TT125-802 Demonstrates Potential in Advanced NSCLC and Solid Tumors

Non–Small Cell Lung Cancer |
Image by Ashling Wahner &
MJH Life Sciences Using AI

TT125-802, a first-in-class oral CBP/p300 bromodomain inhibitor, demonstrated early clinical activity and a favorable safety profile in patients with advanced solid tumors, including treatment-resistant KRAS G12C– and EGFR-mutant non–small cell lung cancer (NSCLC), according to data from an ongoing phase 1 trial (NCT06403436) presented at the 2025 ASCO Annual Meeting.1,2

Findings showed that TT125-802 was generally well tolerated. One dose-limiting toxicity (DLT) of grade 3 hyperglycemia was reported at a dose of 60 mg twice daily. The most frequently reported treatment-related adverse effects (TRAEs) were dysgeusia, hyperglycemia, anemia, transient increased aminotransaminase and amylase/lipase levels, stomatitis, fatigue, and decreased appetite. Notably, 98% of these TRAEs were grade 1 or 2 and reversible, and no cases of thrombocytopenia were observed.

Regarding efficacy, 7 patients experienced clinical benefit lasting at least 6 months, including 1 patient with NSCLC who achieved a deep and durable partial response per RECIST 1.1 criteria.

“Five out of 7 [patients with] NSCLC patients on this study experienced tumor shrinkage following progression on their prior therapy. The two patients with KRAS G12C– or EGFR-mutant NSCLC—the 2 tumor types we had preclinically selected as target indications—each showed deep and durable responses to single-agent TT125-802,” Florian Vogl, MD, PhD, chief medical officer at TOLREMO Therapeutics, explained in a news release. “There remains a large and urgent need for more effective and tolerable therapies, and TT125-802 has the potential to offer an improved therapeutic option through resistance-targeted combinations.”

Phase 1 Trial Design

This phase 1 trial is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of this novel, orally administered CBP/p300 bromodomain inhibitor in patients with advanced solid tumors that are relapsed or refractory to standard-of-care therapies.2

Patients are enrolled into sequential dose cohorts comprising 3 to 6 participants each, and patients in each cohort are undergoing DLT observation period of 21 days.

Under fasting conditions, patients are receiving TT125-802 either once or twice daily. Treatment continues until disease progression, unacceptable toxicity, or withdrawal of consent. Separate cohorts are included to evaluate the effect of food on drug pharmacokinetics and tolerability. Thus far, the agent has been evaluated at 15 mg to 100 mg once per day; 60 mg twice per day under fasting conditions; and 30 mg once per day with food.

To characterize pharmacodynamic (PD) effects and investigate biomarker-driven outcomes, the trial incorporates multiple exploratory translational endpoints. Single-cell RNA sequencing (scRNA-seq) is conducted on paired peripheral blood mononuclear cell samples collected at baseline and during treatment. Optional tumor biopsies are also obtained for scRNA-seq analyses to assess changes in CBP/p300-regulated gene expression and identify potential molecular correlates of response. Bulk RNA sequencing is performed on hair follicle samples to provide a minimally invasive readout of systemic PD activity.

Additionally, circulating tumor DNA was collected throughout treatment to monitor molecular response and evaluate putative predictive biomarkers associated with clinical benefit. This study represents the first clinical evaluation of a CBP/p300 bromodomain inhibitor in solid tumors and integrates biomarker-rich correlative analyses with dose optimization to inform future expansion cohorts and rational combination strategies.

Among the 26 patients enrolled thus far, tumor types included adenoid cystic carcinoma ampullary carcinoma, anal cancer, breast cancer, colorectal cancer, dedifferentiated liposarcoma, enteroid adenocarcinoma, malignant cylindroma, castration-resistant prostate cancer, NSCLC, NUT carcinoma, pancreatic ductal adenocarcinoma, thymic cancer, and undifferentiated pleomorphic sarcoma.

“EGFR- and KRAS-targeted therapies have historically been limited by intrinsic and acquired resistance,” Pasi Jänne, MD, PhD, scientific advisory board member at TOLREMO, as well as senior vice president for Translational Medicine and the director of the Belfer Center for Applied Cancer Science at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, added in a news release.1 “Inhibiting transcriptional mechanisms of resistance via CBP/p300 represents an exciting and much needed opportunity for more effective and tolerable therapies. TT125-802 has shown impressive activity in NSCLC even as a monotherapy, and I look forward to combining the drug with EGFR and KRAS G12C inhibitors to provide better treatment options to my patients.”

References

1. Tolremo Therapeutics announces TT125-802 is the first CBP/p300 bromodomain inhibitor to show clinical activity in solid tumors. News Release. Tolremo Therapeutics. June 4, 2025. Accessed June 13, 2025 https://www.tolremo.com/press-releases/2025/06/04/data-update
2. Vogl F, Antrás JF, Garralda E, et al. TT125-802, a highly selective, well-tolerated bromodomain inhibitor of CBP/p300 with anti-tumor activity in patients with advanced solid tumors: An update on the ongoing phase I study. J Clin Oncol. 2025;43(suppl 16):e15105. doi:10.1200/JCO.2025.43.16_suppl.e15105