IDE397 Shows Early Antitumor Activity, Safety in MTAP-Deletion Urothelial Cancer and NSCLC

The MAT2A inhibitor IDE397 showed antitumor activity, generated responses, and had a manageable safety profile among patients with MTAP-deletion urothelial cancer or non–small cell lung cancer (NSCLC), according to interim results from the expansion cohort of a phase 1 trial (NCT04794699) presented at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.^1,2

In the monotherapy cohort, 33% of evaluable patients (n = 27) achieved a confirmed overall response with the daily 30 mg recommended phase 2 dose (RP2D) of IDE397, including 1 complete response and 8 partial responses (PRs). Further assessment of responses by tumor type showed confirmed overall response rates (ORRs) of 38% in patients with squamous NSCLC (n = 8), 22% in those with non–small cell adenocarcinoma (n = 9), and 40% in patients with urothelial carcinoma (n = 10). The disease control rate (DCR) was 93%.

Fifteen patients are continuing treatment as of the data cutoff date of August 22, 2024, including 7 responders. The median duration of treatment has not been reached but is greater than 6.2 months. The median time to response is approximately 2.7 months. Duration of response (DOR) and progression-free survival (PFS) data are immature.

Among patients who received IDE397, circulating tumor DNA (ctDNA) reduction was observed in those with evaluable samples (n = 21). The ctDNA molecular response rate (MMR) was 81%. Furthermore, 17 patients experienced a 50% or greater ctDNA reduction and 33% achieved a 90% or greater ctDNA reduction. All molecular responses were reported at the first ctDNA evaluation.

“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 [patients with] urothelial cancer with MTAP-deletion,” Benjamin Herzberg, MD, presenting author and assistant professor of medicine at Columbia University in New York, New York, stated in a news release.² “In addition, at the 30-mg once-a-day expansion dose, we observed a manageable safety profile with no drug-related serious adverse effects [AEs] or discontinuations. These data support potential combination development.”

Phase 1 Dose-Escalation Overview

IDE397 is a potent and selective allosteric MAT2A inhibitor that exploits the synthetic lethal relationship between MTAP and MAT2A for potential therapeutic benefit. The loss of MTAP typically confers dependence on MAT2A, thereby resulting in both accumulation of the metabolite MTA, which inhibits the methyltransferase PRMT5, and a reduction of SAM through MAT2A inhibition. This leads to pre-mRNA splicing defects, as well as the prevention of effective DNA replication and DNA damage repair modulation.¹

To assess the therapeutic potential of IDE397, several early-phase studies were conducted. In the current open-label, multicenter, multiple dose, phase 1 dose-escalation study, the agent is being evaluated in patients with NSCLC or urothelial cancer harboring a MTAP homozygous deletion by next-generation sequencing (NGS) or MTAP loss by immunohistochemistry (IHC).^1,3 Patients are also required to have measurable disease by RECIST 1.1 criteria, an ECOG performance status (PS) of 0 or 1; and adequate organ function. Those with NSCLC must have received at least 1 prior line of therapy in the metastatic setting and progressed on a prior anti–PD‐(L)1 and/or targeted therapy.For those with urothelial cancer, previous exposure to more than 1 prior line of therapy and progression on prior cytotoxic and anti–PD‐(L)1 therapy is required.

As of the data cutoff date, 27 patients were enrolled onto the study at the RP2D. The median age was 67 years (range, 50-78), the majority of patients were male (70%), and 41% of patients had an ECOG PS of 1. MTAP loss was detected by NGS in 48% of patients and IHC in 52% of patients. The median number of prior lines of therapy was 2 to 3 (range, 1-7), with most patients receiving 1 to 2 lines (67%). Prior chemotherapy and checkpoint inhibition was reported in 96% and 74% of patients, respectively.

