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Treatment has been initiated in a phase 1/2 study of TNG260 added to pembrolizumab in patients with advanced or metastatic solid tumors.
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TNG260 in combination with pembrolizumab (Keytruda) has been dosed in the first patient in a phase 1/2 clinical trial of patients with advanced solid tumors (NCT05887492).1
TNG260, an inhibitor of the CoREST-selective deacetylase, has been shown to undo α-PD1 resistance resulting from STK11 loss.2
Trial Name: A Phase 1/2, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of TNG260 as Single Agent and in Combination With an Anti-PD-1 Antibody In Patients With STK11 Mutated Advanced Solid Tumors
ClinicalTrials.gov Identifier: NCT05887492
Sponsor: Tango Therapeutics, Inc.
Recruitment Contact: Adam Crystal, MD, PhD, 8573204899, clinicaltrials@tangotx.com
Completion Date: June 2025
“STK11 loss of function results in immune evasion within the tumor microenvironment and renders tumors resistant to various checkpoint inhibitors. This process makes treatment of cancers difficult, particularly those for which we rely on immunotherapy. TNG260 is a CoREST inhibitor which can re-sensitize tumors to checkpoint inhibitors,” Salman R. Punekar, MD, a medical oncologist and assistant professor, Department of Medicine at NYU Grossman School of Medicine, told Targeted Oncology™. “TNG260 in combination with PD-1 blockade in preclinical studies has demonstrated excellent antitumor activity, but also the development of memory responses which can prevent further cancer formation,” Punekar added.
Preclinical data show that the agent is potent and highly selective. When used in combination with an anti-PD-1 agent, like pembrolizumab, TNG260 made the tumor microenvironment more operational, and reduced intratumoral infiltration of neutrophils.2
"STK11 encodes a kinase that has a role in cell death and DNA damage response. It is felt to be a negative prognostic indicator for patients treated with immunotherapy and pdl/pdl1 inhiibitors. Thus far there have been no approved therapies for this mutation. TNG260 is a deacetylase inhibitor that may be able to overcome the effects of STK11 mutations," Alexander I. Spira, MD, PhD, FACP told Targeted Oncology.
In the phase 1/2, open-label study, the safety, tolerability, pharmacokinetics, and preliminary efficacy of TNG260 with pembrolizumab will be assessed in patients with non–small cell lung cancer (NSCLC), endometrial cancer, pancreatic cancer, cervical cancer, breast cancer, and other advanced solid tumors. Approximately 126 patients will be enrolled for this purpose.3
Patients will be treated in 1 of 4 arms, which will be the dose-escalation cohort of patients with STK11-mutant sold tumors. The dose expansion cohort of those with STK11-mutant and KRAS-mutant NSCLC, the dose-expansion arm of patient with STK11-mutant and KRAS-wild-type NSCLC, and the dose-expansion arm of patients with STK11-mutant advanced or metastatic solid tumors.
In the phase 1 portion dose-escalation portion of the study, the primary end point is determining the maximum-tolerated dose and recommended phase 2 dose of TNG260. During phase 2, investigators with evaluate antitumor activity measured by objective response rate, duration of response, and progression-free survival as the primary end point.
Secondary end points of the study include antitumor evidence of TNG260 plus pembrolizumab, antineoplastic activity in phase 1, as well as area under the curve of TNG260, time to maximal concentration of TNG26, maximum observed plasma concentration of the agent, terminal half-life of the agent, characterization of pembrolizumab concentrations when given with TNG260, safety and tolerability, and changes in histone acetylation of pembrolizumab when dosed with TNG260.
Patients aged 18 years or older with an ECOG performance score of 0 or 1, measurable disease per RECIST v1.1, a STK11 mutation, confirmed disease by histology or cytology, and adequate organ, and renal function were eligible for enrollment. Patients must have produced a negative pregnancy test to enroll. The study excludes patients with known allergies, hypersensitivity, or intolerance to the investigation agent, as well as those with uncontrolled intercurrent illness, impaired gastrointestinal function or disease, active infection that needs systemic treatment, active prior or concurrent malignancy, central nervous system metastases, liver disease, and certain forms of cardiovascular disease. Further, patients who have plans to participate in another clinical trial of an investigation agent or device were ineligible to enroll. Female patients who are pregnant were also ineligible.
“We hope that this study will sensitize cancers which are resistant to immunotherapy, particularly those that are primary refractory and will result in deep and durable responses in patients,” said Punekar.
REFERENCES:
1. Tango Therapeutics announces first patient dosed in TNG260 phase 1/2 trial in patients with STK11-mutant cancers. News release. Tango Therapeutics. July 24, 2023. Accessed July 24, 2023. https://tinyurl.com/yckddr7e
2. Ahronian L, Wu X, Zhnag M, et al. 444 TNG260, a CoREST-selective deacetylase inhibitor, reverses anti-PD1 resistance driven by loss of STK11. J Immunother Cancer. 2022;10(suppl 2). doi:10.1136/jitc-2022-SITC2022.0444
3. Study of TNG260 and an anti-PD antibody in STK11 mutated solid tumors. ClinicalTrials.gov. Updated June 15, 2023. Accessed July 24, 2023. https:// clinicaltrials.gov/ct2/show/NCT05887492?term=NCT05887492&draw=2&rank=1
