An experimental cancer drug designed to shut down a signaling pathway that drives many hard-to-treat tumors has cleared its first test in humans, but the trial also revealed safety signals and pharmacokinetic constraints that stopped short of defining an optimal dose. In a first-in-human phase Ia study published in Biomarker Research, the covalent TEAD palmitoylation inhibitor BPI-460372 produced one confirmed partial response among 28 patients with advanced solid tumors, while treatment-emergent toxicities and exposure limitations constrained further dose escalation and prevented definition of an optimal biologically active dose.
The Hippo pathway is a critical regulator of organ development and tissue homeostasis, and its dysregulation contributes to tumor initiation, progression, and therapeutic resistance across multiple solid malignancies. When the upstream regulators NF2 or LATS1/2 are genetically or functionally inactivated, the transcriptional co-activators YAP and TAZ accumulate in the nucleus and drive oncogenic transcription programs through interaction with TEAD1–4. This aberrant signaling axis is particularly enriched in mesothelioma, epithelioid hemangioendothelioma, and a subset of lung cancers, making the Hippo-YAP/TAZ pathway a therapeutically relevant vulnerability. Because the YAP/TAZ-TEAD protein-protein interface is flat and lacks deep binding pockets amenable to classical small molecules, drug developers have instead targeted TEAD autopalmitoylation, a post-translational modification essential for TEAD folding stability and transcriptional activity.
BPI-460372 is an orally available, covalent and irreversible inhibitor of TEAD1, TEAD3, and TEAD4 that binds to the palmitate-binding pocket and blocks TEAD autopalmitoylation. Preclinical studies demonstrated potent antitumor activity in NF2-deficient and LATS1/2-mutant tumor models. Several other TEAD palmitoylation inhibitors, including VT3989, IAG933, IK-930, ISM6331, and SW-682, have entered early-phase clinical development, but their clinical profiles remain incompletely defined, particularly with respect to pharmacokinetic variability, exposure-response relationships, and class-associated toxicities.
The new study was an open-label, multicenter, single-arm dose-escalation trial (NCT05789602) using a modified 3+3 design with accelerated titration. Between April 2023 and December 2024, 36 patients were screened across nine centers in China, and 28 were enrolled and treated. All had locally advanced or metastatic solid tumors that had progressed after standard therapy or lacked standard treatment options. The tumor types included malignant mesothelioma (15 patients), non-small cell lung cancer (7), epithelioid hemangioendothelioma (5), and small cell lung cancer (1). The median age was 60 years, 53.6 percent of patients were female, 82.1 percent had received prior chemotherapy, 57.1 percent had received prior immunotherapy, and the median number of prior therapy lines was two. BPI-460372 was given orally once daily under fasting conditions, with dose escalation from 10 mg to 240 mg daily, and additional cohorts explored twice-daily dosing at 80 mg and 120 mg and postprandial administration at 80 mg and 160 mg.
No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. All 28 patients experienced at least one treatment-emergent adverse event, and treatment-related adverse events occurred in 89.3 percent of patients, with grade 3 or higher events in 39.3 percent. Proteinuria was the most common treatment-related adverse event, affecting 46.4 percent of patients, including 10.7 percent with grade 3 or higher events. Three deaths occurred during the study, including one treatment-related death due to abdominal infection; the other two were attributed to disease progression and acute respiratory failure. Three patients required dose reductions due to treatment-related adverse events, 14 experienced temporary treatment interruption, and four discontinued treatment permanently. The most common reasons for interruption were proteinuria and decreased ejection fraction.
Cardiac adverse events emerged as a notable finding. Treatment-related cardiac events occurred in 50.0 percent of patients, with grade 3 or higher events in 21.4 percent, and no fatal cardiac events occurred. Events occurring in at least 10 percent of patients included QT interval prolongation, decreased ejection fraction, increased NT-proBNP, supraventricular extrasystoles, and ventricular extrasystoles. Among patients who experienced cardiac adverse events, the median time to first onset was 43.5 days, and the median time from onset to resolution or improvement was 237 days. Five patients had a pre-existing cardiovascular condition, and four of them experienced at least one treatment-related cardiac event, compared with 10 of 23 patients without such a history; the authors emphasized that these descriptive data come from a very small sample. Given the established role of the Hippo-YAP pathway in cardiac development and adult myocardial homeostasis, the researchers suggested the findings are consistent with a potential mechanism-based, on-target effect of TEAD inhibition, while noting that the partial reversibility of these events suggests a potential therapeutic window with appropriate monitoring. They recommended enhanced cardiovascular monitoring, including electrocardiography, echocardiography, and early cardioprotective strategies, in future development of TEAD inhibitors.
