Pub Date : 2023-12-09Epub Date: 2023-10-20DOI: 10.1016/S0140-6736(23)02033-0
Yelena Y Janjigian, Akihito Kawazoe, Yuxian Bai, Jianming Xu, Sara Lonardi, Jean Phillipe Metges, Patricio Yanez, Lucjan S Wyrwicz, Lin Shen, Yuriy Ostapenko, Mehmet Bilici, Hyun Cheol Chung, Kohei Shitara, Shu-Kui Qin, Eric Van Cutsem, Josep Tabernero, Kan Li, Chie-Schin Shih, Pooja Bhagia, Sun Young Rha
<p><strong>Background: </strong>Evidence for the efficacy of combined PD-1 and HER2 blockade with chemotherapy on progression-free and overall survival in HER2-positive gastro-oesophageal cancer is scarce. The first interim analysis of the randomised, phase 3 KEYNOTE-811 study showed a superior objective response with pembrolizumab compared with placebo when added to trastuzumab plus fluoropyrimidine and platinum-based chemotherapy. Here, we report results from protocol-specified subsequent interim analyses of KEYNOTE-811.</p><p><strong>Methods: </strong>The randomised, phase 3 KEYNOTE-811 trial involved 168 medical centres in 20 countries worldwide. Patients aged 18 years or older with locally advanced or metastatic HER2-positive gastro-oesophageal junction adenocarcinoma, without previous first-line treatment, were randomly assigned (1:1) by an integrated interactive voice-response and web-response system to intravenous pembrolizumab 200 mg or placebo, both to be combined with standard chemotherapy (fluoropyrimidine and platinum-based therapy) plus trastuzumab every 3 weeks for up to 35 cycles or until disease progression, unacceptable toxic effects, or investigator or participant-initiated withdrawal. Randomisation used a block size of four and was stratified by region, PD-L1 status, and chemotherapy. Dual primary endpoints were progression-free and overall survival, analysed by intention to treat. Safety was assessed in all randomly assigned patients who received at least one dose of study treatment according to the treatment received. KEYNOTE-811 is registered with ClinicalTrials.gov (NCT03615326) and is active but not recruiting.</p><p><strong>Findings: </strong>Between Oct 5, 2018, and Aug 6, 2021, 698 patients were assigned to pembrolizumab (n=350) or placebo (n=348). 564 (81%) were male and 134 (19%) were female. At the third interim analysis, 286 (82%) of 350 patients in the pembrolizumab group and 304 (88%) of 346 in the placebo group who received treatment had discontinued treatment, mostly due to disease progression. At the second interim analysis (median follow-up 28·3 months [IQR 19·4-34·3] in the pembrolizumab group and 28·5 months [20·1-34·3] in the placebo group), median progression-free survival was 10·0 months (95% CI 8·6-11·7) in the pembrolizumab group versus 8·1 months (7·0-8·5) in the placebo group (hazard ratio [HR] 0·72, 95% CI 0·60-0·87; p=0·0002). Median overall survival was 20·0 months (17·8-23·2) versus 16·9 months (15·0-19·8; HR 0·87 [0·72-1·06]; p=0·084). At the third interim analysis (median follow-up 38·4 months [IQR 29·5-44·4] in the pembrolizumab group and 38·6 months [30·2-44·4] in the placebo group), median progression-free survival was 10·0 months (8·6-12·2) versus 8·1 months (7·1-8·6; HR 0·73 [0·61-0·87]), and median overall survival was 20·0 months (17·8-22·1) versus 16·8 months (15·0-18·7; HR 0·84 [0·70-1·01]), but did not meet prespecified criteria for significance and will continue to final analysis. Gr
