase 1 expansion data presented at the 36th EORTC-NCI-AACR Symposium (ENA 2024) in Barcelona, Spain, indicate that the methionine adenosyltransferase 2 alpha (MAT2A) inhibitor IDE397 shows clinical efficacy and tolerability in patients with non-small cell lung cancer (NSCLC) and urothelial cancer harboring methylthioadenosine phosphorylase (MTAP) deletions. The data suggests potential combination development for IDE397 in these cancers.
Objective Response and Disease Control
Treatment with IDE397 at the recommended phase 2 dose (RP2D) of 30 mg once daily resulted in an objective response rate (ORR) of 33% (n = 9/27), with all nine responses confirmed. The disease control rate (DCR) was 93%, with 4% (n = 1/27) of patients achieving a complete response (CR), 30% (n = 8/27) a partial response (PR), and 59% (n = 16/27) stable disease. Most patients were still receiving study treatment at the time of analysis, and responses were ongoing in seven patients.
In squamous NSCLC, the ORR was 38% (n = 3/8), while in adenocarcinoma histology, it was 22% (n = 2/9). For urothelial cancer patients, the ORR was 40% (n = 4/10).
Molecular Response
Circulating tumor DNA (ctDNA) molecular analysis in 21 patients showed that 81% (n = 17/21) had a molecular response, with rapid molecular responses observed at the first assessment. A ctDNA reduction of at least 90% was seen in 33% (n = 7/21) of patients.
Safety and Tolerability
No treatment-related discontinuations due to toxicity were reported, and there were no serious adverse effects (AEs) related to the study treatment. Several patients received IDE397 for at least six cycles, indicating long-term tolerability.
Any-grade treatment-emergent AEs (TEAEs) affected 82% of patients, while treatment-related AEs (TRAEs) affected 54%. Common AEs included fatigue (32% vs 11%), peripheral neuropathy (29% vs 25%), and diminished appetite (25% vs 11%). Grade 3 or higher TEAEs and TRAEs included fatigue (4% vs 0%) and asthenia (4% vs 4%).
Future Directions
Based on these data, investigators plan to evaluate IDE397 in combination with sacituzumab govitecan-hziy (Trodelvy) for MTAP-deletion urothelial cancer in a phase 1 study (NCT04794699). Another ongoing phase 1/2 study (NCT05975073) will assess IDE397 plus AMG 193, an investigational PRMT5 inhibitor.
Expert Commentary
"We are excited by the clinical efficacy and safety profile observed with the potential first-in-class MAT2A inhibitor IDE397 at the 30-mg once-a-day RP2D, including multiple confirmed responses observed as a monotherapy agent in [NSCLC] and urothelial cancer patients with MTAP-deletion," said Benjamin Herzberg, MD, assistant professor of Medicine at Columbia University. "In addition, at the 30-mg once-a-day expansion dose, we observed a manageable safety profile with no drug-related serious [AEs] or discontinuations. These data support potential combination development."
Study Design
The phase 1 expansion study included patients with squamous NSCLC (n = 8), NSCLC adenocarcinoma (n = 9), or urothelial cancer (n = 10) with MTAP homozygous deletions per next-generation sequencing or MTAP loss per immunohistochemistry. Patients needed measurable disease per RECIST v1.1 guidelines, an ECOG performance status of 0 or 1, and adequate organ function. NSCLC patients were required to have one or more prior lines of treatment in the metastatic setting and disease progression on prior anti–PD-L1 or targeted therapy. Urothelial cancer patients needed one or more prior lines of therapy and progression on prior cytotoxic and anti–PD-L1 therapy.
