Orlistat Overcoming Third-generation EGFR-TKI Resistance

EGFR mutation positivity accounts for 50% of lung adenocarcinoma cases. Multiple clinical trials, represented by FLAURA, AENEAS, and FURLONG studies, have confirmed that third-generation EGFR-TKI can provide significant benefits to patients with EGFR sensitive mutations and has become the first-line preferred treatment for EGFR mutation positive NSCLC, with a median PFS of around 19 and OS of around 38 months. These large-scale Phase III studies have confirmed the excellent efficacy of third-generation EGFR-TKI in EGFR mutation positive patients. However, regardless of the targeted drug, resistance will occur within less than 2 years. Blood test data for first-line treatment with osimertinib showed that the most common forms of resistance were secondary MET amplification (20%), EGFR C797S mutation (8%), PIK3CA, Her-2 amplification, and so on. The mechanism of resistance is complex and has many factors. Currently, for the treatment of third-generation EGFR-TKI resistance, the IMPOWER150 and ORIENTAL31 treatment modes are commonly used. Although the combination of these four drugs has good efficacy, the side effects are significant. Some patients are unwilling to undergo chemotherapy due to physical problems and hope to continue taking targeted drugs orally. Orlistat is a long-acting and potent specific gastrointestinal lipase inhibitor that can directly block the absorption of body fat. It is commonly used for weight loss in clinical practice and is relatively inexpensive. Our project team found in vitro and in vivo data that orlistat can effectively promote sensitivity to osimertinib. The combination of orlistat and osimertinib can overcome osimertinib resistance without significant toxic side effects. For patients who are unwilling to undergo chemotherapy and require continued oral targeted therapy, the investigators attempted to add orlistat to see if it can improve resistance.