Tegavivint is being tested in combination with osimertinib in an effort to prolong overall survival and deepen response in EGFR+ NSCLC.
A phase 1 trial of tegavivint in combination with osimertinib (Tagrisso) for the treatment of previously untreated patients with metastatic epidermal growth factor receptor (EGFR)-positive (NSCLC) has been initiated, according to a press release by Iterion Therapeutics.
However, resistance is eventually developed, creating a problem for clinicians.
Tegavivint is a selective molecule inhibitor of Transducin beta-like Protein One (TBL1), which is a novel downstream target in the Wnt/beta catenin signaling pathway. In a mouse model, combining tegavivint with osimertinib has been shown to produce an antitumor response and prolong survival. EGFR- tyrosine kinase inhibitors (TKIs), such as osimertinib, are the recommended first line therapy for the treatment of EGFR-positive NSCLC.
"For the estimated 15-30% of patients in the U.S. who have EGFR-positive NSCLC, treatment with EGFR-TKIs, such as osimertinib, has been shown to be very effective, but unfortunately patients will relapse as a result of their tumors eventually developing resistance," said Regan M. Memmott, MD, PhD, principal investigator for the study in a press release. "Research conducted at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute suggests that combining tegavivint with osimertinib could curtail the osimertinib-induced drug-tolerant persister cells from developing due to tegavivint's ability to act as a beta-catenin inhibitor via TBL1 inhibition. This new Phase 1 clinical trial evaluates osimertinib in combination with tegavivint as a potential first-line treatment for EGFR-positive NSCLC, which is exciting in a disease that is the number 1 cause of cancer-related death in the United States."
The phase 1 trial (NCT04780568) has a target enrollment of 18 participants and an estimated study completion date of December 2024. The primary end point is maximum tolerated dose. Secondary end points include overall response rate, progression-free survival, duration of response, and overall survival. Other end points include the pharmacokinetics of tegavivint, B-catenin pathway activity, circulating tumor deoxyribonucleic acid, and fludeoxyglucose F 18 positron emission tomography imaging.
During the study, all patients will receive osimertinib once daily on days 1 through 28 and tegavivint intravenously on day 1. Treatment repeats every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity.
In order to participate in the study, patients must be 18 years of age or older, have pathology confirmed NSCLC, a common activating mutation in the EGFR gene, the presence of a concurrent T790M mutation, measurable disease, an ECOG performance status of 2 or less, be able to swallow pills, have a life expectancy greater than 3 months, and meet prespecified lab numbers. Patients who have received prior treatment with an EGFR TKI in any setting, have a past medical history of interstitial lung disease, who have an uncontrolled intercurrent illness, are pregnant, have a history of cardiovascular disease, another active malignancy, or severe or uncontrolled disease, are not eligible to participate.
"We are excited to collaborate with OSUCCC and the National Cancer Institute to initiate this Phase 1 first-line study of tegavivint in combination with osimertinib in previously untreated patients with metastatic EGFR-mutant NSCLC," said Rahul Aras, PhD, CEO of Iterion in the press release. "NSCLC is the most common type of lung cancer, accounting for 85% of all lung cancer diagnoses, according to the American Society of Clinical Oncology. This trial has the potential to help this enormous patient population and to further demonstrate tegavivint's unique mechanism of action of TBL1 inhibition, thereby disrupting the oncogenic activity of beta-catenin. Tegavivint has already demonstrated safety in desmoid tumor patients and is currently being investigated in additional clinical trials as a potential treatment for acute myeloid leukemia and solid and hematologic pediatric tumors."
The study is recurrently recruiting in Ohio.