The addition of the β-catenin pathway inhibitor tegavivint to osimertinib produced deep responses in a phase 1b study in first-line EGFR-mutated NSCLC.
The combination of tegavivint and osimertinib (Tagrisso) produced deep responses as first-line therapy in patients with metastatic EGFR-mutated non–small cell lung cancer (NSCLC), according to findings from an investigator-sponsored phase 1b study (NCT04780568).¹
Among all evaluable patients treated across the study (n = 19), the combination elicited an objective response rate (ORR) of 79%, with complete responses (CRs) in 3 patients (16%), including a CR in the single enrolled patient whose tumor harbored a Wnt-pathway–activating mutation. In the dose-escalation portion of the study, the median progression-free survival (PFS) was 19.9 months (95% CI, 6-32.0), and the median overall survival (OS) was 48.8 months (95% CI, 16.8-not reached), although only 6 events had occurred at the time of the analysis.1,2 The combination was well tolerated, with no dose-limiting toxicities reported.
“These promising results provide important early clinical evidence supporting tegavivint’s differentiated mechanism of action and its potential to address one of the fundamental limitations of targeted cancer therapy: the persistence of drug-tolerant tumor cells,” Rahul Aras, PhD, president and chief executive officer of Iterion Therapeutics, stated in a news release.1
EGFR TKIs have improved EGFR-mutated NSCLC management but are not curative for metastatic disease, as slow-cycling, drug-tolerant persister cells can survive treatment and drive treatment resistance. Preclinical research has shown that EGFR-mutated NSCLC cells enter a persistent state due to increased β-catenin transcriptional activity. Additionally, in xenograft models, the combination of an EGFR TKI with a β-catenin pathway inhibitor improved depth and duration of response.
Tegavivint Plus Osimertinib in First-Line EGFR-Mutated NSCLC: Phase 1b Trial Highlights
Tegavivint is a potent, selective, small molecule that inhibits Wnt/β-catenin signaling by binding to transducin β-like protein 1. By disrupting the nuclear β-catenin complex, the agent is designed to suppress the expression of genes that drive tumor growth, survival, and treatment resistance. This phase 1b study was designed to test whether targeting drug-tolerant persister cells with tegavivint could improve the depth and durability of response to EGFR inhibition.
This single-arm, investigator-sponsored trial is evaluating osimertinib in combination with tegavivint in patients with metastatic NSCLC harboring a classical EGFR mutation who have not received prior EGFR TKI therapy.1,2 The dose-escalation portion enrolled 15 evaluable patients, with 4 additional patients enrolled at the highest dose in a dose-expansion cohort.
Patients received osimertinib at 80 mg orally once daily in combination with escalating weekly intravenous doses of tegavivint at 3-8 mg/kg for the first 4 months, after which tegavivint was discontinued and osimertinib monotherapy was continued until disease progression.¹ The primary objectives were safety, tolerability, and determination of the recommended phase 2 dose (RP2D) of tegavivint, and secondary objectives included ORR, PFS, and OS.² The RP2D of tegavivint in combination with osimertinib was identified as 8 mg/kg.
In data from the dose-escalation cohort presented at the 2026 ASCO Annual Meeting, the ORR was 80%, with a CR rate of 13.3%; responses occurred regardless of the presence of high-risk features, such as TP53 mutations. The mean rate of decrease in tumor burden was 65%. Notably, patients in the enrolled population had a higher incidence of central nervous system and liver metastases and a greater median baseline tumor burden (65 mm; range, 19-154) than those in phase 3 first-line EGFR TKI trials.
The combination was well tolerated, with no 4 or 5 adverse effects (AEs), drug-related serious AEs, or pneumonitis of any grade. The most common drug-related AEs were diarrhea (53%), maculopapular rash (47%), anemia (40%), and fatigue (40%); most events were grade 1 or 2. Pharmacokinetic analyses showed dose-proportional tegavivint exposure across the 3-mg/kg to 8-mg/kg range, with no evidence of a drug-drug interaction with osimertinib. Biomarker analyses evaluating the correlation of β-catenin pathway inhibition with clinical outcomes are ongoing.¹
