Sponsor: IDEAYA Biosciences (industry)
Phase: 1
Start date: Dec. 11, 2025
Planned enrollment: 260
IDE397 is an oral, small‑molecule inhibitor of methionine adenosyltransferase 2A (MAT2A) being developed for solid tumors harboring homozygous loss of MTAP. Early clinical data from a Phase 1/2 monotherapy expansion in MTAP‑deleted urothelial cancer (UC) and non‑small cell lung cancer (NSCLC) have shown objective responses and high disease control at a 30 mg once‑daily dose; IDE397 is also being tested in combinations, including with sacituzumab govitecan (Trodelvy) and with the MTA‑cooperative PRMT5 inhibitor AMG 193. IDE397 is not approved for any indication. (media.ideayabio.com)
Monotherapy (Phase 1/2, MTAP‑deleted UC and NSCLC; 30 mg QD expansion dose) - July 8, 2024 interim update (n=18 evaluable): ORR ≈39% (1 CR, 6 PR [2 pending confirmation]), DCR ≈94%, ctDNA molecular response rate ≈81% (>50% reduction). (media.ideayabio.com) - ENA 2024 late‑breaker/Oct 25, 2024 update (n=27 evaluable): Confirmed ORR ≈33% (1 CR + 8 PR), DCR 93%. Subgroups: UC 40% (4/10), squamous NSCLC ≈38% (3/8), adenocarcinoma NSCLC ≈22% (2/9). Median duration of treatment >6.2 months; median time to response ≈2.7 months. (ir.ideayabio.com)
Combination with sacituzumab govitecan (Trodelvy) in MTAP‑deleted UC (Phase 1/2, two dose levels; initial expansion data shared Sept 8, 2025) - Dose level 2 (IDE397 30 mg + Trodelvy 7.5 mg/kg): ORR 57% (4/7; 3 confirmed PR + 1 unconfirmed PR). - Dose level 1 (IDE397 15 mg + Trodelvy 10 mg/kg): ORR 33% (3/9; all confirmed PR). Selection of a recommended Phase 2 dose is planned by end of 2025; next medical‑meeting update anticipated in 1H 2026. (prnewswire.com)
Combination with AMG 193 (MTA‑cooperative PRMT5 inhibitor) - A Phase 1/2 trial (NCT05975073) is evaluating safety and preliminary activity of IDE397 + AMG 193 in MTAP‑null solid tumors, with an NSCLC expansion; the study is active, not recruiting (as of 2025) and has not yet reported efficacy outcomes. Preclinical IDE397+AMG 193 data show deep, durable regressions and mechanistic synergy via maximal pathway suppression. (cdek.pharmacy.purdue.edu)
Monotherapy at 30 mg QD (expansion): - July 8, 2024 update: ~5.6% rate of drug‑related grade ≥3 AEs; no drug‑related serious AEs (SAEs) or discontinuations reported at the expansion dose. (media.ideayabio.com) - ENA 2024 update: no drug‑related SAEs or discontinuations at 30 mg QD. (ir.ideayabio.com)
Combination with Trodelvy (initial expansion data, Sept 8, 2025): - Safety was described as manageable and consistent with known AE profiles of the individual agents; no treatment‑related SAEs reported at IDE397 30 mg + Trodelvy 7.5 mg/kg. (prnewswire.com)
Note: Additional safety characterizations for MAT2A/PRMT5 pathway targeting, including class‑related pharmacodynamic effects and tolerability in humans, have been described with AMG 193 monotherapy (e.g., nausea, fatigue, vomiting as common TRAEs; phase 1 ORR 21.4% across tumor types), supporting the combination rationale but not directly substituting for IDE397 safety. (pubmed.ncbi.nlm.nih.gov)
Disclaimer: Human efficacy and safety data for IDE397 to date are based on interim analyses from ongoing early‑phase studies and company scientific/medical‑meeting disclosures; peer‑reviewed, full‑length clinical publications for IDE397 were not identified as of October 7, 2025. (media.ideayabio.com)
Last updated: Oct 2025
IDE892 is an investigational, small-molecule MTA-cooperative PRMT5 inhibitor being developed by IDEAYA Biosciences for MTAP-deleted solid tumors (with an initial clinical focus reported in MTAP-deleted lung cancer/NSCLC). (biospace.com)
As of February 28, 2026, IDE892 appears to be in early Phase 1 clinical testing (trial registered), and no peer-reviewed human efficacy or safety results were identified in the sources reviewed. (clinicaltrials.gov)
No human efficacy outcomes (e.g., objective response rate) for IDE892 were found in the identified sources as of February 28, 2026. (clinicaltrials.gov)
Preclinical statements from IDEAYA’s SEC filings and press materials describe: - Selective antiproliferative activity in MTAP-deleted tumor models, and - “Durable complete responses” in certain preclinical combination models with IDE397. (sec.gov)
No human safety dataset (rates/types of adverse events) for IDE892 was found in the identified sources as of February 28, 2026. (clinicaltrials.gov)
The registered Phase 1 trial includes standard early-phase safety endpoints (DLTs; AEs/SAEs graded by CTCAE v5.0). (clinicaltrials.gov)
Last updated: Feb 2026
Goal: To define the safety profile, dose-limiting toxicities, and recommended dose(s) of IDE892 given alone and with the MAT2A inhibitor IDE397, and to characterize pharmacokinetics/pharmacodynamics and preliminary antitumor activity in MTAP-deleted advanced solid tumors, with expansion focused on MTAP-deleted NSCLC after standard therapies.
