Mutation-guided chemotherapy-free strategy in first-line immunotherapy for low PD-L1-expressing non-squamous NSCLC
Background The necessity of platinum-doublet chemotherapy in first-line immunotherapy for non-squamous non-small cell lung cancer (nsqNSCLC) with programmed death-ligand 1 (PD-L1) expression on less than 50% of tumor cells remains poorly investigated. Biomarkers predicting this necessity can guide c...
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BMJ Publishing Group
2024-11-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/11/e009693.full |
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| author | Hui Li Liang Zhang Yu Xu Jingjing Liu Guoqiang Wang Ying Cheng Shangli Cai Xinyue Wang Peng Cui Shaowei Lan |
| author_facet | Hui Li Liang Zhang Yu Xu Jingjing Liu Guoqiang Wang Ying Cheng Shangli Cai Xinyue Wang Peng Cui Shaowei Lan |
| author_sort | Hui Li |
| collection | DOAJ |
| description | Background The necessity of platinum-doublet chemotherapy in first-line immunotherapy for non-squamous non-small cell lung cancer (nsqNSCLC) with programmed death-ligand 1 (PD-L1) expression on less than 50% of tumor cells remains poorly investigated. Biomarkers predicting this necessity can guide chemotherapy-free treatment to minimize unnecessary toxicity.Methods Treated with immune checkpoint inhibitor monotherapy (ICI-mono), chemotherapy, or combination (ICI-chemo), 790 low PD-L1-expressing nsqNSCLCs (in-house: n=83; public: n=707) were analyzed for development and validation of the interaction score for additional chemotherapy (ISAC). Transcriptomic (public, n=11) and multiplex immunofluorescence data (in-house, n=100) were analyzed to evaluate the immune microenvironment.Results ICI-chemo, compared with ICI-mono, tended to prolong progression-free survival (PFS; HR=0.72, p=0.004) and overall survival (OS; HR=0.77, p=0.071) as first-line therapy in low PD-L1-expressing nsqNSCLCs. The added value of chemotherapy was observed in the ISAC-low subgroup (PFS: HR=0.48, p<0.001; OS: HR=0.53, p=0.001) rather than the ISAC-high subgroup (PFS: HR=1.08, p=0.65; OS: HR=1.14, p=0.56). This predictive utility was independent of tumor mutational burden and PD-L1 expression, indicated by subgroup and multivariable analyses. A high ISAC was associated with adaptive immune resistance reflected by more proinflammatory (eg, CD8+ T cells and M1 macrophages) rather than anti-inflammatory tumor-infiltrating immune cells (eg, M2 macrophages) and high expression of immune checkpoints except for PD-L1 (eg, programmed cell death protein-1).Conclusion A high ISAC was identified as a significant predictor for virtually no added value of platinum-doublet chemotherapy for first-line ICI treatment in low PD-L1-expressing nsqNSCLC. Our findings may help refine personalized therapeutic strategies for nsqNSCLC, thereby improving efficacy and reducing undue toxicity. |
| format | Article |
| id | doaj-art-c3c2113aa3be4f19abe1f2a8943180b8 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-c3c2113aa3be4f19abe1f2a8943180b82024-12-15T23:20:18ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-11-01121110.1136/jitc-2024-009693Mutation-guided chemotherapy-free strategy in first-line immunotherapy for low PD-L1-expressing non-squamous NSCLCHui Li0Liang Zhang1Yu Xu2Jingjing Liu3Guoqiang Wang4Ying Cheng5Shangli Cai6Xinyue Wang7Peng Cui8Shaowei Lan91 Translational Oncology Research Lab, Jilin Provincial Key Laboratory of Molecular Diagnostics for Lung Cancer, Jilin Cancer Hospital, Changchun, Jilin, China3 Oncology Department, Jilin Cancer Hospital, Changchun, Jilin, China4 Burning Rock Biotech, Guangzhou, Guangdong, China2 Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun, Jilin, China4 