On October 3, 2022 Theseus Pharmaceuticals, Inc. (NASDAQ: THRX) (Theseus or the Company), a clinical-stage biopharmaceutical company focused on improving the lives of cancer patients through the discovery, development, and commercialization of transformative targeted therapies, reported that it has nominated THE-349 as the development candidate for its epidermal growth factor receptor (EGFR) inhibitor program in non-small cell lung cancer (NSCLC) (Press release, Theseus Pharmaceuticals, OCT 3, 2022, View Source [SID1234621656]). THE-349 is designed to address treatment resistance to existing EGFR inhibitors by targeting the common activating mutations in exons 19 and 21 alone or in combination with the most frequently observed resistance mutations, T790M and C797X. In preclinical models, THE-349 potently inhibits single-, double-, and triple-mutant EGFR variants with these mutations that are observed in a post-first- or later-line osimertinib setting.
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Preclinical characterization of THE-349 as a fourth-generation EGFR, central nervous system- (CNS) active, and mutant-selective inhibitor with potent activity against single-, double-, and triple-mutant EGFR variants, including T790M and C797X, will be shared in a poster presentation at the 34th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) (ENA) Symposium taking place in Barcelona on October 26-28, 2022.
"We are delighted to announce THE-349 as the Company’s second development candidate and we look forward to evaluating its potential in patients with EGFR-mutant NSCLC," said William Shakespeare, Ph.D., President of Research and Development at Theseus. "Clonal heterogeneity in patients who develop resistance to osimertinib is complex, and we believe a single EGFR inhibitor capable of targeting all major mutant forms of EGFR activating and resistance mutations is the optimal way to address this urgent medical need."
NSCLC is the most common form of lung cancer. Activating mutations in EGFR occur in 10-15% of Caucasian and up to 50% of Asian NSCLC patients, with up to 90% of those mutations found in exons 19 and 21. Although patients may initially respond to treatment with a first-, second- or third-generation EGFR tyrosine kinase inhibitor (TKI), their tumors eventually develop resistance to therapy. In patients whose tumors progress on osimertinib, point mutations at the C797 position (C797X) in EGFR have been observed at a frequency of up to approximately 12% after first-line osimertinib and 20% after second-line osimertinib. Patients presenting with these mutations have no available targeted therapy options due to current therapies lacking the necessary activity that can address both activating and resistance mutations.
Details for the presentation are as follows:
Title: Preclinical characterization of CNS-active, mutant-selective fourth-generation EGFR inhibitors with potent activity against single, double, and triple mutant EGFR variants including T790M and C797S
Abstract Number: 236
Session: Molecular Targeted Agents 2
Session Date and Time: Thursday, October 27, 2022: 10:00am-5:00pm (CEST)
Presenter: Sen Zhang, Ph.D. (Theseus Pharmaceuticals, Cambridge, USA)
About EGFR-mutant NSCLC
Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85% of the estimated 2.2 million cases of lung cancer diagnosed globally in 2020. Activating mutations in EGFR occur in 10-15% of Caucasian and up to 50% of Asian NSCLC patients, with up to 90% of those mutations found in exons 19 and 21. In response to treatment, patients’ tumors can develop one or more additional EGFR mutations, causing resistance and rendering current therapies ineffective.