First-in-human phase Ia study of the covalent TEAD palmitoylation inhibitor BPI-460372 in patients with advanced solid tumors: pharmacokinetics, exposure-limited dosing, and early antitumor activity

Our plain-English summary of First-in-human phase Ia study of the covalent TEAD palmitoylation inhibitor BPI-460372 in patients with advanced solid tumors: pharmacokinetics, exposure-limited dosing, and early antitumor activity, by H. Liang, Y. Xu, J. Zhao, et al (Biomarker Research, 2026).

The study

• Authors: H. Liang, Y. Xu, J. Zhao, X. Liu, W. Zhong, X. Zheng, H. Liu, M. Chen, X. Han, M. Wang
• Journal: Biomarker Research
• Published: 2026;14(1)
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The Hippo pathway is a critical regulator of tumor development and progression, dysregulation of the Hippo pathway drives tumorigenesis in multiple malignancies. BPI-460,372 is a first‑in‑class covalent irreversible inhibitor of transcriptional enhanced associated domain (TEAD) palmitoylation. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of BPI-460,372 in patients with advanced solid tumors.

Methods: This open-label, multicenter, single-arm phase Ia dose-escalation study enrolled patients with advanced solid tumors who had progressed after standard therapies or lacked available standard treatment options. A modified 3 + 3 design with accelerated titration was used. BPI-460,372 was administered orally once daily under fasting conditions, with dose escalation from 10 mg to 240 mg daily. Additional cohorts evaluated twice-daily dosing (80 mg and 120 mg) and postprandial administration (80 mg and 160 mg) to characterize exposure optimization strategies. Primary endpoints were safety, tolerability, dose-limiting toxicities (DLTs), and the maximum tolerated dose (MTD). Secondary endpoints included pharmacokinetics (PK) and preliminary antitumor efficacy. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; modified criteria were applied for malignant pleural mesothelioma.

Results: Between April 2023 and December 2024, 36 patients were screened, and 28 patients were enrolled and treated. No DLTs were observed, and the MTD was not reached. All patients experienced at least one treatment-emergent adverse event (TEAE). Treatment-related adverse events (TRAEs) occurred in 89.3% of patients, with grade ≥ 3 events occurring in 39.3%. Proteinuria was the most common TRAE (46.4%, including 10.7% grade ≥ 3). Three deaths occurred during the study, including one treatment-related death due to abdominal infection. Pharmacokinetic analyses demonstrated rapid absorption, dose-dependent increases in exposure, achievement of steady-state exposure after repeated dosing, and limited drug accumulation. Among 28 evaluable patients, one confirmed partial response (PR) was observed in the 120 mg twice-daily cohort. The objective response rate (ORR) and disease control rate (DCR) were 3.6% (95% CI: 0.1-18.4) and 64.3% (95% CI: 44.1-81.4), respectively. Median progression-free survival (PFS) was 5.6 months (95% CI: 2.4-7.0), and median overall survival (OS) was 13.2 months (95% CI: 7.4-15.1).

Conclusion: BPI-460,372 demonstrated a distinct pharmacokinetic profile and showed preliminary antitumor activity in patients with advanced solid tumors. However, treatment-emergent toxicities and exposure limitations constrained further dose escalation and prevented definition of an optimal biologically active dose. These findings support further clinical evaluation of BPI-460,372 using optimized dosing strategies, particularly in tumors with Hippo pathway dependency.

Trial Registration: ClinicalTrials.gov NCT05789602. Registered on 29 March 2023.

© 2026. The Author(s).

