A PHASE 1/2 STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND EFFICACY OF TNG260 IN COMBINATION WITH PEMBROLIZUMAB IN PATIENTS WITH STK11-MUTATED ADVANCED SOLID TUMORS

Document Type

Conference Proceeding

Publication Date

11-4-2025

Publication Title

J Immunother Cancer

Keywords

histone deacetylase, pembrolizumab, programmed death 1 ligand 1, adult, aged, checkpoint inhibitor therapy, clinical trial, cohort analysis, conference abstract, controlled study, cytopenia, cytotoxic T lymphocyte, drug dose, drug dose comparison, drug dose escalation, drug therapy, fatigue, female, gene expression, human, loss of function mutation, male, maximum tolerated dose, non small cell lung cancer, pharmacokinetics, phase 1 clinical trial, phase 2 clinical trial, side effect, solid tumor, therapy

Abstract

Background STK11 loss-of-function mutations, found in approximately 20% of non-small cell lung cancers (NSCLC), are associated with primary resistance to immune checkpoint therapy. TNG260 is a small molecule inhibitor of CoREST, a chromatin complex that regulates gene expression through histone deacetylase (HDAC) activity. Preclinical work demonstrated that CoREST inhibition by TNG260 sensitizes STK11-mutant tumors to anti-PD1 treatment. TNG260, in combination with pembrolizumab, is being evaluated in a phase 1/2 clinical trial (NCT05887492). Methods Patients with STK11-mutated, locally advanced or metastatic solid tumors received TNG260 at 40 mg, 80 mg or 120 mg administered once daily (QD) in combination with pembrolizumab at the standard dose of 200 mg IV every 3 weeks. Patients were evaluated to determine the TNG260 pharmacokinetics, safety, tolerability, and preliminary efficacy of the combination therapy, as well as the recommended phase 2 dose (RP2D). Results Forty-one patients with STK11-mutant, locally advanced or metastatic solid tumors were enrolled into 4 dose escalation cohorts. TNG260 achieved exposures in the range predicted to be efficacious by preclinical studies. Paired biopsies from patients that received 80 mg and 120 mg QD doses of TNG260 showed CoREST inhibition in tumor tissue, increased PD-L1 expression, and increased intratumoral infiltration of cytotoxic T cells, providing proof-of-mechanism that TNG260 can remodel the immune microenvironment of STK11-mutant tumors. Dose-limiting toxicities were on-target and consistent with HDAC inhibition, including cytopenias and fatigue. Adverse events with TNG260 were dose-dependent. The maximal tolerated dose (MTD) was determined to be 80 mg. Patients with STK11 mutant/KRAS wild-type NSCLC (representing approximately 50% of STK11 mutant NSCLC patients) receiving clinically active doses of TNG260 plus pembrolizumab exhibited a median PFS of 27 weeks, a marked improvement over the SOC PFS of approximately 10 weeks. Limited clinical activity was observed in patients with KRAS mutant NSCLC and in other solid tumors. Conclusions TNG260 in combination with pembrolizumab is a promising new treatment strategy for reversing immune evasion in STK11 mutant NSCLC tumors, demonstrating a marked improvement in PFS over the current standard of care (SOC). Dose expansion is ongoing at the RP2D of 80 mg TNG260 plus standard dose pembrolizumab for patients with advanced KRAS wild-type/STK11 mutant NSCLC. Ethics Approval The study protocol was approved by the appropriate institutional review board at each participating site. All study subjects provided written informed consent prior to their participation in the trial.

Volume

13

First Page

A641

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