{"title":"Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial.","authors":"Yelena Y Janjigian, Akihito Kawazoe, Yuxian Bai, Jianming Xu, Sara Lonardi, Jean Phillipe Metges, Patricio Yanez, Lucjan S Wyrwicz, Lin Shen, Yuriy Ostapenko, Mehmet Bilici, Hyun Cheol Chung, Kohei Shitara, Shu-Kui Qin, Eric Van Cutsem, Josep Tabernero, Kan Li, Chie-Schin Shih, Pooja Bhagia, Sun Young Rha","doi":"10.1016/S0140-6736(23)02033-0","DOIUrl":"10.1016/S0140-6736(23)02033-0","url":null,"abstract":"<p><strong>Background: </strong>Evidence for the efficacy of combined PD-1 and HER2 blockade with chemotherapy on progression-free and overall survival in HER2-positive gastro-oesophageal cancer is scarce. The first interim analysis of the randomised, phase 3 KEYNOTE-811 study showed a superior objective response with pembrolizumab compared with placebo when added to trastuzumab plus fluoropyrimidine and platinum-based chemotherapy. Here, we report results from protocol-specified subsequent interim analyses of KEYNOTE-811.</p><p><strong>Methods: </strong>The randomised, phase 3 KEYNOTE-811 trial involved 168 medical centres in 20 countries worldwide. Patients aged 18 years or older with locally advanced or metastatic HER2-positive gastro-oesophageal junction adenocarcinoma, without previous first-line treatment, were randomly assigned (1:1) by an integrated interactive voice-response and web-response system to intravenous pembrolizumab 200 mg or placebo, both to be combined with standard chemotherapy (fluoropyrimidine and platinum-based therapy) plus trastuzumab every 3 weeks for up to 35 cycles or until disease progression, unacceptable toxic effects, or investigator or participant-initiated withdrawal. Randomisation used a block size of four and was stratified by region, PD-L1 status, and chemotherapy. Dual primary endpoints were progression-free and overall survival, analysed by intention to treat. Safety was assessed in all randomly assigned patients who received at least one dose of study treatment according to the treatment received. KEYNOTE-811 is registered with ClinicalTrials.gov (NCT03615326) and is active but not recruiting.</p><p><strong>Findings: </strong>Between Oct 5, 2018, and Aug 6, 2021, 698 patients were assigned to pembrolizumab (n=350) or placebo (n=348). 564 (81%) were male and 134 (19%) were female. At the third interim analysis, 286 (82%) of 350 patients in the pembrolizumab group and 304 (88%) of 346 in the placebo group who received treatment had discontinued treatment, mostly due to disease progression. At the second interim analysis (median follow-up 28·3 months [IQR 19·4-34·3] in the pembrolizumab group and 28·5 months [20·1-34·3] in the placebo group), median progression-free survival was 10·0 months (95% CI 8·6-11·7) in the pembrolizumab group versus 8·1 months (7·0-8·5) in the placebo group (hazard ratio [HR] 0·72, 95% CI 0·60-0·87; p=0·0002). Median overall survival was 20·0 months (17·8-23·2) versus 16·9 months (15·0-19·8; HR 0·87 [0·72-1·06]; p=0·084). At the third interim analysis (median follow-up 38·4 months [IQR 29·5-44·4] in the pembrolizumab group and 38·6 months [30·2-44·4] in the placebo group), median progression-free survival was 10·0 months (8·6-12·2) versus 8·1 months (7·1-8·6; HR 0·73 [0·61-0·87]), and median overall survival was 20·0 months (17·8-22·1) versus 16·8 months (15·0-18·7; HR 0·84 [0·70-1·01]), but did not meet prespecified criteria for significance and will continue to final analysis. Gr","PeriodicalId":18014,"journal":{"name":"The Lancet","volume":" ","pages":"2197-2208"},"PeriodicalIF":168.9,"publicationDate":"2023-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49691292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-02Epub Date: 2023-09-26DOI: 10.1016/S0140-6736(23)01701-4
Ophira Ginsburg, Verna Vanderpuye, Ann Marie Beddoe, Nirmala Bhoo-Pathy, Freddie Bray, Carlo Caduff, Narjust Florez, Ibtihal Fadhil, Nazik Hammad, Shirin Heidari, Ishu Kataria, Somesh Kumar, Erica Liebermann, Jennifer Moodley, Miriam Mutebi, Deborah Mukherji, Rachel Nugent, Winnie K W So, Enrique Soto-Perez-de-Celis, Karla Unger-Saldaña, Gavin Allman, Jenna Bhimani, María T Bourlon, Michelle A B Eala, Peter S Hovmand, Yek-Ching Kong, Sonia Menon, Carolyn D Taylor, Isabelle Soerjomataram
