Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study
The options for first-line treatment of advanced oesophageal squamous cell carcinoma are scarce, and the outcomes remain poor. The anti-PD-1 antibody, tislelizumab, has shown antitumour activity in previously treated patients with advanced oesophageal squamous cell carcinoma. We report interim analy...
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| Veröffentlicht in: | The lancet oncology 2023-05, Vol.24 (5), p.483-495 |
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| creator | Xu, Jianming Kato, Ken Raymond, Eric Hubner, Richard A Shu, Yongqian Pan, Yueyin Park, Sook Ryun Ping, Lu Jiang, Yi Zhang, Jingdong Wu, Xiaohong Yao, Yuanhu Shen, Lin Kojima, Takashi Gotovkin, Evgeny Ishihara, Ryu Wyrwicz, Lucjan Van Cutsem, Eric Jimenez-Fonseca, Paula Lin, Chen-Yuan Wang, Lei Shi, Jingwen Li, Liyun Yoon, Harry H |
| description | The options for first-line treatment of advanced oesophageal squamous cell carcinoma are scarce, and the outcomes remain poor. The anti-PD-1 antibody, tislelizumab, has shown antitumour activity in previously treated patients with advanced oesophageal squamous cell carcinoma. We report interim analysis results from the RATIONALE-306 study, which aimed to assess tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma.
This global, randomised, double-blind, parallel-arm, placebo-controlled, phase 3 study was conducted at 162 medical centres across Asia, Europe, Oceania, and North America. Patients (aged ≥18 years) with unresectable, locally advanced, recurrent or metastatic oesophageal squamous cell carcinoma (regardless of PD-L1 expression), Eastern Cooperative Oncology Group performance status of 0–1, and measurable or evaluable disease per Response Evaluation Criteria in Solid Tumours (version 1.1) were recruited. Patients were randomly assigned (1:1), using permuted block randomisation (block size of four) and stratified by investigator-chosen chemotherapy, region, and previous definitive therapy, to tislelizumab 200 mg or placebo intravenously every 3 weeks on day 1, together with an investigator-chosen chemotherapy doublet, comprising a platinum agent (cisplatin 60–80 mg/m2 intravenously on day 1 or oxaliplatin 130 mg/m2 intravenously on day 1) plus a fluoropyrimidine (fluorouracil [750–800 mg/m2 intravenously on days 1–5] or capecitabine [1000 mg/m2 orally twice daily on days 1–14]) or paclitaxel (175 mg/m2 intravenously on day 1). Treatment was continued until disease progression or unacceptable toxicity. Investigators, patients, and sponsor staff or designees were masked to treatment. The primary endpoint was overall survival. The efficacy analysis was done in the intention-to-treat population (ie, all randomly assigned patients) and safety was assessed in all patients who received at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03783442.
Between Dec 12, 2018, and Nov 24, 2020, 869 patients were screened, of whom 649 were randomly assigned to tislelizumab plus chemotherapy (n=326) or placebo plus chemotherapy (n=323). Median age was 64·0 years (IQR 59·0–69·0), 563 (87%) of 649 participants were male, 86 (13%) were female, 486 (75%) were Asian, and 155 (24%) were White. 324 (99%) of 326 patients in the tislelizumab |
| doi_str_mv | 10.1016/S1470-2045(23)00108-0 |
| format | Article |
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This global, randomised, double-blind, parallel-arm, placebo-controlled, phase 3 study was conducted at 162 medical centres across Asia, Europe, Oceania, and North America. Patients (aged ≥18 years) with unresectable, locally advanced, recurrent or metastatic oesophageal squamous cell carcinoma (regardless of PD-L1 expression), Eastern Cooperative Oncology Group performance status of 0–1, and measurable or evaluable disease per Response Evaluation Criteria in Solid Tumours (version 1.1) were recruited. Patients were randomly assigned (1:1), using permuted block randomisation (block size of four) and stratified by investigator-chosen chemotherapy, region, and previous definitive therapy, to tislelizumab 200 mg or placebo intravenously every 3 weeks on day 1, together with an investigator-chosen chemotherapy doublet, comprising a platinum agent (cisplatin 60–80 mg/m2 intravenously on day 1 or oxaliplatin 130 mg/m2 intravenously on day 1) plus a fluoropyrimidine (fluorouracil [750–800 mg/m2 intravenously on days 1–5] or capecitabine [1000 mg/m2 orally twice daily on days 1–14]) or paclitaxel (175 mg/m2 intravenously on day 1). Treatment was continued until disease progression or unacceptable toxicity. Investigators, patients, and sponsor staff or designees were masked to treatment. The primary endpoint was overall survival. The efficacy analysis was done in the intention-to-treat population (ie, all randomly assigned patients) and safety was assessed in all patients who received at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03783442.