Patients: Adults (≥18 years) with locally advanced recurrent or metastatic solid tumors with centrally confirmed MTAP homozygous loss/deletion, ECOG 0–1, measurable disease by RECIST 1.1, adequate organ function, and life expectancy >3 months. Dose-escalation cohorts include mesothelioma (pleural/peritoneal), gastroesophageal cancers, NSCLC, and urothelial cancer after progression on standard therapy. Dose-expansion cohorts are restricted to MTAP-deleted NSCLC that has progressed after platinum chemotherapy and PD-1/PD-L1 therapy (unless contraindicated/intolerant), with no more than 3 prior lines total (≤2 chemotherapy lines), and prior appropriate targeted therapy if a standard actionable alteration is present.
Design: Multicenter, open-label, non-randomized Phase 1 study with four parts: IDE892 monotherapy dose escalation using a Bayesian Optimal Interval design; IDE892 monotherapy NSCLC dose expansion; IDE892+IDE397 combination dose escalation using a modified toxicity probability interval design; and IDE892+IDE397 combination NSCLC dose expansion. Treatment is administered in 21-day cycles, with escalation to establish MTD and/or recommended dose(s) for expansion and evaluation of preliminary efficacy in expansion cohorts.
Treatments: IDE892 is administered as monotherapy and in combination with IDE397. IDE892 is an investigational small-molecule, MTA-cooperative inhibitor of PRMT5 intended to exploit the elevated methylthioadenosine milieu in MTAP-deleted tumors to increase tumor selectivity of PRMT5 inhibition; as of the current study stage, peer-reviewed human efficacy and detailed safety results for IDE892 have not been reported. IDE397 is an oral MAT2A inhibitor designed to reduce SAM production and deepen the methylation stress created by MTAP loss; it is included to potentially enhance therapeutic index and antitumor activity when paired with PRMT5 inhibition. The combination strategy aims to intensify the MTAP-deletion–associated methylation vulnerability through dual targeting of PRMT5 and MAT2A.
Outcomes: Primary endpoints are dose-limiting toxicities during the first 21 days of IDE892 exposure in the escalation parts (monotherapy and combination), overall incidence and severity of AEs/SAEs graded by CTCAE v5.0 across all parts, and investigator-assessed objective response rate and duration of response by RECIST 1.1 in the NSCLC expansion parts. Secondary endpoints include ORR and DOR in the escalation parts, disease control rate and duration of stable disease across all parts, and extensive IDE892 pharmacokinetic parameters (including Cmax, Tmax, AUClast, AUCinf, half-life, steady-state measures, clearance, volume of distribution, and accumulation) assessed primarily on Cycle 1 Day 1 and Day 15.
Burden on patient: High. This is an early-phase, multi-part dose-escalation/expansion study that requires archival tumor submission for central MTAP confirmation and mandates serial blood sampling for biomarkers and intensive pharmacokinetic profiling, with multiple PK time points concentrated around Cycle 1 Day 1 and Day 15. Patients can expect frequent clinic visits early in therapy for safety monitoring and DLT assessment, along with routine imaging for RECIST-based response assessment over time, and potential added travel burden typical of multicenter Phase 1 trials that often concentrate at specialized sites.
Last updated: Feb 2026
Inclusion Criteria:
* Are ≥ 18 years of age at the time of signing the ICF.
* Have a histologically confirmed diagnosis of a locally advanced recurrent or metastatic solid tumor type of interest with MTAP deletion (for dose escalation: mesothelioma \[pleural or peritoneal\], gastroesophageal cancers \[squamous and adenocarcinoma of esophagus, gastric adenocarcinoma, gastroesophageal junction cancers\], NSCLC \[adenocarcinoma, squamous cell carcinoma, and adeno-squamous\] and UC \[including mixed urothelial-squamous histology\]; for dose expansion: NSCLC that has progressed on at least one prior line of treatment and for which additional effective standard therapy is not available or for which the participant is not a candidate due to intolerance).