{"title":"Women, power, and cancer: a Lancet Commission.","authors":"Ophira Ginsburg, Verna Vanderpuye, Ann Marie Beddoe, Nirmala Bhoo-Pathy, Freddie Bray, Carlo Caduff, Narjust Florez, Ibtihal Fadhil, Nazik Hammad, Shirin Heidari, Ishu Kataria, Somesh Kumar, Erica Liebermann, Jennifer Moodley, Miriam Mutebi, Deborah Mukherji, Rachel Nugent, Winnie K W So, Enrique Soto-Perez-de-Celis, Karla Unger-Saldaña, Gavin Allman, Jenna Bhimani, María T Bourlon, Michelle A B Eala, Peter S Hovmand, Yek-Ching Kong, Sonia Menon, Carolyn D Taylor, Isabelle Soerjomataram","doi":"10.1016/S0140-6736(23)01701-4","DOIUrl":"10.1016/S0140-6736(23)01701-4","url":null,"abstract":"","PeriodicalId":18014,"journal":{"name":"The Lancet","volume":" ","pages":"2113-2166"},"PeriodicalIF":168.9,"publicationDate":"2023-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41142198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-02Epub Date: 2023-09-26DOI: 10.1016/S0140-6736(23)02183-9
Rachael Davies
{"title":"Ophira Ginsburg: educating and empowering women with cancer.","authors":"Rachael Davies","doi":"10.1016/S0140-6736(23)02183-9","DOIUrl":"10.1016/S0140-6736(23)02183-9","url":null,"abstract":"","PeriodicalId":18014,"journal":{"name":"The Lancet","volume":" ","pages":"2063"},"PeriodicalIF":168.9,"publicationDate":"2023-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41131230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-02Epub Date: 2023-09-26DOI: 10.1016/S0140-6736(23)01737-3
Sondra Davoren, Suzanne Zhou, Evita Ricafort, Daiana Buresova, Andrea Lucas, Tarishi Desai, Hayley Jones
{"title":"The transformative potential of law for gender and cancer.","authors":"Sondra Davoren, Suzanne Zhou, Evita Ricafort, Daiana Buresova, Andrea Lucas, Tarishi Desai, Hayley Jones","doi":"10.1016/S0140-6736(23)01737-3","DOIUrl":"10.1016/S0140-6736(23)01737-3","url":null,"abstract":"","PeriodicalId":18014,"journal":{"name":"The Lancet","volume":" ","pages":"2051-2053"},"PeriodicalIF":168.9,"publicationDate":"2023-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41142258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-02Epub Date: 2023-09-26DOI: 10.1016/S0140-6736(23)01847-0
Monica M Bertagnolli
{"title":"Women, power, and cancer: a need for change and a force for progress.","authors":"Monica M Bertagnolli","doi":"10.1016/S0140-6736(23)01847-0","DOIUrl":"10.1016/S0140-6736(23)01847-0","url":null,"abstract":"","PeriodicalId":18014,"journal":{"name":"The Lancet","volume":" ","pages":"2053-2055"},"PeriodicalIF":168.9,"publicationDate":"2023-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41133372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-25Epub Date: 2023-09-22DOI: 10.1016/S0140-6736(23)01126-1
Georg Schett, Andreas Mackensen, Dimitrios Mougiakakos
Despite the tremendous progress in the clinical management of autoimmune diseases, many patients do not respond to the currently used treatments. Autoreactive B cells play a key role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. B-cell-depleting monoclonal antibodies, such as rituximab, have poor therapeutic efficacy in autoimmune diseases, mainly due to the persistence of autoreactive B cells in lymphatic organs and inflamed tissues. The adoptive transfer of T cells engineered to target tumour cells via chimeric antigen receptors (CARs) has emerged as an effective treatment modality in B-cell malignancies. In the last 2 years treatment with autologous CAR T cells directed against the CD19 antigen has been introduced in therapy of autoimmune disease. CD19 CAR T cells induced a rapid and sustained depletion of circulating B cells, as well as in a complete clinical and serological remission of refractory systemic lupus erythematosus and dermatomyositis. In this paper, we discuss the evolving strategies for targeting autoreactive B cells via CAR T cells, which might be used for targeted therapy in autoimmune diseases.
