ODM-212（一种新型泛TEAD抑制剂）在原发性和转移性实体瘤患者中的离体试验

BACKGROUND: The Hippo signaling pathway is a highly conserved signaling cascade that controls the activation or inactivation of YAP/TAZ proteins. In cancer cells, genomic alterations can result in deactivation of the Hippo pathway and consequent hyperactivation of the YAP/TAZ to promote oncogenesis. Since YAP/TAZ induce the oncogenic effects by binding to TEAD transcription factors, TEAD targeting has emerged as a therapeutic opportunity in various solid cancers. ODM-212 is a novel small molecule that binds specifically to all TEAD/TEF transcription factors (TEAD1-4). ODM-212 effectively inhibits growth and viability of patient-derived solid tumor models with or without hippo pathway genetic alterations. Here we present pan-cancer ex vivo efficacy and biomarker discovery results of ODM-212 in primary and advanced solid tumors. METHODS: Parallel to an ongoing multi-site, open-label, first-in-human study of ODM-212 in advanced solid tumor (TEADES, NCT06725758), ODM-212 therapy efficacy was studied using ex vivo drug screening in patient-derived functional tumor models. Vital tumor cells dissociated from excess tissues obtained in context of patients´ standard therapy were used to assess ODM-212 and 150 other therapies while DNA sequencing was used for exploratory biomarker evaluation. To assess predictive value of ex vivo drug screening, the results will be correlated with observed responses in eligible patients upon completion of the TEADES study. RESULTS: 395 (n=46 solid cancer types) patient-derived tumor samples were included in the ex vivo study of ODM-212 efficacy. 83/395 samples were derived from primary untreated tumors and rest from recurrent metastatic tumors. Largest individual indications included, bladder cancer (n=45), brain tumors (n=61), HNSCC (n=93), lung cancer (n=20), melanoma (n=21) and sarcoma (n=27). ODM-212 demonstrated potent anti-tumor activity in select patient samples across all included main anatomical sites supporting genomic medicine approaches for patient stratification. Highest therapeutic efficacy was seen in Hippo pathway altered, KRAS and YAP driven solid tumors. CONCLUSIONS: ODM-212 shows potent pan-cancer ex vivo efficacy in both primary untreated and heavily pre-treated metastatic tumors. Single agent efficacy correlates with Hippo pathway alterations while encouraging anti-tumor activity is seen also in select patient samples with no known Hippo alterations. This confirms ODM-212 as a potent novel therapeutic to target TEAD transcription factors in solid tumors supporting further clinical development.