IDE397 Shows Preliminary Efficacy in MTAP+ NSCLC and Urothelial Cancer

Phase 1 expansion data may support potential combination development for IDE397 in NSCLC and urothelial cancer harboring MTAP deletions.

The investigational methionine adenosyltransferase 2 alpha (MAT2A) inhibitor IDE397 demonstrated clinical efficacy and tolerability among a small cohort of patients with non–small cell lung cancer (NSCLC) and urothelial cancer harboring methylthioadenosine phosphorylase (MTAP) deletions, according to phase 1 expansion data presented at the 36th edition of the EORTC-NCI-AACR Symposium (ENA 2024) in Barcelona, Spain.¹

Treatment with IDE397 at the recommended phase 2 dose (RP2D) of 30 mg once daily elicited an objective response rate (ORR) of 33% (n = 9/27); all 9 responses were confirmed. Responses were ongoing in 7 patients, and most patients were still receiving study treatment at the time of analysis. Specifically, 4% (n = 1/27) of patients had a complete response (CR), 30% (n = 8/27) had a partial response (PR), and 59% (n = 16/27) had stable disease, which resulted in a disease control rate (DCR) of 93%.

Regarding specific tumor types, the ORR was 38% (n = 3/8) for patients with squamous NSCLC and 22% (n = 2/9) for those with adenocarcinoma histology. Treatment produced an ORR of 40% (n = 4/10) for patients with urothelial cancer.

Based on a circulating tumor DNA (ctDNA) molecular analysis among 21 patients, 81% (n = 17/21) had a molecular response, and 81% (n = 17/21) experienced a rapid molecular response at the time of first assessment. Additionally, ctDNA reduction of at least 90% occurred in 33% (n = 7/21) of patients.

Investigators reported no treatment-related discontinuations due to toxicity; there were no serious adverse effects (AEs) that were related to study treatment. Additionally, several patients received treatment with IDE397 for at least 6 cycles, indicating the agent’s long-term tolerability.

Any-grade treatment-emergent AEs (TEAEs) and treatment-related AEs (TRAEs), respectively, affected 82% and 54% of patients, with the most common including fatigue (32% vs 11%), peripheral neuropathy (29% vs 25%), and diminished appetite (25% vs 11%). The most common grade 3 or higher TEAEs and TRAEs included fatigue (4% vs 0%) and asthenia (4% vs 4%).

Based on these phase 1 expansion data, investigators plan to assess treatment with IDE397 in combination with sacituzumab govitecan-hziy (Trodelvy) among those with MTAP-deletion urothelial cancer in a phase 1 study (NCT04794699). Additionally, another ongoing combination study will assess IDE397 plus AMG 193, an investigational PRMT5 inhibitor, in a phase 1/2 study (NCT05975073).

“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,” Benjamin Herzberg, MD, an assistant professor of Medicine at Columbia University, said in a press release on these findings.² “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.”

In this phase 1 expansion study, patients with squamous NSCLC (n = 8), NSCLC adenocarcinoma (n = 9), or urothelial cancer (n = 10) harboring MTAP homozygous deletions per next-generation sequencing or MTAP loss per immunohistochemistry were assigned to receive treatment with IDE397. Other eligibility criteria included having measurable disease per RECIST v1.1 guidelines, an ECOG performance status of 0 or 1, and adequate organ function.

Specifically, those with NSCLC were required to have 1 or more prior lines of treatment in the metastatic setting and disease progression on prior anti–PD-L1 or targeted therapy agents to enroll on the study. Those with urothelial cancer needed to have 1 or more prior lines of therapy and progression on prior cytotoxic and anti–PD-L1 therapy to be eligible for study entry.

References

1. Herzberg B, Johnson M, Kim CG, et al. Phase 1 expansion results of IDE397, a first-in-class, oral, MAT2A inhibitor in MTAP deleted non-small cell lung cancer and urothelial cancer. Presented at the 36th EORTC-NCI-AACR Symposium (ENA 2024); October 23-25, 2024; Barcelona, Spain. LBA501.
2. IDEAYA announces positive interim phase 1 expansion data of IDE397 in MTAP-deletion urothelial and lung cancer as late-breaker oral presentation at EORTC-NCI-AACR 2024. News release. IDEAYA Biosciences, Inc. October 25, 2024. Accessed October 28, 2024. https://tinyurl.com/yc4fy45r