尽管自身免疫性疾病的临床管理取得了巨大进展，但许多患者对目前使用的治疗方法没有反应。自身反应性B细胞在自身免疫性疾病的发病机制中发挥着关键作用，如系统性红斑狼疮、类风湿性关节炎和多发性硬化症。消耗B细胞的单克隆抗体，如利妥昔单抗，在自身免疫性疾病中的治疗效果较差，主要是由于自身反应性B细胞在淋巴器官和炎症组织中的持续存在。通过嵌合抗原受体（CARs）过继转移经工程改造的靶向肿瘤细胞的T细胞已成为B细胞恶性肿瘤的一种有效治疗方式。在过去的两年中，针对CD19抗原的自体CAR T细胞的治疗已被引入自身免疫性疾病的治疗中。CD19 CAR T细胞诱导循环B细胞的快速和持续耗竭，以及难治性系统性红斑狼疮和皮肌炎的完全临床和血清学缓解。在本文中，我们讨论了通过CAR T细胞靶向自身反应性B细胞的进化策略，该策略可能用于自身免疫性疾病的靶向治疗。
{"title":"CAR T-cell therapy in autoimmune diseases.","authors":"Georg Schett, Andreas Mackensen, Dimitrios Mougiakakos","doi":"10.1016/S0140-6736(23)01126-1","DOIUrl":"10.1016/S0140-6736(23)01126-1","url":null,"abstract":"<p><p>Despite the tremendous progress in the clinical management of autoimmune diseases, many patients do not respond to the currently used treatments. Autoreactive B cells play a key role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. B-cell-depleting monoclonal antibodies, such as rituximab, have poor therapeutic efficacy in autoimmune diseases, mainly due to the persistence of autoreactive B cells in lymphatic organs and inflamed tissues. The adoptive transfer of T cells engineered to target tumour cells via chimeric antigen receptors (CARs) has emerged as an effective treatment modality in B-cell malignancies. In the last 2 years treatment with autologous CAR T cells directed against the CD19 antigen has been introduced in therapy of autoimmune disease. CD19 CAR T cells induced a rapid and sustained depletion of circulating B cells, as well as in a complete clinical and serological remission of refractory systemic lupus erythematosus and dermatomyositis. In this paper, we discuss the evolving strategies for targeting autoreactive B cells via CAR T cells, which might be used for targeted therapy in autoimmune diseases.</p>","PeriodicalId":18014,"journal":{"name":"The Lancet","volume":" ","pages":"2034-2044"},"PeriodicalIF":168.9,"publicationDate":"2023-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41132582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Are we listening? Acting on commitments to social participation for universal health coverage.","authors":"Justin Koonin, Shraddha Mishra, Amandeep Saini, Misimi Kakoti, Emma Feeny, Devaki Nambiar","doi":"10.1016/S0140-6736(23)01969-4","DOIUrl":"10.1016/S0140-6736(23)01969-4","url":null,"abstract":"","PeriodicalId":18014,"journal":{"name":"The Lancet","volume":" ","pages":"1948-1949"},"PeriodicalIF":168.9,"publicationDate":"2023-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41135239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-25Epub Date: 2023-08-24DOI: 10.1016/S0140-6736(23)01686-0
David T Zhu, Joseph Friedman, Philippe Bourgois, Fernando Montero, Suzanne Tamang
{"title":"The emerging fentanyl-xylazine syndemic in the USA: challenges and future directions.","authors":"David T Zhu, Joseph Friedman, Philippe Bourgois, Fernando Montero, Suzanne Tamang","doi":"10.1016/S0140-6736(23)01686-0","DOIUrl":"10.1016/S0140-6736(23)01686-0","url":null,"abstract":"","PeriodicalId":18014,"journal":{"name":"The Lancet","volume":" ","pages":"1949-1952"},"PeriodicalIF":168.9,"publicationDate":"2023-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10842070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10439141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：