IDE397 Plus Sacituzumab Govitecan Elicits Responses in MTAP-Deletion Urothelial Cancer

The combination of the MAT2A inhibitor IDE397 paired with sacituzumab govitecan-hziy (Trodelvy) induced responses and had a manageable toxicity profile in patients with late-line MTAP-deletion urothelial cancer, according to initial data from two expansion cohorts of an ongoing phase 1/2 trial (NCT04794699).1

At a data cutoff date of August 25, 2025, those who received IDE397 at a dose of 15 mg plus sacituzumab govitecan at 10 mg/kg (dose level 1 cohort; n = 9) experienced an objective response rate (ORR) of 33%, which comprised 3 confirmed partial responses (cPRs), including 1 patient with a confirmed response after cutoff; the disease control rate (DCR) was 100%. Those who received IDE397 at a dose of 30 mg plus sacituzumab govitecan at 7.5 mg/kg (dose level 2 cohort; n = 7) achieved an ORR of 57%, which included 3 cPRs and 1 unconfirmed PR; in this group, the DCR was 71%. To date, the median duration of response and progression-free survival have not yet been reached.

The preliminary findings with the combination trend favorably with historical efficacy data on single-agent sacituzumab govitecan in metastatic urothelial cancer, according to a news release issued by IDEAYA Biosciences, Inc.

Regarding safety, no serious treatment-related adverse effects (TRAEs) were reported at dose level 2. At dose level 1, the most frequently experienced TRAEs that were grade 3 or higher included anemia and neutropenia; at dose level 2, they were anemia, asthenia, and diarrhea.

“We are pleased with the progress we are making with the Trodelvy and IDE397 combination and are encouraged by the early response rate data we are seeing in previously treated MTAP-deleted urothelial cancer,” Darrin Beaupre, chief medical officer at IDEAYA Biosciences, stated in a news release. “These results set the stage for further testing of the combination in non-small cell lung cancer, where we have just dosed the first patient in our clinical trial.”

What Was the Design of the Early-Phase Trial Evaluating IDE397?

The trial enrolled patients with advanced or metastatic solid tumors that had progressed on at least 1 previous line of therapy or whose disease was intolerant to additional effective standard approaches.2 They were at least 18 years of age, had homozygous loss of MTAP or MTAP deletion, measurable disease, an ECOG performance status of 0 or 1, and acceptable organ function.

If they had known symptomatic brain metastases, a known primary central nervous system malignancy, current liver or biliary disease, impaired gastrointestinal function, active uncontrolled infection, or clinically significant cardiac abnormalities, they were excluded.

The trial is comprised of several parts. The first two parts examined IDE397 as a monotherapy in solid tumors for the dose-escalation portion and then in specific tumors such as non–small cell lung cancer (NSCLC) and urothelial cancer for the dose-expansion portion. Parts 3 and 4 evaluate IDE397 plus docetaxel or paclitaxel in select tumors like NSCLC and urothelial cancer, and parts 5 and 6 evaluated IDE397 in combination with sacituzumab govitecan specifically in urothelial cancer.

Primary end points included dose-limiting toxicities, identification of the maximum tolerated dose and/or the recommended phase 2 dose (RP2D), and to examine preliminary antitumor activity of IDE397 in the combination expansion arms. Secondary end points comprised pharmacokinetics, drug interaction between IDE397 and docetaxel or paclitaxel or sacituzumab govitecan, pharmacodynamics, and preliminary antitumor activity in escalation arms.

What Additional IDE397 Data Have Been Reported From the Trial?

A total of 19 patients with late-line MTAP deletion urothelial cancer received the combination of IDE397 and sacituzumab govitecan; 16 of the patients were efficacy evaluable in that they underwent at least 1 post-baseline tumor assessment by RECIST 1.1 criteria.1,3 More than half (68%) of patients evaluated had disease that progressed on at least 2 prior therapies; 84% previously received immune-oncology therapy and 32% had prior exposure to enfortumab vedotin-ejfv (Padcev).

Prior data from the monotherapy cohort (n = 27) of the study, which comprised those with MTAP-deletion urothelial cancer or NSCLC, were shared during the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.4,5 Of evaluable patients, 33% achieved a confirmed overall response when IDE397 was given at the RP2D of 30 mg; this included 1 complete response and 8 PRs. In those with squamous NSCLC (n = 8) and non–small cell adenocarcinoma (n = 9), the confirmed ORRs were 38% and 22%, respectively.

Common any-grade treatment-emergent and -related adverse effects reported with IDE397 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%).

References

1. IDEAYA Biosciences announces positive data from phase 1/2 combination trial of IDE397, a potential first-in-class MAT2A inhibitor, and Trodelvy in MTAP-deletion urothelial cancer. News release. IDEAYA Biosciences, Inc. September 8, 2025. Accessed September 10, 2025. https://ir.ideayabio.com/2025-09-08-IDEAYA-Biosciences-Announces-Positive-Data-From-Phase-1-2-Combination-Trial-of-IDE397,-a-potential-first-in-class-MAT2A-inhibitor,-and-Trodelvy-R-in-MTAP-Deletion-Urothelial-Cancer
2. Study of IDE397 in participants with solid tumors harboring MTAP deletion. ClinicalTrials.gov. Updated November 18, 2024. Accessed September 10, 2025. https://clinicaltrials.gov/study/NCT04794699
3. IDEAYA Biosciences: September 2025 Investor Corporate Presentation. IDEAYA Biosciences website. Accessed September 10, 2025. https://filecache.investorroom.com/mr5ir_ideayabio/501/20250902_IDEAYA_Investor_Corporate_Presentation_September_2025_vFF.pdf
4. 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.
5. 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 September 10, 2025. 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