Between Dec 12, 2018, and Nov 24, 2020, 869 patients were screened, of whom 649 were randomly assigned to tislelizumab plus chemotherapy (n=326) or placebo plus chemotherapy (n=323). Median age was 64·0 years (IQR 59·0–69·0), 563 (87%) of 649 participants were male, 86 (13%) were female, 486 (75%) were Asian, and 155 (24%) were White. 324 (99%) of 326 patients in the tislelizumab group and 321 (99%) of 323 in the placebo group received at least one dose of the study drug. As of data cutoff (Feb 28, 2022), median follow-up was 16·3 months (IQR 8·6–21·8) in the tislelizumab group and 9·8 months (IQR 5·8–19·0) in the placebo group, and 196 (60%) of 326 patients in the tislelizumab group versus 226 (70%) of 323 in the placebo group had died. Median overall survival in the tislelizumab group was 17·2 months (95% CI 15·8–20·1) and in the placebo group was 10·6 months (9·3–12·1; stratified hazard ratio 0·66 [95% CI 0·54–0·80]; one-sided p<0·0001). 313 (97%) of 324 patients in the tislelizumab group and 309 (96%) of 321 in the placebo group had treatment-related treatment-emergent adverse events. The most common grade 3 or 4 treatment-related treatment-emergent adverse events were decreased neutrophil count (99 [31%] in the tislelizumab group vs 105 [33%] in the placebo group), decreased white blood cell count (35 [11%] vs 50 [16%]), and anaemia (47 [15%] vs 41 [13%]). Six deaths in the tislelizumab group (gastrointestinal and upper gastrointestinal haemorrhage [n=2], myocarditis [n=1], pulmonary tuberculosis [n=1], electrolyte imbalance [n=1], and respiratory failure [n=1]) and four deaths in the placebo group (pneumonia [n=1], septic shock [n=1], and unspecified death [n=2]) were determined to be treatment-related.
Tislelizumab plus chemotherapy as a first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma provided superior overall survival with a manageable safety profile versus placebo plus chemotherapy. Given that the interim analysis met its superiority boundary for the primary endpoint, as confirmed by the independent data monitoring committee, this Article represents the primary study analysis.
BeiGene.</description><identifier>ISSN: 1470-2045</identifier><identifier>EISSN: 1474-5488</identifier><identifier>DOI: 10.1016/S1470-2045(23)00108-0</identifier><identifier>PMID: 37080222</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>5-Fluorouracil ; Adolescent ; Adult ; Adverse events ; Antibodies, Monoclonal, Humanized ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Cancer therapies ; Chemotherapy ; Cisplatin ; Clinical medicine ; Cytotoxicity ; Disease ; Double-Blind Method ; Esophageal cancer ; Esophageal Neoplasms ; Esophageal Squamous Cell Carcinoma ; Esophagus ; Female ; Heart diseases ; Hemorrhage ; Humans ; Leukocytes (neutrophilic) ; Male ; Medical practices ; Medical prognosis ; Metastases ; Metastasis ; Middle Aged ; Monoclonal antibodies ; Myocarditis ; Oxaliplatin ; Paclitaxel ; Patients ; PD-1 protein ; PD-L1 protein ; Placebos ; Respiratory failure ; Septic shock ; Solid tumors ; Squamous cell carcinoma ; Survival analysis ; Targeted cancer therapy ; Toxicity ; Tumors</subject><ispartof>The lancet oncology, 2023-05, Vol.24 (5), p.483-495</ispartof><rights>2023 Elsevier Ltd</rights><rights>Copyright © 2023 Elsevier Ltd. All rights reserved.</rights><rights>2023. Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c445t-ef6ada7781ab30f4adc879d8ba976d24024feb68c1280ffceca09bd4710e87073</citedby><cites>FETCH-LOGICAL-c445t-ef6ada7781ab30f4adc879d8ba976d24024feb68c1280ffceca09bd4710e87073</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1470204523001080$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37080222$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xu, Jianming</creatorcontrib><creatorcontrib>Kato, Ken</creatorcontrib><creatorcontrib>Raymond, Eric</creatorcontrib><creatorcontrib>Hubner, Richard A</creatorcontrib><creatorcontrib>Shu, Yongqian</creatorcontrib><creatorcontrib>Pan, Yueyin</creatorcontrib><creatorcontrib>Park, Sook Ryun</creatorcontrib><creatorcontrib>Ping, Lu</creatorcontrib><creatorcontrib>Jiang, Yi</creatorcontrib><creatorcontrib>Zhang, Jingdong</creatorcontrib><creatorcontrib>Wu, Xiaohong</creatorcontrib><creatorcontrib>Yao, Yuanhu</creatorcontrib><creatorcontrib>Shen, Lin</creatorcontrib><creatorcontrib>Kojima, Takashi</creatorcontrib><creatorcontrib>Gotovkin, Evgeny</creatorcontrib><creatorcontrib>Ishihara, Ryu</creatorcontrib><creatorcontrib>Wyrwicz, Lucjan</creatorcontrib><creatorcontrib>Van Cutsem, Eric</creatorcontrib><creatorcontrib>Jimenez-Fonseca, Paula</creatorcontrib><creatorcontrib>Lin, Chen-Yuan</creatorcontrib><creatorcontrib>Wang, Lei</creatorcontrib><creatorcontrib>Shi, Jingwen</creatorcontrib><creatorcontrib>Li, Liyun</creatorcontrib><creatorcontrib>Yoon, Harry H</creatorcontrib><title>Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study</title><title>The lancet oncology</title><addtitle>Lancet Oncol</addtitle><description>The options for first-line treatment of advanced oesophageal squamous cell carcinoma are scarce, and the outcomes remain poor. The anti-PD-1 antibody, tislelizumab, has shown antitumour activity in previously treated patients with advanced oesophageal squamous cell carcinoma. We report interim analysis results from the RATIONALE-306 study, which aimed to assess tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma.
This global, randomised, double-blind, parallel-arm, placebo-controlled, phase 3 study was conducted at 162 medical centres across Asia, Europe, Oceania, and North America. Patients (aged ≥18 years) with unresectable, locally advanced, recurrent or metastatic oesophageal squamous cell carcinoma (regardless of PD-L1 expression), Eastern Cooperative Oncology Group performance status of 0–1, and measurable or evaluable disease per Response Evaluation Criteria in Solid Tumours (version 1.1) were recruited. Patients were randomly assigned (1:1), using permuted block randomisation (block size of four) and stratified by investigator-chosen chemotherapy, region, and previous definitive therapy, to tislelizumab 200 mg or placebo intravenously every 3 weeks on day 1, together with an investigator-chosen chemotherapy doublet, comprising a platinum agent (cisplatin 60–80 mg/m2 intravenously on day 1 or oxaliplatin 130 mg/m2 intravenously on day 1) plus a fluoropyrimidine (fluorouracil [750–800 mg/m2 intravenously on days 1–5] or capecitabine [1000 mg/m2 orally twice daily on days 1–14]) or paclitaxel (175 mg/m2 intravenously on day 1). Treatment was continued until disease progression or unacceptable toxicity. Investigators, patients, and sponsor staff or designees were masked to treatment. The primary endpoint was overall survival. The efficacy analysis was done in the intention-to-treat population (ie, all randomly assigned patients) and safety was assessed in all patients who received at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03783442.