* Are willing and able to provide blood/tumor tissue samples for biomarker testing. An archival tumor tissue specimen must be provided for central confirmation of MTAP loss.
* Must be willing and able to provide the blood/serum/plasma samples
* Have evidence of homozygous loss of MTAP or MTAP deletion (pre-screening available after signing pre-screening ICF)
* Have at least 1 measurable lesion according to RECIST version 1.1
* Have Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1
* Have life expectancy \> 3 months
* Have adequate bone marrow and organ function
* Able to retain administered study drug/IMP.
* Male and female: willing to use contraception
Exclusion Criteria:
* Known symptomatic brain metastases requiring supraphysiologic doses of systemic corticosteroids
* Have a known primary central nervous system (CNS) malignancy
* Have had other malignancies within 2 years prior to the first dose, with some exceptions
* Impaired cardiac function or clinically significant cardiac diseases
* Have presence of uncontrolled pleural, peritoneal, or pericardial effusion within 2 weeks before the first study dose, requiring recurrent drainage procedures or an indwelling drainage catheter
* Have a history of severe infections within 4 weeks prior to the start of study treatment
* Hypertension (e.g., \> 150/100 mmHg) that cannot be controlled by medications despite optimal medical therapy
* Other acute or chronic medical or psychiatric condition
* Have a history of immunodeficiency, with a positive human immunodeficiency virus(HIV) test at screening
* Known or suspected viral hepatitis
* Had an adverse reaction to a previous antitumor treatment that has not recovered to CTCAE Grade ≤ 1
* Have received chemotherapy within 3 weeks of the first dose of IMP; immunotherapy or biologic targeted antitumor treatments within 2 weeks before the first dose of IMP; small molecule inhibitors within 2 weeks before the first dose of IMP, or other investigational products within 4 weeks
* Current radiation-related toxicity or radiation therapy within 2 weeks before the first dose of IMP
* Administration of any of the following within 2 weeks before the first dose of IDE892 as a monotherapy: Strong inhibitors or inducers of cytochrome P450, Strong inhibitors of P-glycoprotein, Narrow therapeutic index and sensitive substrates of multidrug and toxin extrusion (MATE)1 and MATE2-K, Narrow therapeutic index and sensitive substrates of P-gp and breast cancer resistance protein
* Administration of any of the following within 2 weeks before the first dose of IDE892: Strong inhibitors or inducers of CYP3A4/5, Strong inhibitors of P-gp and/or BCRP, Narrow therapeutic index and sensitive substrates of MATE1 and MATE2-K, Narrow therapeutic index and sensitive substrates of P-gp and BCRP
* Use of proton pump inhibitors (PPIs) within 7 days prior to the first dose of IMP or planned use during the study
* Use of drugs with known risk for QT prolongation within 2 weeks prior to the first dose of IDE892
* Previous treatment with a MAT2A inhibitor and/or Protein arginine N-methyltransferase (PRMT) inhibitor
* Major surgery within 4 weeks before study entry
* Prior irradiation to \> 25% of the bone marrow
* Known or suspected hypersensitivity to IDE892
Disease-Specific Eligibility Criteria NSCLC
* Must have histologically confirmed diagnosis of advanced or metastatic NSCLC that has progressed after prior treatment with platinum chemotherapy and a PD-1/PD-L1 inhibitor (unless contraindicated or participant developed intolerance) in the metastatic setting
* Treatment with no more than 3 prior lines, including no more than 2 prior lines of chemotherapy.
* If considered standard of care and available, participants whose cancers have proven targetable oncogene alterations must have had disease progression on (unless contraindicated or participant developed intolerance) at least 1 prior line containing appropriate targeted therapy.
Urothelial Cancer (Bladder and Upper Urinary Tract), Mesothelioma (Pleural or Peritoneal) and Gastroesophageal Cancers
* Must have histologically confirmed diagnosis of advanced or metastatic UC, mesothelioma, or gastroesophageal cancer
* Must have progressed following at least 1 prior line of therapy
* Treatment with no more than 3 prior lines, including no more than 2 prior lines of chemotherapy
Irving, Texas, 75039, United States
[email protected] / 972-893-8800
Status: Recruiting
Houston, Texas, 77054, United States
[email protected] / 832-384-7912
Status: Recruiting
Fairfax, Virginia, 22031, United States
[email protected] / 703-783-4518
Status: Recruiting