Development and Evaluation of a Quantitative Systems Pharmacology Model for Mechanism Interpretation and Efficacy Prediction of Atezolizumab in Combination with Carboplatin and Nab-Paclitaxel in Patients with Non-Small-Cell Lung Cancer

被引:0
作者
Wang, Chen-Yu [1 ]
Dai, Hao-Ran [1 ]
Tan, Yu-Ping [1 ]
Yang, Di-Hong [1 ,2 ]
Niu, Xiao-Min [3 ]
Han, Lu [1 ]
Wang, Wen [4 ]
Ma, Ling-Ling [4 ]
Julku, Aleksi [4 ]
Jiao, Zheng [1 ]
机构
[1] Shanghai Jiao Tong Univ, Shanghai Chest Hosp, Dept Pharm, Sch Med, Shanghai 200030, Peoples R China
[2] Chinese Acad Sci, Zhejiang Canc Hosp, Inst Basic Med & Canc IBMC, Dept Pharm, Hangzhou 310022, Peoples R China
[3] Shanghai Jiao Tong Univ, Shanghai Chest Hosp, Sch Med, Dept Oncol, Shanghai 200030, Peoples R China
[4] Puissan Biotech Oy, Helsinki 00510, Finland
关键词
quantitative systems pharmacology; atezolizumab; nab-paclitaxel; carboplatin; non-small-cell lung cancer;
D O I
10.3390/ph17020238
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Immunotherapy has shown clinical benefit in patients with non-small-cell lung cancer (NSCLC). Due to the limited response of monotherapy, combining immune checkpoint inhibitors (ICIs) and chemotherapy is considered a treatment option for advanced NSCLC. However, the mechanism of combined therapy and the potential patient population that could benefit from combined therapy remain undetermined. Here, we developed an NSCLC model based on the published quantitative systems pharmacology (QSP)-immuno-oncology platform by making necessary adjustments. After calibration and validation, the established QSP model could adequately characterise the biological mechanisms of action of the triple combination of atezolizumab, nab-paclitaxel, and carboplatin in patients with NSCLC, and identify predictive biomarkers for precision dosing. The established model could efficiently characterise the objective response rate and duration of response of the IMpower131 trial, reproducing the efficacy of alternative dosing. Furthermore, CD8+ and CD4+ T cell densities in tumours were found to be significantly related to the response status. This significant extension of the QSP model not only broadens its applicability but also more accurately reflects real-world clinical settings. Importantly, it positions the model as a critical foundation for model-informed drug development and the customisation of treatment plans, especially in the context of combining single-agent ICIs with platinum-doublet chemotherapy.
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页数:12
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