Between Dec 12, 2018, and Nov 24, 2020, 869 patients were screened, of whom 649 were randomly assigned to tislelizumab plus chemotherapy (n=326) or placebo plus chemotherapy (n=323). Median age was 64·0 years (IQR 59·0–69·0), 563 (87%) of 649 participants were male, 86 (13%) were female, 486 (75%) were Asian, and 155 (24%) were White. 324 (99%) of 326 patients in the tislelizumab group and 321 (99%) of 323 in the placebo group received at least one dose of the study drug. As of data cutoff (Feb 28, 2022), median follow-up was 16·3 months (IQR 8·6–21·8) in the tislelizumab group and 9·8 months (IQR 5·8–19·0) in the placebo group, and 196 (60%) of 326 patients in the tislelizumab group versus 226 (70%) of 323 in the placebo group had died. Median overall survival in the tislelizumab group was 17·2 months (95% CI 15·8–20·1) and in the placebo group was 10·6 months (9·3–12·1; stratified hazard ratio 0·66 [95% CI 0·54–0·80]; one-sided p<0·0001). 313 (97%) of 324 patients in the tislelizumab group and 309 (96%) of 321 in the placebo group had treatment-related treatment-emergent adverse events. The most common grade 3 or 4 treatment-related treatment-emergent adverse events were decreased neutrophil count (99 [31%] in the tislelizumab group vs 105 [33%] in the placebo group), decreased white blood cell count (35 [11%] vs 50 [16%]), and anaemia (47 [15%] vs 41 [13%]). Six deaths in the tislelizumab group (gastrointestinal and upper gastrointestinal haemorrhage [n=2], myocarditis [n=1], pulmonary tuberculosis [n=1], electrolyte imbalance [n=1], and respiratory failure [n=1]) and four deaths in the placebo group (pneumonia [n=1], septic shock [n=1], and unspecified death [n=2]) were determined to be treatment-related.
Tislelizumab plus chemotherapy as a first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma provided superior overall survival with a manageable safety profile versus placebo plus chemotherapy. Given that the interim analysis met its superiority boundary for the primary endpoint, as confirmed by the independent data monitoring committee, this Article represents the primary study analysis.
BeiGene.</description><subject>5-Fluorouracil</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Adverse events</subject><subject>Antibodies, Monoclonal, Humanized</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Cancer therapies</subject><subject>Chemotherapy</subject><subject>Cisplatin</subject><subject>Clinical medicine</subject><subject>Cytotoxicity</subject><subject>Disease</subject><subject>Double-Blind Method</subject><subject>Esophageal cancer</subject><subject>Esophageal Neoplasms</subject><subject>Esophageal Squamous Cell Carcinoma</subject><subject>Esophagus</subject><subject>Female</subject><subject>Heart diseases</subject><subject>Hemorrhage</subject><subject>Humans</subject><subject>Leukocytes (neutrophilic)</subject><subject>Male</subject><subject>Medical practices</subject><subject>Medical prognosis</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Middle Aged</subject><subject>Monoclonal antibodies</subject><subject>Myocarditis</subject><subject>Oxaliplatin</subject><subject>Paclitaxel</subject><subject>Patients</subject><subject>PD-1 protein</subject><subject>PD-L1 protein</subject><subject>Placebos</subject><subject>Respiratory failure</subject><subject>Septic shock</subject><subject>Solid tumors</subject><subject>Squamous cell carcinoma</subject><subject>Survival analysis</subject><subject>Targeted cancer