Induction PD-1 inhibitor toripalimab plus chemotherapy followed by concurrent chemoradiotherapy and consolidation toripalimab for bulky locally advanced non-small-cell lung cancer: protocol for a randomized phase II trial (InTRist study)
BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for locally advanced non-small-cell lung cancer (LA-NSCLC), whereas responses to anti-programmed cell death-1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) are heterogeneous. Though consolidation ICI followi...
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1341584/full |
| _version_ | 1797355310993637376 |
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| author | Yu Wang Lei Deng Jianyang Wang Tao Zhang Wenqing Wang Xin Wang Wenyang Liu Yuqi Wu Jima Lv Qinfu Feng Zongmei Zhou Jie Wang Luhua Wang Zhijie Wang Nan Bi Nan Bi |
| author_facet | Yu Wang Lei Deng Jianyang Wang Tao Zhang Wenqing Wang Xin Wang Wenyang Liu Yuqi Wu Jima Lv Qinfu Feng Zongmei Zhou Jie Wang Luhua Wang Zhijie Wang Nan Bi Nan Bi |
| author_sort | Yu Wang |
| collection | DOAJ |
| description | BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for locally advanced non-small-cell lung cancer (LA-NSCLC), whereas responses to anti-programmed cell death-1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) are heterogeneous. Though consolidation ICI following concurrent chemoradiotherapy (cCRT) improves survival of NSCLC, this regimen is challenging for patients with bulky tumors due to excessive target volumes and radiation-resistant hypoxia during upfront cCRT, leading to higher risk of pneumonitis and inferior local-regional control. Recent trials have demonstrated neoadjuvant ICI brought greater benefit to stage III than stage I-II NSCLC. Our previous study also supported the therapeutic advantage of 2-cycle induction ICI for patients with bulky unresectable stage III NSCLC. In the context of induction immunotherapy, radiotherapy is more likely to exert immune synergistic effects, reverse anti-PD-1 resistance, and activate abscopal immune responses. Prospective trials to determine the efficacy and safety of induction ICI for bulky LA-NSCLC are necessary.MethodsThis randomized, open-label, two-arm phase II study aims to explore whether 2 cycles of induction anti-PD-1 toripalimab plus chemotherapy can improve progression-free survival (PFS) in bulky LA-NSCLC. Bulky tumors are defined as primary lesion ≥5 cm in greatest dimension or metastatic lymph nodes ≥2 cm in shortest diameter. A total of 50 patients with bulky unresectable stage III NSCLC will be recruited and 1:1 randomized into the experimental arm: 2-cycle induction PD-1 inhibitor toripalimab plus chemotherapy followed by cCRT and consolidation toripalimab; or control arm: 2-cycle induction chemotherapy followed by cCRT and consolidation toripalimab. Patients are stratified by pathology (squamous versus non-squamous). The primary endpoint is PFS. Secondary endpoints are overall survival, overall response rate, disease control rate, duration of response, and incidence of adverse events. Exploratory analyses include PD-L1 expression and liquid biopsy-based biomarker testing, tumor microenvironment profiling at single-cell levels, and quality-of-life assessments.DiscussionThe InTRist study is the first randomized phase II trial to investigate the feasibility of induction anti-PD-1 toripalimab plus chemotherapy followed by cCRT and consolidation toripalimab in bulky LA-NSCLC, providing novel evidence for the synergistic strategy combining anti-PD-1 blockade with radiotherapy to prolong immunotherapy benefits, overcome resistance, and enhance abscopal immune response.Clinical trial registrationClinicalTrials.gov, identifier NCT05888402. |
| first_indexed | 2024-03-08T14:09:19Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-03-08T14:09:19Z |
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| spelling | doaj.art-b6eb33ba539b4d87be38094077e11b812024-01-15T04:17:22ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-01-011410.3389/fimmu.2023.13415841341584Induction PD-1 inhibitor toripalimab plus chemotherapy followed by concurrent chemoradiotherapy and consolidation toripalimab for bulky locally advanced non-small-cell lung cancer: protocol for a randomized phase II trial (InTRist study)Yu Wang0Lei Deng1Jianyang Wang2Tao Zhang3Wenqing Wang4Xin Wang5Wenyang Liu6Yuqi Wu7Jima Lv8Qinfu Feng9Zongmei Zhou10Jie Wang11Luhua Wang12Zhijie Wang13Nan Bi14Nan Bi15Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 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 and Peking Union Medical College, Beijing, ChinaDepartment of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 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 and Peking Union Medical College, Beijing, ChinaDepartment of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaState Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaBackgroundImmune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for locally advanced non-small-cell lung cancer (LA-NSCLC), whereas