Burning Rock Biotech, Guangzhou, Guangdong, China2 Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun, Jilin, China4 Burning Rock Biotech, Guangzhou, Guangdong, China5 Postdoctoral Research Workstation, Jilin Cancer Hospital, Changchun, Jilin, China4 Burning Rock Biotech, Guangzhou, Guangdong, China1 Translational Oncology Research Lab, Jilin Provincial Key Laboratory of Molecular Diagnostics for Lung Cancer, Jilin Cancer Hospital, Changchun, Jilin, ChinaBackground The necessity of platinum-doublet chemotherapy in first-line immunotherapy for non-squamous non-small cell lung cancer (nsqNSCLC) with programmed death-ligand 1 (PD-L1) expression on less than 50% of tumor cells remains poorly investigated. Biomarkers predicting this necessity can guide chemotherapy-free treatment to minimize unnecessary toxicity.Methods Treated with immune checkpoint inhibitor monotherapy (ICI-mono), chemotherapy, or combination (ICI-chemo), 790 low PD-L1-expressing nsqNSCLCs (in-house: n=83; public: n=707) were analyzed for development and validation of the interaction score for additional chemotherapy (ISAC). Transcriptomic (public, n=11) and multiplex immunofluorescence data (in-house, n=100) were analyzed to evaluate the immune microenvironment.Results ICI-chemo, compared with ICI-mono, tended to prolong progression-free survival (PFS; HR=0.72, p=0.004) and overall survival (OS; HR=0.77, p=0.071) as first-line therapy in low PD-L1-expressing nsqNSCLCs. The added value of chemotherapy was observed in the ISAC-low subgroup (PFS: HR=0.48, p<0.001; OS: HR=0.53, p=0.001) rather than the ISAC-high subgroup (PFS: HR=1.08, p=0.65; OS: HR=1.14, p=0.56). This predictive utility was independent of tumor mutational burden and PD-L1 expression, indicated by subgroup and multivariable analyses. A high ISAC was associated with adaptive immune resistance reflected by more proinflammatory (eg, CD8+ T cells and M1 macrophages) rather than anti-inflammatory tumor-infiltrating immune cells (eg, M2 macrophages) and high expression of immune checkpoints except for PD-L1 (eg, programmed cell death protein-1).Conclusion A high ISAC was identified as a significant predictor for virtually no added value of platinum-doublet chemotherapy for first-line ICI treatment in low PD-L1-expressing nsqNSCLC. Our findings may help refine personalized therapeutic strategies for nsqNSCLC, thereby improving efficacy and reducing undue toxicity.https://jitc.bmj.com/content/12/11/e009693.full |
| spellingShingle | Hui Li Liang Zhang Yu Xu Jingjing Liu Guoqiang Wang Ying Cheng Shangli Cai Xinyue Wang Peng Cui Shaowei Lan Mutation-guided chemotherapy-free strategy in first-line immunotherapy for low PD-L1-expressing non-squamous NSCLC Journal for ImmunoTherapy of Cancer |
| title | Mutation-guided chemotherapy-free strategy in first-line immunotherapy for low PD-L1-expressing non-squamous NSCLC |
| title_full | Mutation-guided chemotherapy-free strategy in first-line immunotherapy for low PD-L1-expressing non-squamous NSCLC |
| title_fullStr | Mutation-guided chemotherapy-free strategy in first-line immunotherapy for low PD-L1-expressing non-squamous NSCLC |
| title_full_unstemmed | Mutation-guided chemotherapy-free strategy in first-line immunotherapy for low PD-L1-expressing non-squamous NSCLC |
| title_short | Mutation-guided chemotherapy-free strategy in first-line immunotherapy for low PD-L1-expressing non-squamous NSCLC |
| title_sort | mutation guided chemotherapy free strategy in first line immunotherapy for low pd l1 expressing non squamous nsclc |
| url | https://jitc.bmj.com/content/12/11/e009693.full |
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