The study’s primary end points are dose-limiting toxicities with IDE397 and identification of the maximum tolerated dose and/or RP2D of the agent. Secondary end points include pharmacokinetics, pharmacodynamics, and initial antitumor activity.³

Initial Safety Data for IDE397

No treatment-related discontinuations or serious AEs were observed with IDE397 in the safety population (n = 28), and 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, 18% of which were grade 3 or higher. Any-grade treatment-emergent AEs (TEAEs) were reported in 82% of patients, 39% of which were grade 3 or higher.¹

Common any-grade TEAEs and TRAEs included fatigue (TEAE, 32%; TRAE, 11%), peripheral neuropathy (29%; 25%), decreased appetite (25%; 11%), constipation (21%; 4%), blood creatinine increase (18%; 11%), nausea (18%; 11%), and asthenia (18%; 7%).

Further Investigations of IDE397 as Monotherapy and in Combination

Results from the first preliminary clinical case study of IDE397 and sacituzumab govitecan-hziy (Trodelvy) in MTAP-deletion urothelial cancer were also reported in the current analysis. One patient with both a MTAP-deletion and a FGFR3-TACC3 fusion achieved a PR by RECIST 1.1 criteria at 12 weeks and is continuing on treatment. Moreover, 2 patients with MTAP-deletion urothelial cancer reported a greater than 95% reduction in ctDNA at their first molecular response evaluation, suggesting rapid responses with the combination. 

Based on these data, investigators plan to initiate a phase 1 combination expansion cohort evaluating IDE397 plus sacituzumab govitecan in MTAP-deletion urothelial carcinoma in addition to their ongoing phase 1/2 combination study (NCT05975073) assessing AMG 193 plus IDE397 in MTAP-deletion solid tumors.

The monotherapy expansion cohort study of IDE397 will continue at the RP2D in both NSCLC and urothelial carcinoma. Data revealing the agent’s mechanism of action and differentiated toxicity profile from this cohort provide a clear rationale for further combination testing

with PRMT5 and topoisomerase payload–containing antibody-drug conjugates in MTAP‐deletion solid tumors.

“IDE397 is rapidly advancing as a monotherapy agent in MTAP-deletion urothelial cancer and NSCLC. Next, we are well positioned to advance our broad and potential first-in-class IDE397 rational combination strategy, including the targeted expansion in the fourth quarter with sacituzumab govitecan in urothelial cancer, the ongoing combination with AMG 193 with targeted expansion in NSCLC, combinations with IDEAYA’s internal MTAP-deletion pipeline that includes a targeted development candidate by year-end, among others,” Yujiro S. Hata, president and chief executive officer of IDEAYA Biosciences, concluded in the news release.¹

Disclosures: Dr Herzberg reports employment at Columbia University;

Involvement in corporate sponsored research with AstraZeneca (Institutional), Repare Therapeutics (Institutional), IDEAYA Biosciences (Institutional), Amgen (Institutional), Revolution Medicines (Institutional), Astellas (Institutional), Monte Rosa Therapeutics (Institutional), Prelude Therapeutics (Institutional), Nested Therapeutics (Institutional), Stand up to Cancer (Personal), NIH/NCI ECIA 3P30CA013696‐49S2 (Personal), NIH/NCI Cancer Moonshot Biobank supplementary funding (Personal); serving as a consultant for Amgen, Astellas, AstraZeneca, Eli Lilly, Guidepoint Advisors; and receiving honoraria from Boxer Capital, OncLive/MJH Life Sciences, IDEOlogy Health, and Eisai.

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: EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; October 23-25, 2024; Barcelona, Spain. Abstract 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. October 25, 2024. Accessed October 29, 2024. https://www.prnewswire.com/news-releases/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-2024-302286733.html
3. Study of IDE397 in participants with solid tumors harboring MTAP deletion. ClinicalTrials.gov. Updated June 27, 2024. Accessed October 29, 2024. https://clinicaltrials.gov/study/NCT04794699?tab=history&a=1