TNG462 Trial: PRMT5 Inhibitor for MTAP-Deleted Mesothelioma
Phase 1/2 trial (NCT05732831) of TNG462, an oral PRMT5 inhibitor, for MTAP-deleted solid tumors. Mesothelioma is an expansion cohort. Now recruiting.
Tango Therapeutics is running an early-phase clinical trial of TNG462, an oral targeted drug, for people whose tumors carry a specific genetic deletion. Mesothelioma is one of the cancer types included in the study.
The trial, designated NCT05732831, is a Phase 1/2 study testing TNG462 as a single agent and in combination, in patients with MTAP-deleted advanced or metastatic solid tumors. It plans to enroll up to 225 participants and is currently recruiting.
What the Trial Is Testing
TNG462 is described in the trial record as a selective PRMT5 inhibitor that is taken by mouth. The study is a first-in-human trial, which means it is the first time this drug has been given to people.
The trial enrolls patients whose tumors have a documented loss of a gene called MTAP. The study requires a confirmed bi-allelic (homozygous) deletion of MTAP detected by next-generation sequencing, or absence of the MTAP protein detected by immunohistochemistry. This is a targeted-therapy approach: the drug is matched to a feature of the tumor rather than to the organ where the cancer started.
The study has two parts:
- Dose escalation (Phase 1): Participants receive escalating doses of TNG462, given as a single agent and in combination with pembrolizumab, to estimate the maximum tolerated dose.
- Dose expansion (Phase 2): Once a recommended dose is identified, separate cohorts test that dose in specific MTAP-deleted tumor types.
The expansion cohorts cover non-small cell lung cancer, mesothelioma, pancreatic ductal adenocarcinoma, sarcoma, and other solid tumors. In the mesothelioma cohort, participants receive TNG462 on its own at the identified recommended Phase 2 dose. Pembrolizumab is combined with TNG462 only in the dose-escalation portion and in a separate non-small cell lung cancer cohort, not in the mesothelioma cohort.
Who Can Participate
The trial is open to adults aged 18 and older of any sex. Key eligibility requirements listed in the trial record include:
- An ECOG performance status of 0 to 1
- A confirmed diagnosis of a locally advanced, metastatic, or unresectable solid tumor
- Prior standard therapy, as available
- A documented bi-allelic (homozygous) MTAP deletion by next-generation sequencing, or absence of MTAP protein by immunohistochemistry
- Adequate organ, liver, and renal function per local labs
People are excluded for reasons that include known hypersensitivity to TNG462 (or to pembrolizumab in the combination arms), uncontrolled intercurrent illness, active infection requiring systemic therapy, active prior or concurrent malignancy, central nervous system metastases with progressive neurological symptoms, active liver disease, and clinically relevant cardiovascular disease. People who are pregnant or lactating are not eligible.
This trial is listed on ClinicalTrials.gov as NCT05732831. The full record, including current site contact details and the most recent eligibility criteria, is available there. Anyone considering a trial should review the listing with their own oncology team.
Where the Trial Is Running
The trial record lists 26 sites across three countries: 15 in the United States, 4 in France, and 7 in Spain. United States sites listed as recruiting include Stanford University in Palo Alto, Sylvester Comprehensive Cancer Center in Miami, the University of Chicago Medicine, Massachusetts General Hospital and Dana-Farber Cancer Institute in Boston, NYU Langone Health in New York, the University of Texas MD Anderson Cancer Center in Houston, and the Huntsman Cancer Institute in Salt Lake City. One United States site, Florida Cancer Specialists & Research Institute in Lake Mary, is listed as completed.
How the Trial Measures Results
The primary measures differ by phase. In Phase 1, the trial measures the maximum tolerated dose and the dosing schedule. In Phase 2, it measures the anti-neoplastic activity of TNG462 given as a single agent and in combination. Secondary measures include the adverse event profile, pharmacokinetic measures such as plasma concentration over time, maximum plasma concentration, half-life, clearance, and volume of distribution, and tumor levels of SDMA, a marker related to how the drug acts.
The trial began on May 26, 2023. Its estimated primary completion date is May 2026, with an estimated overall completion date of September 2026.
Why This Trial Matters for Mesothelioma
Most mesothelioma trials test immunotherapy or chemotherapy. This study takes a different angle by targeting a genetic vulnerability that some tumors carry. MTAP deletion is a feature found in a share of cancers, including some mesotheliomas, and drugs that block PRMT5 are being studied specifically for tumors that have lost MTAP.
For people with mesothelioma whose tumors carry an MTAP deletion, a trial like this offers a treatment matched to that genetic feature. Because mesothelioma is one cohort within a larger basket study, the mesothelioma-specific data will build as that cohort fills.
Limitations to Consider
This is an early-phase, open-label trial. The dose-escalation portion is designed mainly to find a safe and tolerable dose, and the expansion portion provides a first read on activity rather than definitive proof of benefit. The study is non-randomized, so there is no comparison group within the trial.
Eligibility hinges on a confirmed MTAP deletion, so the trial is open only to a subset of mesothelioma patients whose tumors have been tested and found to carry that change. Results will take time, and the trial record does not report efficacy outcomes for the mesothelioma cohort at this stage.
References
ClinicalTrials.gov. Safety and Tolerability of TNG462 in Patients With MTAP-deleted Solid Tumors.
https://clinicaltrials.gov/study/NCT05732831
Reader Q&A
Frequently Asked Questions
What drug does the TNG462 trial test?
The trial tests TNG462, which the study record describes as a selective PRMT5 inhibitor taken by mouth. It is being studied on its own and, in some arms, in combination with pembrolizumab, an anti-PD-1 antibody given intravenously. Pembrolizumab is not part of the mesothelioma-only cohort.
Who sponsors the trial and what phase is it?
The trial is sponsored by Tango Therapeutics, Inc. It is a Phase 1/2 study with a dose-escalation part and a dose-expansion part, planned to enroll up to 225 participants.
What is MTAP deletion and why does it matter here?
MTAP is a gene that some tumors lose. The trial enrolls only people whose tumors have a confirmed bi-allelic deletion of MTAP, detected by next-generation sequencing, or an absence of MTAP protein detected by immunohistochemistry. PRMT5 inhibitors like TNG462 are being studied specifically for tumors that have lost MTAP.
Can people with mesothelioma join this trial?
Yes. Mesothelioma is one of the dose-expansion cohorts. To be eligible, a person’s mesothelioma must carry a confirmed MTAP deletion, and they must meet the trial’s other criteria, including being 18 or older with an ECOG performance status of 0 to 1.
Where is the trial being conducted?
The trial record lists 26 sites across the United States, France, and Spain. United States sites include Stanford, Dana-Farber, Massachusetts General Hospital, MD Anderson, NYU Langone, and others. The current list of recruiting sites is on the ClinicalTrials.gov record under NCT05732831.
Does the trial report whether TNG462 works for mesothelioma?
Not yet. This is an early-phase study, and the trial record does not report efficacy results for the mesothelioma cohort. The Phase 2 portion is designed to provide a first read on anti-tumor activity once cohorts fill and follow-up matures.