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
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...
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MDPI AG
2024-02-01
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| Online Access: | https://www.mdpi.com/1424-8247/17/2/238 |
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| author | Chen-Yu Wang Hao-Ran Dai Yu-Ping Tan Di-Hong Yang Xiao-Min Niu Lu Han Wen Wang Ling-Ling Ma Aleksi Julku Zheng Jiao |
| author_facet | Chen-Yu Wang Hao-Ran Dai Yu-Ping Tan Di-Hong Yang Xiao-Min Niu Lu Han Wen Wang Ling-Ling Ma Aleksi Julku Zheng Jiao |
| author_sort | Chen-Yu Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T22:18:06Z |
| format | Article |
| id | doaj.art-98792215705147cfaf50405dfe373f0a |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-07T22:18:06Z |
| publishDate | 2024-02-01 |
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| series | Pharmaceuticals |
| spelling | doaj.art-98792215705147cfaf50405dfe373f0a2024-02-23T15:30:48ZengMDPI AGPharmaceuticals1424-82472024-02-0117223810.3390/ph17020238Development 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 CancerChen-Yu Wang0Hao-Ran Dai1Yu-Ping Tan2Di-Hong Yang3Xiao-Min Niu4Lu Han5Wen Wang6Ling-Ling Ma7Aleksi Julku8Zheng Jiao9Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, ChinaDepartment of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, ChinaDepartment of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, ChinaDepartment of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, ChinaDepartment of Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, ChinaDepartment of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, ChinaPuissan Biotech Oy, 00510 Helsinki, FinlandPuissan Biotech Oy, 00510 Helsinki, FinlandPuissan Biotech Oy, 00510 Helsinki, FinlandDepartment of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, ChinaImmunotherapy 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.https://www.mdpi.com/1424-8247/17/2/238quantitative systems pharmacologyatezolizumabnab-paclitaxelcarboplatinnon-small-cell lung cancer |
| spellingShingle | Chen-Yu Wang Hao-Ran Dai Yu-Ping Tan Di-Hong Yang Xiao-Min Niu Lu Han Wen Wang Ling-Ling Ma Aleksi Julku Zheng Jiao 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 Pharmaceuticals quantitative systems pharmacology atezolizumab nab-paclitaxel carboplatin non-small-cell lung cancer |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | quantitative systems pharmacology atezolizumab nab-paclitaxel carboplatin non-small-cell lung cancer |
| url | https://www.mdpi.com/1424-8247/17/2/238 |
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