therapy</subject><subject>Toxicity</subject><subject>Tumors</subject><issn>1470-2045</issn><issn>1474-5488</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqFksFu1DAQhiMEoqXwCCBLXLZSA47jJF4uaFUVqLSiEixna2JPuq6cOLWdlZaX5VVwdlsOCImTR6Nvxv_MP1n2uqDvClrU778XvKE5o7xasPKc0oKKnD7JTlOa5xUX4ukhPiIn2YsQ7hLUFLR6np2UDRWUMXaa_dqYYNGan1MPLRntFIjaYu_iFj2Me7JDH1JutKCwdf8AIJDO-BBzawYk0SPEHodIOucJ6B0MCjVJcY8RQoRoFHEY3LiFWwRLwv0EvZuborVEgVdmcD2QxbfV5vrm62p9lZe0Pv9AgNxa14K9IB4G7XoTUF886sqVG6J31h5yWwhIShLipPcvs2cd2ICvHt6z7Menq83ll3x98_n6crXOFedVzLGrQUPTiALaknYctBLNUosWlk2tGaeMd9jWQhVM0K5TqIAuW83TPlE0tCnPssWx7-jd_YQhyqRwngkGTOPJVFZRtqwO6Nu_0Ds3-SGpmylR8TqZlKjqSCnvQvDYydGbHvxeFlTOFyAPFyBneyUr5eECJE11bx66T22P-k_Vo-UJ-HgEMK1jZ9DLoAzONhmPKkrtzH---A3gw8RM</recordid><startdate>202305</startdate><enddate>202305</enddate><creator>Xu, Jianming</creator><creator>Kato, 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study</title><author>Xu, Jianming ; Kato, Ken ; Raymond, Eric ; Hubner, Richard A ; Shu, Yongqian ; Pan, Yueyin ; Park, Sook Ryun ; Ping, Lu ; Jiang, Yi ; Zhang, Jingdong ; Wu, Xiaohong ; Yao, Yuanhu ; Shen, Lin ; Kojima, Takashi ; Gotovkin, Evgeny ; Ishihara, Ryu ; Wyrwicz, Lucjan ; Van Cutsem, Eric ; Jimenez-Fonseca, Paula ; Lin, Chen-Yuan ; Wang, Lei ; Shi, Jingwen ; Li, Liyun ; Yoon, Harry H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c445t-ef6ada7781ab30f4adc879d8ba976d24024feb68c1280ffceca09bd4710e87073</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>5-Fluorouracil</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Adverse events</topic><topic>Antibodies, Monoclonal, Humanized</topic><topic>Antineoplastic Combined Chemotherapy Protocols - adverse effects</topic><topic>Cancer 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Eric</creatorcontrib><creatorcontrib>Jimenez-Fonseca, Paula</creatorcontrib><creatorcontrib>Lin, Chen-Yuan</creatorcontrib><creatorcontrib>Wang, Lei</creatorcontrib><creatorcontrib>Shi, Jingwen</creatorcontrib><creatorcontrib>Li, Liyun</creatorcontrib><creatorcontrib>Yoon, Harry H</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Pharma and Biotech Premium PRO</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Nursing and Allied Health Journals</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma 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Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><jtitle>The lancet oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xu, Jianming</au><au>Kato, Ken</au><au>Raymond, Eric</au><au>Hubner, Richard A</au><au>Shu, Yongqian</au><au>Pan, Yueyin</au><au>Park, Sook Ryun</au><au>Ping, Lu</au><au>Jiang, Yi</au><au>Zhang, Jingdong</au><au>Wu, Xiaohong</au><au>Yao, Yuanhu</au><au>Shen, Lin</au><au>Kojima, Takashi</au><au>Gotovkin, Evgeny</au><au>Ishihara, Ryu</au><au>Wyrwicz, Lucjan</au><au>Van Cutsem, Eric</au><au>Jimenez-Fonseca, Paula</au><au>Lin, Chen-Yuan</au><au>Wang, Lei</au><au>Shi, Jingwen</au><au>Li, Liyun</au><au>Yoon, Harry H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study</atitle><jtitle>The lancet oncology</jtitle><addtitle>Lancet Oncol</addtitle><date>2023-05</date><risdate>2023</risdate><volume>24</volume><issue>5</issue><spage>483</spage><epage>495</epage><pages>483-495</pages><issn>1470-2045</issn><eissn>1474-5488</eissn><abstract>The options for first-line treatment of advanced oesophageal squamous cell carcinoma are scarce, and the outcomes remain poor. The anti-PD-1 antibody, tislelizumab, has shown antitumour activity in previously treated patients with advanced oesophageal squamous cell carcinoma. We report interim analysis results from the RATIONALE-306 study, which aimed to assess tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma.
