First-in-human trial of the TEAD inhibitor ODM-212 in patients with advanced solid tumors (TEADES).

Abstract

3111 Background: The Hippo pathway is implicated in multiple human cancers including mesothelioma and epithelioid hemangioendothelioma (EHE). When Hippo signalling is inactive, Yes-associated protein 1 (YAP1) and WW-domain-containing transcription regulator 1 (TAZ) locate to the nucleus, activating TEA domain family member (TEAD) transcription factors (TEAD1-4) to impact transcription and key oncogenic cellular processes. ODM-212 is a small molecule oral pan-TEAD inhibitor with in vitro and in vivo antitumour activity in solid tumours. Methods: TEADES is a multi-site, open-label, first-in-human trial of ODM-212 enrolling patients ≥18 years of age with various types of advanced, metastatic solid tumours where the Hippo pathway is implicated, with or without relevant genetic alterations. The study followed a Bayesian optimal interval (BOIN) design with a dose escalation with backfill cohorts, followed by expansion in tumour types of interest. Main objectives were safety (including dose-limiting toxicity (DLT)), preliminary efficacy and pharmacokinetics. ODM-212 was administered orally, once or twice daily, in a continuous 4-week cycle. Results: Between 7 November 2023 and 5 January 2026, 76 patients (mesothelioma 29, EHE 15, other 32) of mean age 62.1 years and all ECOG 0-1 received ODM-212 at doses between 20-320 mg/day, with 44 continuing on treatment at time of data cut-off. Previous treatment included checkpoint inhibitors (N=38), chemotherapy (N=59) or both (N=36). The longest exposure at data cut-off was 18-months. ODM-212 was well tolerated. No DLTs were reported and the maximum tolerated dose (MTD) was not identified. The most frequent treatment-related adverse event (TRAE) was proteinuria (19.7%), which was reversible and resulted in treatment adjustment in 6 (7.9%) patients. Other common TRAE’s were increased lipase (15.8%) and nausea (10.5%). Grade ≥3 TRAE’s occurred in 6.6% patients (anemia and increases in amylase, lipase, alanine aminotransferase and aspartate aminotransferase). Treatment responses by RECIST 1.1 were observed across multiple doses (ORR 7/45 = 15.6%), predominantly in patients with mesothelioma (ORR 27.8% in 18 evaluable patients, disease control rate (DCR) 77.8%) and EHE (ORR 22.2% in 9 evaluable patients, DCR 100%). ODM-212 demonstrated a predictable pharmacokinetic profile, with steady state achieved by 15 days and mean elimination half-life of 1-2 days, supporting once or twice daily dosing. Conclusions: ODM-212 administration to extensively treated patients with advanced cancer was well tolerated and resulted in some promising tumour responses (particularly in mesothelioma and EHE). The phase 2 portion of TEADES is currently enrolling patients. Clinical trial information: NCT06725758 .