The pharmacokinetic profile proved to be a defining feature of the trial. BPI-460372 exhibited a terminal half-life of 35 to 59 hours with limited accumulation, and exposure increased in an approximately dose-proportional manner after single-dose administration. At higher once-daily doses of 80 to 240 mg, however, steady-state exposure plateaued, indicating absorption-limited pharmacokinetics. Although escalation to 320 mg was initially planned, once-daily escalation was terminated at 240 mg because no meaningful further exposure increase was anticipated. Twice-daily dosing increased steady-state exposure by 1.7- to 2.3-fold compared with once-daily dosing, partially overcoming absorption saturation, but the gain from 80 mg twice daily to 120 mg twice daily was only about 9 percent, so further escalation of that schedule was not pursued. Food intake increased exposure by approximately 1.8- to 2.0-fold at the 160 mg dose level, whereas minimal effect was observed at 80 mg. The authors noted that the specific mechanism underlying the apparent absorption limitation remains unknown, and no responsible transporter has been identified. They also cautioned that although the covalent mechanism could in principle allow pathway inhibition to persist beyond measurable free-drug exposure, this theoretical advantage was not directly demonstrated, because longitudinal measurements of TEAD target occupancy or tumor pharmacodynamic pathway suppression were not available.
Antitumor activity was modest but measurable. Among the 28 patients, the objective response rate was 3.6 percent (one of 28; 95 percent confidence interval, 0.1 to 18.4 percent) and the disease control rate was 64.3 percent (18 of 28; 95 percent confidence interval, 44.1 to 81.4 percent). The median progression-free survival was 5.6 months (95 percent confidence interval, 2.4 to 7.0 months) and the median overall survival was 13.2 months (95 percent confidence interval, 7.4 to 15.1 months). The single confirmed partial response occurred in the 120 mg twice-daily cohort, in a 40-year-old man with malignant pleural mesothelioma who had received one prior line of therapy; he achieved a 56.7 percent reduction in target lesions, with the response confirmed on a subsequent scan and a duration of response of 1.4 months, censored. The authors interpreted the findings as suggesting potential disease-stabilizing activity in a subset of patients, while stressing that the observed activity did not fully reflect the drug’s potential, since dose escalation was terminated early due to absorption-limited exposure and treatment-emergent toxicities.
Exploratory biomarker analyses yielded limited signals. Plasma ctDNA profiling was available for all 28 patients, whereas evaluable tumor tissue next-generation sequencing results were available for only 11 of 28 patients. Tissue sequencing identified a TAZ-CAMTA1 fusion in one patient with epithelioid hemangioendothelioma, and plasma ctDNA detected a loss-of-function NF2 mutation in one patient with mesothelioma. No consistent association between genomic alterations and clinical response was observed, and the authors emphasized that because tissue sequencing covered fewer than half of the population and multiple tumor types were enrolled, these frequencies may not reflect the prevalence of Hippo pathway alterations in any individual tumor type. They also noted that NF2 protein expression and promoter methylation were not prospectively evaluated, so functional NF2 loss in patients without detectable genomic alterations could not be determined.
The authors outlined the study’s limitations: the phase Ia dose-escalation design limited the sample size and statistical inference, the heterogeneity of enrolled tumor types restricted tumor-specific conclusions, and the primary objective was safety and tolerability rather than efficacy, so the antitumor activity signals should be interpreted as exploratory and hypothesis-generating. Nevertheless, they concluded that BPI-460372 demonstrated clinical evidence of TEAD-targeted antitumor activity, including a confirmed response in malignant pleural mesothelioma, and that its distinct pharmacokinetic profile, with exposure partially modifiable through dosing frequency and food intake, supports further clinical evaluation using optimized dosing strategies, particularly in tumors with Hippo pathway dependency, ideally integrating target-engagement and pathway-level pharmacodynamic biomarkers with pharmacokinetic and safety assessments.
Subject of Research: A first-in-human phase Ia trial of the TEAD palmitoylation inhibitor BPI-460372 in advanced solid tumors
Article Title: 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
Article References: Liang, H., Xu, Y., Zhao, J., Liu, X., Zhong, W., Zheng, X., Liu, H., Chen, M., Han, X., & Wang, M. (2026). 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. Biomarker Research, 14(1), Article 138. https://doi.org/10.1186/s40364-026-01012-z
Image Credits: AI Generated
DOI: 10.1186/s40364-026-01012-z
Keywords: BPI-460372, TEAD inhibitor, Hippo pathway, phase Ia trial, advanced solid tumors, pharmacokinetics, proteinuria, cardiac adverse events, malignant mesothelioma, dose escalation, absorption saturation, YAP/TAZ
News Source: Ophelia Keating. (October 28, 2026). First-in-human trial of TEAD inhibitor BPI-460372 shows early signals and safety limits. Scienmag.