In plain English

This first-in-human phase Ia study tested BPI-460,372, an oral drug that blocks TEAD proteins in the Hippo signaling pathway. From April 2023 to December 2024, 28 patients with advanced solid tumors were treated at nine Chinese centers. Fifteen had malignant mesothelioma, 7 non-small cell lung cancer, 5 epithelioid hemangioendothelioma, 1 small cell lung cancer. Once-daily doses rose from 10 mg to 240 mg; twice-daily and with-food dosing were also tested. No dose-limiting toxicities occurred. Treatment-related side effects affected 89.3% of patients, 39.3% at grade 3 or higher. Protein in the urine (proteinuria) was most common (46.4%). Treatment-related heart side effects affected 50.0%. One death, from abdominal infection, was treatment-related. Single-dose drug levels rose roughly in proportion to dose, but with repeated once-daily dosing at 80 to 240 mg they plateaued. One patient, a man with malignant pleural mesothelioma on 120 mg twice daily, had a confirmed partial response. Disease control (tumors shrinking or staying stable) was 64.3% (18 of 28; 95% CI 44.1% to 81.4%). The authors concluded that toxicities, particularly cardiac events, and limited drug exposure prevented defining an optimal biologically active dose.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Open-label, multicenter, single-arm phase Ia dose-escalation study (first-in-human drug trial) using a modified 3 + 3 design with accelerated titration
• Who was studied: 28 patients with advanced solid tumors, treated at nine centers in China between April 2023 and December 2024: malignant mesothelioma (n = 15), non-small cell lung cancer (n = 7), epithelioid hemangioendothelioma (n = 5) and small cell lung cancer (n = 1). The median age was 60 years (range 34 to 73) and 53.6% were female.
• Exposure: The experimental drug BPI-460,372 (a covalent TEAD palmitoylation inhibitor) taken by mouth once daily while fasting at 10, 20, 40, 80, 160 and 240 mg/d. Additional cohorts tested twice-daily dosing (80 mg and 120 mg) and dosing after food (80 mg and 160 mg). Asbestos exposure is not addressed.
• Main results:
  • In all 28 patients, no dose-limiting toxicities were observed and the maximum tolerated dose was not reached.
  • Treatment-related adverse events occurred in 89.3% of the 28 patients.
  • Grade 3 or higher treatment-related adverse events occurred in 39.3% of patients.
  • Proteinuria was the most common treatment-related adverse event (46.4% of patients), with grade 3 or higher events in three patients (10.7%).
  • Three deaths occurred during the study. One was treatment-related, due to abdominal infection.
  • Treatment-related cardiac adverse events were observed in 50.0% of patients.
  • Grade 3 or higher cardiac adverse events occurred in 21.4% of patients, and no fatal cardiac events occurred.
  • After a single dose, drug exposure increased approximately in proportion to dose.
  • At higher once-daily doses (80 to 240 mg), steady-state exposure (after repeated dosing) plateaued. The authors described this as suggesting absorption-limited pharmacokinetics.
  • Twice-daily dosing increased steady-state exposure by 1.7 to 2.3-fold compared with once-daily dosing.
  • Taking the drug with food increased exposure at the 160 mg dose (approximately 1.8 to 2.0-fold), with minimal effect at 80 mg.
  • Among the 28 patients, the objective response rate was 3.6% (1/28; 95% CI 0.1% to 18.4%) and the disease control rate was 64.3% (18/28; 95% CI 44.1% to 81.4%).
  • Median progression-free survival was 5.6 months (95% CI 2.4 to 7.0) and median overall survival was 13.2 months (95% CI 7.4 to 15.1).
  • The single confirmed partial response was in a 40-year-old man with malignant pleural mesothelioma in the 120 mg twice-daily cohort, with a 56.7% reduction in target lesions.
  • In the exploratory genomic analyses, no consistent association between genomic alterations and clinical response was observed.
• The authors' conclusion: The authors concluded that BPI-460,372 showed TEAD-targeted antitumor activity, including a confirmed response in malignant pleural mesothelioma. They also concluded that treatment-emergent toxicities, particularly cardiac events, and exposure limitations constrained further dose escalation and prevented definition of an optimal biologically active dose.
• Limitations the authors state:
  • The small sample size restricted statistical inference.
  • Enrolled tumor types were heterogeneous, which limits tumor-specific conclusions.
  • The primary objective was safety rather than efficacy, so the antitumor activity signals are exploratory and hypothesis-generating.
  • No measurements of TEAD target occupancy or tumor pathway suppression over time were available.
  • Tissue sequencing was available for fewer than half of the patients.
  • Because of the small sample size, the comparison of cardiac events by pre-existing cardiovascular history is descriptive only.

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Pleural Mesothelioma, Progression-Free Survival, Median Overall Survival.

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