Prof. YANG Peng:Investigation of Sex-Based Differences in the Anti-Tumor Efficacy of Fourth-Generation EGFR Inhibitors

Project lead

1. Research Background and Rationale

In the field of precision therapy for non-small cell lung cancer (NSCLC), the development of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) has significantly improved outcomes for patients with EGFR-sensitive mutations (e.g., Del19 and L858R). However, substantial clinical evidence indicates significant sex-based disparities in drug efficacy. When treated with first-generation (gefitinib, erlotinib) and second-generation (afatinib) EGFR-TKIs, female patients consistently demonstrate a superior progression-free survival (PFS) compared to males, suggesting that sex may be an independent biological factor influencing drug response.

The third-generation EGFR-TKI osimertinib, now a first-line treatment, has partially overcome the acquired T790M resistance mutation, yet the sex-based difference in its efficacy is less pronounced than with earlier generations. A more critical challenge is the emergence of new acquired resistance mechanisms, primarily the EGFR C797S mutation, leading to treatment failure after approximately 10 months. Consequently, fourth-generation EGFR inhibitors targeting the triple mutations (Del19/L858R + T790M + C797S), such as TRX-221 and TQB-3804, have emerged as the most promising strategy to overcome Osimertinib resistance and have entered clinical trials. Despite this progress, no study has systematically investigated potential sex-related differences in the efficacy of these fourth-generation inhibitors. Addressing this critical knowledge gap is essential for achieving truly individualized and precision medicine.

2. Research Content and Methodology

Our team has long been dedicated to the development of fourth-generation EGFR inhibitors. Building on our expertise and the scientific question outlined above, we propose a systematic investigation into the sex-based differences in the therapeutic efficacy of these agents through the following approaches:

Sex-stratified analysis of clinical data: We will first perform a retrospective collection and re-analysis of existing clinical trial data for investigational fourth-generation EGFR inhibitors (e.g., TRX-221, TQB-3804). This analysis will focus on correlating key efficacy endpoints, such as PFS and objective response rate (ORR), with patient sex to obtain preliminary clinical evidence.

Development of sex-specific preclinical resistance models: To delve deeper into the underlying biology, we will utilize patient-derived samples from osimertinib-resistant cases to systematically establish and expand a biobank of humanized organoids and patient-derived xenograft (PDX) models. A crucial aspect of this work will be the strict stratification and annotation of these models based on donor sex from the outset, thereby creating parallel Male and Female preclinical model cohorts to form a solid foundation for subsequent comparative studies.

Efficacy evaluation and sex-informed drug optimization: Building upon our established sex-stratified preclinical models, we will systematically evaluate the differences in anti-tumor activity of various investigational fourth-generation EGFR inhibitors and our proprietary novel drug candidates between male and female models. By comparing key pharmacodynamic parameters, we will precisely quantify the association between drug efficacy and model sex. Leveraging the obtained sex-efficacy correlation data, we will perform further structural optimization. This effort is aimed at developing next-generation, sex-specific lead compounds with enhanced specificity and efficacy for either male or female patients.

Multi-omics mechanistic investigation: To delve deeper into the molecular mechanisms underlying the observed efficacy differences, we will conduct high-throughput proteomic and transcriptomic sequencing on tumor tissues from treated PDX models. Through integrated bioinformatics analysis of the vast datasets, we will systematically identify key signaling pathways, metabolic networks, and specific molecular markers that are closely associated with drug response in male and female contexts. This approach will elucidate the fundamental mechanisms behind the sex-related differences in drug inhibitory activity from a systems biology perspective.

3. Research Significance and Innovation

This project represents the first study to systematically evaluate the efficacy of fourth-generation EGFR inhibitors with sex as a core variable. It not only holds the potential to reveal sex-based disparities in this emerging therapy, providing a direct theoretical basis for future clinical precision medicine, but also may, through multi-omics analysis, discover key biological pathways driving these differences, making an original contribution to understanding the fundamental nature of sex-specific drug responses. Ultimately, this research aims to ensure that both male and female patients can derive equal and maximal benefit from the latest anticancer drugs, thereby advancing precision oncology towards a more inclusive and effective future.

Team members: Weijiao Chen, Huanaoyu Yang