A Phase 1/2, Multi-Center, Open-Label Study to Evaluate the Safety, Tolerability, and Preliminary Anti-tumor Activity of TNG462 as a Single Agent and in Combination in Patients With MTAP-deleted Advanced or Metastatic Solid Tumors

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Overview

TNG462 is an investigational MTA-cooperative PRMT5 inhibitor developed by Tango Therapeutics, designed to target cancers with MTAP deletions, which occur in approximately 10-15% of solid tumors. (ir.tangotx.com)

Mechanism of Action

TNG462 selectively inhibits PRMT5 in the presence of MTA, a metabolite that accumulates in MTAP-deleted cancer cells. This selective inhibition aims to induce cytotoxicity in cancer cells while sparing normal cells. (ir.tangotx.com)

Efficacy

In a Phase 1/2 clinical trial initiated in July 2023, TNG462 demonstrated clinical activity across multiple tumor types, including non-small cell lung cancer (NSCLC) and pancreatic cancer. As of October 2024, among seven cholangiocarcinoma patients, three achieved confirmed partial responses, resulting in an objective response rate (ORR) of 43%. The median time on treatment was 24 weeks and was still increasing at the time of reporting. (ir.tangotx.com)

Safety

TNG462 has been well-tolerated, with thrombocytopenia identified as the dose-limiting toxicity. Other adverse events, such as nausea, vomiting, diarrhea, and fatigue, were predominantly grade 1 and occurred in less than 20% of patients. (ir.tangotx.com)

Further Reading

• Tango Therapeutics Reports Positive TNG462 Clinical Data and Provides Update on PRMT5 Development Program
• Tango Therapeutics Reports Third Quarter 2024 Financial Results and Provides Business Highlights
• Tango Therapeutics Announces First Patient Dosed in TNG462 Phase 1/2 Trial in Patients With MTAP-deleted Solid Tumors

Last updated: Aug 2025

Inclusion Criteria:

1. Age: ≥18 years-of-age at the time of signature of the main study ICF

2. Performance status: ECOG Performance Score of 0 to 1

3. Confirmed histologic or cytologic diagnosis of a locally advanced, metastatic, and/or unresectable solid tumor

4. Prior standard therapy, as available

5. Documented bi-allelic (homozygous) deletion of MTAP in a tumor detected by next- generation sequencing or absence of MTAP protein in a tumor detected by IHC.

6. Adequate organ function/reserve per local labs

7. Adequate liver function per local labs

8. Adequate renal function per local labs

9. Negative serum pregnancy test result at screening

10. Written informed consent must be obtained according to local guidelines

Exclusion Criteria:

1. Known allergies, hypersensitivity, or intolerance to TNG462, or its excipients or to pembrolizumab in the combination treatment arms

2. Uncontrolled intercurrent illness that will limit compliance with the study requirements

3. Active infection requiring systemic therapy

4. Currently participating in or has planned participation in a study of another investigational agent or device

5. Impairment of GI function or disease that may significantly alter the absorption of oral TNG462

6. Active prior or concurrent malignancy.

7. Central nervous system metastases associated with progressive neurological symptoms

8. Current active liver disease from any cause

9. Known to be HIV positive, unless all of the following criteria are met:

1. CD4+ count ≥300/μL

2. Undetectable viral load

3. Receiving highly active antiretroviral therapy

10. Clinically relevant cardiovascular disease

11. A female patient who is pregnant or lactating

12. Patient is unwilling or unable to comply with the scheduled visits, drug administration plan, laboratory tests, biopsy, or other study procedures and study restrictions

13. Patient has a prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the investigator's opinion, may affect the safety of the patient or impair the assessment of study results