This global, randomised, double-blind, parallel-arm, placebo-controlled, phase 3 study was conducted at 162 medical centres across Asia, Europe, Oceania, and North America. Patients (aged ≥18 years) with unresectable, locally advanced, recurrent or metastatic oesophageal squamous cell carcinoma (regardless of PD-L1 expression), Eastern Cooperative Oncology Group performance status of 0–1, and measurable or evaluable disease per Response Evaluation Criteria in Solid Tumours (version 1.1) were recruited. Patients were randomly assigned (1:1), using permuted block randomisation (block size of four) and stratified by investigator-chosen chemotherapy, region, and previous definitive therapy, to tislelizumab 200 mg or placebo intravenously every 3 weeks on day 1, together with an investigator-chosen chemotherapy doublet, comprising a platinum agent (cisplatin 60–80 mg/m2 intravenously on day 1 or oxaliplatin 130 mg/m2 intravenously on day 1) plus a fluoropyrimidine (fluorouracil [750–800 mg/m2 intravenously on days 1–5] or capecitabine [1000 mg/m2 orally twice daily on days 1–14]) or paclitaxel (175 mg/m2 intravenously on day 1). Treatment was continued until disease progression or unacceptable toxicity. Investigators, patients, and sponsor staff or designees were masked to treatment. The primary endpoint was overall survival. The efficacy analysis was done in the intention-to-treat population (ie, all randomly assigned patients) and safety was assessed in all patients who received at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03783442.
Between Dec 12, 2018, and Nov 24, 2020, 869 patients were screened, of whom 649 were randomly assigned to tislelizumab plus chemotherapy (n=326) or placebo plus chemotherapy (n=323). Median age was 64·0 years (IQR 59·0–69·0), 563 (87%) of 649 participants were male, 86 (13%) were female, 486 (75%) were Asian, and 155 (24%) were White. 324 (99%) of 326 patients in the tislelizumab group and 321 (99%) of 323 in the placebo group received at least one dose of the study drug. As of data cutoff (Feb 28, 2022), median follow-up was 16·3 months (IQR 8·6–21·8) in the tislelizumab group and 9·8 months (IQR 5·8–19·0) in the placebo group, and 196 (60%) of 326 patients in the tislelizumab group versus 226 (70%) of 323 in the placebo group had died. Median overall survival in the tislelizumab group was 17·2 months (95% CI 15·8–20·1) and in the placebo group was 10·6 months (9·3–12·1; stratified hazard ratio 0·66 [95% CI 0·54–0·80]; one-sided p<0·0001). 313 (97%) of 324 patients in the tislelizumab group and 309 (96%) of 321 in the placebo group had treatment-related treatment-emergent adverse events. The most common grade 3 or 4 treatment-related treatment-emergent adverse events were decreased neutrophil count (99 [31%] in the tislelizumab group vs 105 [33%] in the placebo group), decreased white blood cell count (35 [11%] vs 50 [16%]), and anaemia (47 [15%] vs 41 [13%]). Six deaths in the tislelizumab group (gastrointestinal and upper gastrointestinal haemorrhage [n=2], myocarditis [n=1], pulmonary tuberculosis [n=1], electrolyte imbalance [n=1], and respiratory failure [n=1]) and four deaths in the placebo group (pneumonia [n=1], septic shock [n=1], and unspecified death [n=2]) were determined to be treatment-related.
Tislelizumab plus chemotherapy as a first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma provided superior overall survival with a manageable safety profile versus placebo plus chemotherapy. Given that the interim analysis met its superiority boundary for the primary endpoint, as confirmed by the independent data monitoring committee, this Article represents the primary study analysis.
BeiGene.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>37080222</pmid><doi>10.1016/S1470-2045(23)00108-0</doi><tpages>13</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1470-2045 |
| ispartof | The lancet oncology, 2023-05, Vol.24 (5), p.483-495 |
| issn | 1470-2045 1474-5488 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | 5-Fluorouracil Adolescent Adult Adverse events Antibodies, Monoclonal, Humanized Antineoplastic Combined Chemotherapy Protocols - adverse effects Cancer therapies Chemotherapy Cisplatin Clinical medicine Cytotoxicity Disease Double-Blind Method Esophageal cancer Esophageal Neoplasms Esophageal Squamous Cell Carcinoma Esophagus Female Heart diseases Hemorrhage Humans Leukocytes (neutrophilic) Male Medical practices Medical prognosis Metastases Metastasis Middle Aged Monoclonal antibodies Myocarditis Oxaliplatin Paclitaxel Patients PD-1 protein PD-L1 protein Placebos Respiratory failure Septic shock Solid tumors Squamous cell carcinoma Survival analysis Targeted cancer therapy Toxicity Tumors |
| title | Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study |
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