Trial launches of MAT2A inhibitor plus sacituzumab govitecan in bladder cancer

The first patient has been dosed in a phase 1 study exploring IDE397, an investigational MAT2A inhibitor, in combination with sacituzumab govitecan-hziy (Trodelvy), a Trop-2 directed antibody drug conjugate, in patients with methylthioadenosine phosphorylase (MTAP)-deletion bladder cancer, IDEAYA announced in a news release.¹

The study is being conducted as an arm in a larger, ongoing clinical trial of IDE397 in combination with other agents in patients with advanced or metastatic MTAP-deleted solid tumors.

"We are pleased to have dosed our first patient with MTAP-deletion bladder cancer in this phase 1 trial evaluating combination treatment with IDE397 and Trodelvy,” said Darrin M. Beaupre, MD, PhD, chief medical officer of IDEAYA Biosciences, in the news release.¹ “The MAT2A-Trop2 ADC combination targets 2 distinct, yet complementary nodes in patients with MTAP-deleted urothelial cancer and has first-in-class potential to improve clinical outcomes for bladder cancer patients with poor prognosis associated with MTAP-deletion.”

According to IDEAYA, “IDE397 is a potent and selective small molecule inhibitor targeting methionine adenosyltransferase 2 alpha (MAT2A) in patients having solid tumors with methylthioadenosine phosphorylase (MTAP) deletion.”¹

Overall, the phase 1 trial will assess the safety, tolerability, pharamacokinetics, pharmacodynamics, and preliminary efficacy of IDE397 in combination with sacituzumab govitecan in adult patients with bladder cancer. The study is being conducted as an arm in a larger, ongoing clinical trial (NCT04794699) of IDE397 in combination with other agents in adult patients with advanced or metastatic MTAP-deleted solid tumors.²

In total, the larger open-label, dose expansion/dose escalation trial plans to enroll 180 patients across multiple solid tumor types, including urothelial carcinoma, non-small cell lung cancer, and EG. For the study, IDE397 will be assessed in combination with either sacituzumab govitecan or a taxane therapy (docetaxel or paclitaxel).

Patients will be enrolled across clinical trial sites in the US, Australia, Europe, and Asia. To be eligible for the study, patients must have an advanced or metastatic solid tumor that has progressed on at least 1 prior therapy or is intolerant to additional effective standard therapy, a homozygous loss of MTAP or MTAP depletion, an ECOG performance status of less than or equal to 1, and adequate organ function. Additionally, patients must have recovered from all acute effects of prior therapy.

The primary outcome measures for the study include assessment of dose-limiting toxicities, determination of a maximum tolerated dose and/or a recommended phase 2 dose level, and an evaluation of preliminary anti-tumor activity. Secondary outcome measures include pharmacokinetics of IDE397 and the drug interactions of the therapy with sacituzumab govitecan in the urothelial carcinoma arm, or with docetaxel or paclitaxel in the other cohorts.

The study also includes a phase 2 expansion arm for IDE397 as a monotherapy in MTAP-deletion solid tumors. According to the news release, the company is planning to have a clinical update on the phase 2 IDE397 monotherapy expansion dose in approximately 15 patients with MTAP-depletion bladder and lung cancer in the second half of 2024.

Additional news on sacituzumab govitecan

In April 2021, the FDA granted an accelerated approval indication to sacituzumab govitecan for patients with locally advanced or metastatic urothelial carcinoma who have previously received a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor.³ The approval was supported by overall response rate (ORR) and duration of response data from the phase 2 TROPHY U-01 trial (NCT03547973), which enrolled 112 patients to evaluate the safety and efficacy of sacituzumab govitecan as a monotherapy or with novel combinations.

Continued approval of sacituzumab govitecan for this indication is contingent upon data from confirmatory trials, including the TROPiCS-04 trial. Gilead recently reported topline results from the phase 3 TROPiCS-04 trial (NCT04527991),⁴ showing that sacituzumab govitecan as a monotherapy failed to meet the primary end point of overall survival (OS) vs single-agent chemotherapy in patients with metastatic urothelial carcinoma who had previously received platinum-containing chemotherapy and anti-PD-(L)1 therapy.

A numerical improvement in OS favoring sacituzumab govitecan was observed, though the end point was not reached in the intent-to-treat population. Further, trends in improvement on the secondary end points of progression-free survival and ORR were noted among pre-specified subgroups of patients, though the analyses were not alpha-controlled for formal statistical testing.

Among the entire study population, more deaths due to adverse events (AEs) were observed among patients who received sacituzumab govitecan vs those who received single-agent chemotherapy. AEs leading to death generally occurred early in treatment and were related to neutropenic complications, including infection.

There are no new changes to the known safety profile of sacituzumab govitecan for the approved indications.

References

1. IDEAYA Biosciences announces first-patient-in for phase 1 clinical trial evaluating IDE397 and Trodelvy combination in MTAP-deletion bladder cancer. News release. IDEAYA Biosciences, Inc. Published online June 25, 2024. Accessed June 26, 2024. https://www.prnewswire.com/news-releases/ideaya-biosciences-announces-first-patient-in-for-phase-1-clinical-trial-evaluating-ide397-and-trodelvy-combination-in-mtap-deletion-bladder-cancer-302181366.html

2. Study of IDE397 in participants with solid tumors harboring MTAP deletion. ClinicalTrials.gov. Last updated May 7, 2024. Accessed June 26, 2024. https://clinicaltrials.gov/study/NCT04794699

3. FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. News release. US Food & Drug Administration. April 13, 2021. Accessed May 31, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sacituzumab-govitecan-advanced-urothelial-cancer

4. Gilead provides update on phase 3 TROPiCS-04 Study. News release. Gilead Sciences. May 30, 2024. Accessed May 31, 2024. https://www.gilead.com/news-and-press/press-room/press-releases/2024/5/gilead-provides-update-on-phase-3-tropics-04-study