Discovery of a Novel Potent EGFR Inhibitor Against EGFR Activating Mutations and On-Target Resistance in NSCLC
Eun Ji Lee1, Seung Yeon Oh1, You Won Lee2
1Department of Biomedical Science institute, Graduated School of Medical Science, Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
Purpose:
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) serve as the standard first-line therapy for EGFR-mutated non-small cell lung cancer (NSCLC). Despite the sustained clinical benefits achieved through optimal EGFR-TKI treatments, including the third-generation EGFR-TKI osimertinib, resistance inevitably develops. Currently, there are no targeted therapeutic options available postprogression on osimertinib. Here, we assessed the preclinical efficacy of BI-4732, a novel fourth-generation EGFR-TKI, using patient-derived preclinical models reflecting various clinical scenarios.
Experimental Design:
The antitumor activity of BI-4732 was evaluated using Ba/F3 cells and patient-derived cell/organoid/xenograft models with diverse EGFR mutations. Intracranial antitumor activity of BI-4732 was evaluated in a brain-metastasis mouse model.
Results:
We demonstrated the remarkable antitumor efficacy of BI-4732 as a single agent in various patient-derived models with EGFR_C797S-mediated osimertinib resistance. Moreover, BI-4732 exhibited activity comparable to osimertinib in inhibiting EGFR-activating (E19del and L858R) and T790M mutations. In a combination treatment strategy with osimertinib, BI-4732 exhibited a synergistic effect at significantly lower concentrations than those used in monotherapy. Importantly, BI-4732 displayed potent antitumor activity in an intracranial model, with low efflux at the blood-brain barrier.
Conclusions:
Our findings highlight the potential of BI-4732, a selective EGFR-TKI with high blood-brain barrier penetration, targeting a broad range of EGFR mutations, including C797S, warranting clinical development.
Insights
A new fourth-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), BI-4732, shows potent efficacy against EGFR-mutated non-small cell lung cancer (NSCLC) with resistance to prior therapies. BI-4732 demonstrates significant antitumor activity, including in brain metastases, and warrants further clinical investigation.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard first-line treatments for EGFR-mutated non-small cell lung cancer (NSCLC).
- Resistance to third-generation EGFR-TKIs like osimertinib is a significant clinical challenge, with no current targeted therapies available post-progression.
- Novel therapeutic strategies are urgently needed to overcome resistance mechanisms and improve patient outcomes in advanced NSCLC.
Purpose of the Study:
- To evaluate the preclinical efficacy of BI-4732, a novel fourth-generation EGFR-TKI, in patient-derived models of non-small cell lung cancer (NSCLC).
- To assess the activity of BI-4732 against various EGFR mutations, including those conferring resistance to osimertinib.
- To investigate the potential of BI-4732 in treating brain metastases and its blood-brain barrier penetration.
Main Methods:
- Utilized Ba/F3 cells and patient-derived cell, organoid, and xenograft models harboring diverse EGFR mutations.
- Assessed the antitumor activity of BI-4732 as a single agent and in combination with osimertinib.
- Evaluated intracranial antitumor activity in a brain-metastasis mouse model to determine blood-brain barrier penetration.
Main Results:
- BI-4732 demonstrated remarkable antitumor efficacy as a single agent in models with EGFR_C797S-mediated osimertinib resistance.
- BI-4732 showed activity comparable to osimertinib against EGFR-activating mutations (E19del, L858R) and the T790M mutation.
- BI-4732 exhibited synergistic effects when combined with osimertinib at lower concentrations and potent intracranial antitumor activity with low blood-brain barrier efflux.
Conclusions:
- BI-4732 is a selective fourth-generation EGFR-TKI with broad activity against a range of EGFR mutations, including C797S.
- The drug exhibits potent antitumor activity, including in models of brain metastasis, due to high blood-brain barrier penetration.
- These preclinical findings support the clinical development of BI-4732 for patients with EGFR-mutated NSCLC who have progressed on existing therapies.
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