responses to anti-programmed cell death-1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) are heterogeneous. Though consolidation ICI following concurrent chemoradiotherapy (cCRT) improves survival of NSCLC, this regimen is challenging for patients with bulky tumors due to excessive target volumes and radiation-resistant hypoxia during upfront cCRT, leading to higher risk of pneumonitis and inferior local-regional control. Recent trials have demonstrated neoadjuvant ICI brought greater benefit to stage III than stage I-II NSCLC. Our previous study also supported the therapeutic advantage of 2-cycle induction ICI for patients with bulky unresectable stage III NSCLC. In the context of induction immunotherapy, radiotherapy is more likely to exert immune synergistic effects, reverse anti-PD-1 resistance, and activate abscopal immune responses. Prospective trials to determine the efficacy and safety of induction ICI for bulky LA-NSCLC are necessary.MethodsThis randomized, open-label, two-arm phase II study aims to explore whether 2 cycles of induction anti-PD-1 toripalimab plus chemotherapy can improve progression-free survival (PFS) in bulky LA-NSCLC. Bulky tumors are defined as primary lesion ≥5 cm in greatest dimension or metastatic lymph nodes ≥2 cm in shortest diameter. A total of 50 patients with bulky unresectable stage III NSCLC will be recruited and 1:1 randomized into the experimental arm: 2-cycle induction PD-1 inhibitor toripalimab plus chemotherapy followed by cCRT and consolidation toripalimab; or control arm: 2-cycle induction chemotherapy followed by cCRT and consolidation toripalimab. Patients are stratified by pathology (squamous versus non-squamous). The primary endpoint is PFS. Secondary endpoints are overall survival, overall response rate, disease control rate, duration of response, and incidence of adverse events. Exploratory analyses include PD-L1 expression and liquid biopsy-based biomarker testing, tumor microenvironment profiling at single-cell levels, and quality-of-life assessments.DiscussionThe InTRist study is the first randomized phase II trial to investigate the feasibility of induction anti-PD-1 toripalimab plus chemotherapy followed by cCRT and consolidation toripalimab in bulky LA-NSCLC, providing novel evidence for the synergistic strategy combining anti-PD-1 blockade with radiotherapy to prolong immunotherapy benefits, overcome resistance, and enhance abscopal immune response.Clinical trial registrationClinicalTrials.gov, identifier NCT05888402.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1341584/fullimmune checkpoint inhibitorchemoradiotherapyinduction therapyprogrammed cell death-1non-small-cell lung cancer |
| spellingShingle | Yu Wang Lei Deng Jianyang Wang Tao Zhang Wenqing Wang Xin Wang Wenyang Liu Yuqi Wu Jima Lv Qinfu Feng Zongmei Zhou Jie Wang Luhua Wang Zhijie Wang Nan Bi Nan Bi Induction PD-1 inhibitor toripalimab plus chemotherapy followed by concurrent chemoradiotherapy and consolidation toripalimab for bulky locally advanced non-small-cell lung cancer: protocol for a randomized phase II trial (InTRist study) Frontiers in Immunology immune checkpoint inhibitor chemoradiotherapy induction therapy programmed cell death-1 non-small-cell lung cancer |
| title | Induction PD-1 inhibitor toripalimab plus chemotherapy followed by concurrent chemoradiotherapy and consolidation toripalimab for bulky locally advanced non-small-cell lung cancer: protocol for a randomized phase II trial (InTRist study) |
| title_full | Induction PD-1 inhibitor toripalimab plus chemotherapy followed by concurrent chemoradiotherapy and consolidation toripalimab for bulky locally advanced non-small-cell lung cancer: protocol for a randomized phase II trial (InTRist study) |
| title_fullStr | Induction PD-1 inhibitor toripalimab plus chemotherapy followed by concurrent chemoradiotherapy and consolidation toripalimab for bulky locally advanced non-small-cell lung cancer: protocol for a randomized phase II trial (InTRist study) |
| title_full_unstemmed | Induction PD-1 inhibitor toripalimab plus chemotherapy followed by concurrent chemoradiotherapy and consolidation toripalimab for bulky locally advanced non-small-cell lung cancer: protocol for a randomized phase II trial (InTRist study) |
| title_short | Induction PD-1 inhibitor toripalimab plus chemotherapy followed by concurrent chemoradiotherapy and consolidation toripalimab for bulky locally advanced non-small-cell lung cancer: protocol for a randomized phase II trial (InTRist study) |
| title_sort | induction pd 1 inhibitor toripalimab plus chemotherapy followed by concurrent chemoradiotherapy and consolidation toripalimab for bulky locally advanced non small cell lung cancer protocol for a randomized phase ii trial intrist study |
| topic | immune checkpoint inhibitor chemoradiotherapy induction therapy programmed cell death-1 non-small-cell lung cancer |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1341584/full |
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