Comparison of efficacy discrepancy between early-phase clinical trials and phase III trials of PD-1/PD-L1 inhibitors
Background Phase III clinical trials are pivotal for evaluating therapeutics, yet a concerning failure rate has been documented, particularly impacting oncology where accelerated approvals of immunotherapies are common. These failures are predominantly attributed to a lack of therapeutic efficacy, i...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2024-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/1/e007959.full |
| _version_ | 1827359575914840064 |
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| author | Xiang Li Jiuliang Zhao Mengtao Li Guanqiao Li Jiachen Xu Bing Xu Yangzhong Zhou Yunhe Qin |
| author_facet | Xiang Li Jiuliang Zhao Mengtao Li Guanqiao Li Jiachen Xu Bing Xu Yangzhong Zhou Yunhe Qin |
| author_sort | Xiang Li |
| collection | DOAJ |
| description | Background Phase III clinical trials are pivotal for evaluating therapeutics, yet a concerning failure rate has been documented, particularly impacting oncology where accelerated approvals of immunotherapies are common. These failures are predominantly attributed to a lack of therapeutic efficacy, indicating overestimation of results from phase II studies. Our research aims to systematically assess overestimation in early-phase trials involving programmed cell death-1 (PD-1)/programmed cell death-ligand 1(PD-L1) inhibitors compared with phase III trials and identify contributing factors.Methods We matched 51 pairs of early-phase and phase III clinical trials from a pool of over 9,600 PD-1/PD-L1 inhibitor trials. The matching criteria included identical treatment regimens, cancer types, treatment lines, and biomarker enrichment strategies. To assess overestimation, we compared the overall response rates (ORR) between early-phase and phase III trials. We established independent variables related to eligibility criteria, and trial design features of participants to analyze the factors influencing the observed discrepancy in efficacy between the two phases through univariable and multivariable logistic analyses.Result Early-phase trial outcomes systematically overestimated the subsequent phase III results, yielding an odds ratio (OR) comparing ORR in early-phase versus phase III: 1.66 (95% CI: 1.43 to 1.92, p<0.05). This trend of inflated ORR was consistent across trials testing PD-1/PD-L1 monotherapies and combination therapies involving PD-1/PD-L1. Among the examined factors, the exclusion of patients with autoimmune diseases was significantly associated with the disparity in efficacy between early-phase trials and phase III trials (p=0.023). We calculated a Ward statistic of 2.27 to validate the effectiveness of the model.Conclusion These findings underscore the tendency of overestimation of efficacy in early-phase trials involving immunotherapies. The observed differences could be attributed to variations in the inclusion of patients with autoimmune disorders in early-phase trials. These insights have the potential to inform stakeholders in the future development of cancer immunotherapies. |
| first_indexed | 2024-03-08T06:31:12Z |
| format | Article |
| id | doaj.art-525569cbd2394e49975deaa69f1027a8 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-08T06:31:12Z |
| publishDate | 2024-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-525569cbd2394e49975deaa69f1027a82024-02-03T11:20:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-01-0112110.1136/jitc-2023-007959Comparison of efficacy discrepancy between early-phase clinical trials and phase III trials of PD-1/PD-L1 inhibitorsXiang Li0Jiuliang Zhao1Mengtao Li2Guanqiao Li3Jiachen Xu4Bing Xu5Yangzhong Zhou6Yunhe Qin71Peter MacCallum Cancer Centre, Laboratory Research, Melbourne, AustraliaState Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, ChinaDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, The Ministry of Education Key Laboratory, Beijing, ChinaInstitute for Healthy China, Tsinghua University, Beijing, Beijing, ChinaState Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaVanke School of Public Health, Tsinghua University, Beijing, Beijing, ChinaDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences, Peking Union Medical College; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, ChinaPharmcube (Beijing) Co Ltd, Beijing, ChinaBackground Phase III clinical trials are pivotal for evaluating therapeutics, yet a concerning failure rate has been documented, particularly impacting oncology where accelerated approvals of immunotherapies are common. These failures are predominantly attributed to a lack of therapeutic efficacy, indicating overestimation of results from phase II studies. Our research aims to systematically assess overestimation in early-phase trials involving programmed cell death-1 (PD-1)/programmed cell death-ligand 1(PD-L1) inhibitors compared with phase III trials and identify contributing factors.Methods We matched 51 pairs of early-phase and phase III clinical trials from a pool of over 9,600 PD-1/PD-L1 inhibitor trials. The matching criteria included identical treatment regimens, cancer types, treatment lines, and biomarker enrichment strategies. To assess overestimation, we compared the overall response rates (ORR) between early-phase and phase III trials. We established independent variables related to eligibility criteria, and trial design features of participants to analyze the factors influencing the observed discrepancy in efficacy between the two phases through univariable and multivariable logistic analyses.Result Early-phase trial outcomes systematically overestimated the subsequent phase III results, yielding an odds ratio (OR) comparing ORR in early-phase versus phase III: 1.66 (95% CI: 1.43 to 1.92, p<0.05). This trend of inflated ORR was consistent across trials testing PD-1/PD-L1 monotherapies and combination therapies involving PD-1/PD-L1. Among the examined factors, the exclusion of patients with autoimmune diseases was significantly associated with the disparity in efficacy between early-phase trials and phase III trials (p=0.023). We calculated a Ward statistic of 2.27 to validate the effectiveness of the model.Conclusion These findings underscore the tendency of overestimation of efficacy in early-phase trials involving immunotherapies. The observed differences could be attributed to variations in the inclusion of patients with autoimmune disorders in early-phase trials. These insights have the potential to inform stakeholders in the future development of cancer immunotherapies.https://jitc.bmj.com/content/12/1/e007959.full |
| spellingShingle | Xiang Li Jiuliang Zhao Mengtao Li Guanqiao Li Jiachen Xu Bing Xu Yangzhong Zhou Yunhe Qin Comparison of efficacy discrepancy between early-phase clinical trials and phase III trials of PD-1/PD-L1 inhibitors Journal for ImmunoTherapy of Cancer |
| title | Comparison of efficacy discrepancy between early-phase clinical trials and phase III trials of PD-1/PD-L1 inhibitors |
| title_full | Comparison of efficacy discrepancy between early-phase clinical trials and phase III trials of PD-1/PD-L1 inhibitors |
| title_fullStr | Comparison of efficacy discrepancy between early-phase clinical trials and phase III trials of PD-1/PD-L1 inhibitors |
| title_full_unstemmed | Comparison of efficacy discrepancy between early-phase clinical trials and phase III trials of PD-1/PD-L1 inhibitors |
| title_short | Comparison of efficacy discrepancy between early-phase clinical trials and phase III trials of PD-1/PD-L1 inhibitors |
| title_sort | comparison of efficacy discrepancy between early phase clinical trials and phase iii trials of pd 1 pd l1 inhibitors |
| url | https://jitc.bmj.com/content/12/1/e007959.full |
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