First-in-Class CBP/p300 Inhibitor TT125-802 Shows Promise in Treatment-Resistant NSCLC
核心洞察
TT125-802, a novel oral CBP/p300 (搜索) bromodomain inhibitor, demonstrated early clinical activity in advanced solid tumors with a favorable safety profile in an ongoing phase 1 trial.
Five out of seven NSCLC patients experienced tumor shrinkage following progression on prior therapy, with deep and durable responses observed in KRAS G12C (搜索)- and EGFR (搜索)-mutant NSCLC patients.
The treatment showed a best-in-class safety profile with 98% of treatment-related adverse events being grade 1 or 2 and reversible, notably without thrombocytopenia.
TT125-802, a first-in-class oral CBP/p300 (搜索) bromodomain inhibitor developed by TOLREMO Therapeutics (搜索), has demonstrated early clinical activity and a favorable safety profile in patients with advanced solid tumors, including treatment-resistant KRAS G12C (搜索)- and EGFR (搜索)-mutant non-small cell lung cancer (NSCLC), according to data from an ongoing phase 1 trial presented at the 2025 ASCO Annual Meeting.
Clinical Activity in Treatment-Resistant NSCLC
The trial results showed particularly promising activity in NSCLC patients who had progressed on prior therapies. Five out of seven NSCLC patients experienced tumor shrinkage following progression on their previous treatment. Most notably, the two patients with KRAS G12C (搜索)- or EGFR (搜索)-mutant NSCLC—the tumor types preclinically selected as target indications—each showed deep and durable responses to single-agent TT125-802.
"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 (搜索)– or EGFR (搜索)-mutant NSCLC—the 2 tumor types we had preclinically selected as target indications—each showed deep and durable responses to single-agent TT125-802," explained Florian Vogl, MD, PhD, chief medical officer at TOLREMO Therapeutics (搜索).
Seven patients across all tumor types experienced clinical benefit lasting at least 6 months, including one patient with NSCLC who achieved a deep and durable partial response per RECIST 1.1 criteria.
Best-in-Class Safety Profile
TT125-802 demonstrated a favorable safety profile that distinguishes it from other inhibitors in its class. Only one dose-limiting toxicity of grade 3 hyperglycemia was reported at a dose of 60 mg twice daily. The most frequently reported treatment-related adverse effects included dysgeusia, hyperglycemia, anemia, transient increased aminotransaminase and amylase/lipase levels, stomatitis, fatigue, and decreased appetite.
Critically, 98% of treatment-related adverse events were grade 1 or 2 and reversible. Notably, no cases of thrombocytopenia were observed—a significant advantage as thrombocytopenia represents the primary toxicity associated with this class of inhibitors.
Phase 1 Trial Design and Patient Population
The ongoing phase 1 trial is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of TT125-802 in patients with advanced solid tumors that are relapsed or refractory to standard-of-care therapies. Patients are enrolled into sequential dose cohorts of 3 to 6 participants each, with a 21-day dose-limiting toxicity observation period.
Under fasting conditions, patients receive TT125-802 either once or twice daily, with treatment continuing until disease progression, unacceptable toxicity, or withdrawal of consent. The agent has been evaluated at doses ranging from 15 mg to 100 mg once per day, 60 mg twice per day under fasting conditions, and 30 mg once per day with food.
Among the 26 patients enrolled, 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.
Addressing Treatment Resistance
The mechanism of action of TT125-802 addresses a critical unmet need in oncology by targeting transcriptional mechanisms of resistance. "EGFR (搜索)- and KRAS-targeted therapies have historically been limited by intrinsic and acquired resistance," noted Pasi Jänne, MD, PhD, scientific advisory board member at TOLREMO and senior vice president for Translational Medicine at Dana-Farber Cancer Institute. "Inhibiting transcriptional mechanisms of resistance via CBP/p300 (搜索) represents an exciting and much needed opportunity for more effective and tolerable therapies."
Biomarker-Rich Translational Research
The trial incorporates multiple exploratory translational endpoints to characterize pharmacodynamic effects and investigate biomarker-driven outcomes. Single-cell RNA sequencing is conducted on paired peripheral blood mononuclear cell samples collected at baseline and during treatment. Optional tumor biopsies are obtained for single-cell RNA sequencing analyses to assess changes in CBP/p300 (搜索)-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 pharmacodynamic activity. Additionally, circulating tumor DNA is collected throughout treatment to monitor molecular response and evaluate putative predictive biomarkers associated with clinical benefit.
Future Development Strategy
The promising single-agent activity and favorable safety profile position TT125-802 for combination therapy development. "TT125-802 has shown impressive activity in NSCLC even as a monotherapy, and I look forward to combining the drug with EGFR (搜索) and KRAS G12C (搜索) inhibitors to provide better treatment options to my patients," Jänne added.
According to Stefanie Flückiger-Mangual, PhD, CEO and co-founder of TOLREMO, the compound's development approach was unique: "The best-in-class safety and activity in solid tumors is particularly notable because we didn't set out to develop a CBP/p300 (搜索) inhibitor - initially, TT125-802 was developed phenotypically to inhibit non-oncogene addiction in cancer. By starting with the biology around transcriptional addiction, it led us to CBP/p300 as a novel target in this space and yielded best-in-class chemistry, enabling a wider therapeutic window and broadening the clinical potential of our asset both in hematological malignancies as well as in solid tumors."
This study represents the first clinical evaluation of a CBP/p300 (搜索) bromodomain inhibitor in solid tumors and integrates biomarker-rich correlative analyses with dose optimization to inform future expansion cohorts and rational combination strategies.