Iterion's tegavivint plus osimertinib hits 79% ORR in first-line EGFR-mutated NSCLC
核心洞察
Iterion Therapeutics (搜索) reported a 79% objective response rate for tegavivint plus osimertinib in first-line metastatic EGFR-mutated NSCLC (搜索), with complete responses in 16% of patients.
The Phase 1b dose-escalation cohort showed median progression-free survival of 19.9 months and median overall survival of 48.8 months versus 37.6 months historically for osimertinib alone.
The combination produced no dose-limiting toxicities, no Grade 4 or 5 events and no drug-related serious adverse events or pneumonitis of any grade.
Iterion Therapeutics (搜索) has reported results from an investigator-sponsored Phase 1b study of tegavivint combined with osimertinib as first-line therapy in metastatic EGFR (搜索)-mutated non-small cell lung cancer (搜索) (NSCLC), showing an objective response rate of 79% and complete responses in 16% of evaluable patients. The trial, NCT04780568, was conducted at The Ohio State University Comprehensive Cancer Center (搜索) – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and led by principal investigator Regan Memmott, M.D., Ph.D.
The company said the complete response rate compares with approximately 1% historically for osimertinib alone. In the dose-escalation portion of the study, median progression-free survival (mPFS) was 19.9 months and median overall survival (mOS) was 48.8 months, against a historical median overall survival of 37.6 months for osimertinib monotherapy. Only six events had occurred at the time of the analysis.
Trial design and dosing
The dose-escalation cohort enrolled 15 evaluable patients with metastatic EGFR-mutated NSCLC (搜索) who had not previously received an EGFR (搜索) tyrosine kinase inhibitor (TKI). Four additional patients were enrolled at the highest dose in a dose-expansion cohort, giving 19 evaluable patients overall.
Patients received osimertinib 80 mg orally once daily plus escalating weekly intravenous doses of tegavivint (3 to 8 mg/kg) for the first four months. Tegavivint was then discontinued and osimertinib monotherapy continued until disease progression.
Patient demographics were similar to Phase 3 first-line EGFR (搜索) TKI studies such as FLAURA with respect to sex, histology and prevalence of EGFR mutation type, but the study population had a higher incidence of CNS and liver metastases and a greater median tumor burden.
Tolerability and pharmacokinetics
The combination was well tolerated, with no dose-limiting toxicities, no Grade 4 or 5 events, no drug-related serious adverse events and no pneumonitis of any grade. The most common drug-related adverse events were those typically associated with osimertinib, including diarrhea, maculopapular rash, anemia and fatigue, most of which were Grade 1 or 2.
Pharmacokinetic analyses showed dose-proportional tegavivint exposure with no evidence of a drug-drug interaction with osimertinib. Preliminary results suggest the combination may be better tolerated than current FDA-approved combinations.
Rationale: targeting drug-tolerant persister cells
EGFR (搜索) TKIs have transformed treatment of EGFR-mutated NSCLC (搜索) but are not curative in the metastatic setting. Slow-cycling, drug-tolerant persister (DTP) cells can survive treatment and drive resistance. Preclinical research suggests EGFR-mutated NSCLC cells enter this persistent state through increased beta-catenin (搜索) transcriptional activity, and combining an EGFR TKI with beta-catenin pathway inhibition improved the depth and duration of response in xenograft models.
"The biology underlying the persistence of cancer to EGFR (搜索)-targeted therapy provides a rationale for combining osimertinib with tegavivint," Memmott said. "Increased beta-catenin (搜索) transcriptional activity appears to play an important role in allowing a population of tumor cells to persist despite EGFR inhibition. The clinical activity observed in this study is consistent with our hypothesis that targeting these DTP cells may deepen responses and delay the emergence of resistance."
Rahul Aras, Ph.D., President and Chief Executive Officer of Iterion Therapeutics (搜索), said the results provide early clinical evidence supporting tegavivint's differentiated mechanism of action and its potential to address the persistence of drug-tolerant tumor cells. "We are particularly excited by the depth of tumor reduction, complete responses and survival observed in this study, together with the favorable tolerability profile of the combination," he said.
Response details and Wnt-pathway mutation
Among all evaluable patients treated, complete responses were observed in 3 of 19 patients (16%), including a complete response in the single patient enrolled whose lung cancer harbored a Wnt-pathway activating mutation. The data from the dose-escalation portion of the study were shared in an oral presentation at ASCO 2026 (Abstract #547976).
Tegavivint mechanism and company pipeline
Tegavivint is a potent and selective small molecule that acts as a downstream inhibitor of the Wnt/beta-catenin signaling pathway (搜索) by binding to TBL1 (搜索). By disrupting the nuclear beta-catenin (搜索) complex, tegavivint aims to inhibit expression of genes that drive tumor growth, survival and resistance to therapy across multiple cancer types.
Iterion Therapeutics (搜索) describes tegavivint as the first and only small-molecule inhibitor of TBL1 (搜索), a transcriptional regulator required for nuclear beta-catenin (搜索) stability and oncogenic gene expression. The agent has shown clinical tolerability, target engagement and monotherapy activity in multiple complex solid tumors, including advanced hepatocellular carcinoma (搜索). Iterion is advancing a clinical strategy anchored by its lead program in hepatocellular carcinoma, with expansion into additional Wnt-driven cancers including pediatric and rare oncology indications. The company has received $26 million in Product Development Awards from the Cancer Prevention and Research Institute of Texas (搜索) (CPRIT).