Pub Date : 2026-01-03DOI: 10.1016/S0140-6736(25)02596-6
The Lancet
{"title":"No health without peace.","authors":"The Lancet","doi":"10.1016/S0140-6736(25)02596-6","DOIUrl":"https://doi.org/10.1016/S0140-6736(25)02596-6","url":null,"abstract":"","PeriodicalId":18014,"journal":{"name":"The Lancet","volume":"407 10523","pages":"1"},"PeriodicalIF":88.5,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896660","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 : 2025-12-21Epub Date: 2024-08-28DOI: 10.1016/S0140-6736(24)01564-2
Wyatte C Hall, Julia L Hecht
{"title":"Primary health-care practices for deaf children should include early incorporation of a signed language.","authors":"Wyatte C Hall, Julia L Hecht","doi":"10.1016/S0140-6736(24)01564-2","DOIUrl":"10.1016/S0140-6736(24)01564-2","url":null,"abstract":"","PeriodicalId":18014,"journal":{"name":"The Lancet","volume":" ","pages":"2498-2500"},"PeriodicalIF":98.4,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108869","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 : 2025-12-13Epub Date: 2025-10-23DOI: 10.1016/S0140-6736(25)01497-7
Lana Moayad, Ariana Mihan, Sanne A E Peters, Harriette G C Van Spall
Randomised controlled trials have commonly excluded women who are pregnant, lactating, or of reproductive potential. When there is clinical equipoise, the exclusion of these women raises concerns regarding the principles of autonomy, beneficence, and justice. This exclusion also shifts evidence generation from the monitored setting of randomised controlled trials to clinical settings, where data can take several years to accrue. Here, we highlight key health, ethical, scientific, and regulatory considerations surrounding the inclusion of women who are pregnant, lactating, or of reproductive potential in clinical trials to guide further discussions. We offer recommendations for a judicious approach to inclusivity, highlighting regulatory, sponsor, and clinical trial design considerations. We highlight the need for patient engagement and interdisciplinary discourse throughout the research lifecycle.
{"title":"Inclusion of women who are pregnant, lactating, or of reproductive potential in clinical trials: health, ethical, and regulatory considerations.","authors":"Lana Moayad, Ariana Mihan, Sanne A E Peters, Harriette G C Van Spall","doi":"10.1016/S0140-6736(25)01497-7","DOIUrl":"https://doi.org/10.1016/S0140-6736(25)01497-7","url":null,"abstract":"<p><p>Randomised controlled trials have commonly excluded women who are pregnant, lactating, or of reproductive potential. When there is clinical equipoise, the exclusion of these women raises concerns regarding the principles of autonomy, beneficence, and justice. This exclusion also shifts evidence generation from the monitored setting of randomised controlled trials to clinical settings, where data can take several years to accrue. Here, we highlight key health, ethical, scientific, and regulatory considerations surrounding the inclusion of women who are pregnant, lactating, or of reproductive potential in clinical trials to guide further discussions. We offer recommendations for a judicious approach to inclusivity, highlighting regulatory, sponsor, and clinical trial design considerations. We highlight the need for patient engagement and interdisciplinary discourse throughout the research lifecycle.</p>","PeriodicalId":18014,"journal":{"name":"The Lancet","volume":"406 10521","pages":"2858-2864"},"PeriodicalIF":88.5,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810458","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 : 2025-11-29Epub Date: 2025-10-21DOI: 10.1016/S0140-6736(25)01669-1
Adam Gaffney, Steffie Woolhandler, David U Himmelstein, Danny McCormick
Despite extraordinary scientific and medical resources, the US health-care system underperforms. In this Review we consider the damage wrought by decades of market-based policies that have stimulated profit-seeking by insurers and health-care providers. Policy makers have subcontracted coverage under the public Medicaid and Medicare programmes for people with low incomes and those older than 64 years to private insurance firms-which now derive most of their revenues from those programmes-raising taxpayers' costs and constricting patients' care. Despite worrisome evidence of misbehaviour, firms obligated to prioritise shareholders' interests-and, more recently, private equity firms with a single-minded focus on short-term profit-have gained control of vital clinical resources. President Biden rescinded some of Donald Trump's most egregious first-term policies, expanded coverage for lower-income Americans, and initiated modest drug price controls. Since regaining office, President Trump has laid siege to science and public health, cut US$990 billion from Medicaid to offset tax reductions for the wealthy, and is accelerating Medicare's privatisation. State governments can tighten regulation of profit-driven abuses, and the medical community should resist Trump's health-harming agenda. But neither restoring the pre-Trump status quo, nor further attempts to reconcile the human rights of patients with the property claims of investors will suffice. Reforms must, instead, decommercialise insurance and care provision.
{"title":"Health care in the USA: money has become the mission.","authors":"Adam Gaffney, Steffie Woolhandler, David U Himmelstein, Danny McCormick","doi":"10.1016/S0140-6736(25)01669-1","DOIUrl":"10.1016/S0140-6736(25)01669-1","url":null,"abstract":"<p><p>Despite extraordinary scientific and medical resources, the US health-care system underperforms. In this Review we consider the damage wrought by decades of market-based policies that have stimulated profit-seeking by insurers and health-care providers. Policy makers have subcontracted coverage under the public Medicaid and Medicare programmes for people with low incomes and those older than 64 years to private insurance firms-which now derive most of their revenues from those programmes-raising taxpayers' costs and constricting patients' care. Despite worrisome evidence of misbehaviour, firms obligated to prioritise shareholders' interests-and, more recently, private equity firms with a single-minded focus on short-term profit-have gained control of vital clinical resources. President Biden rescinded some of Donald Trump's most egregious first-term policies, expanded coverage for lower-income Americans, and initiated modest drug price controls. Since regaining office, President Trump has laid siege to science and public health, cut US$990 billion from Medicaid to offset tax reductions for the wealthy, and is accelerating Medicare's privatisation. State governments can tighten regulation of profit-driven abuses, and the medical community should resist Trump's health-harming agenda. But neither restoring the pre-Trump status quo, nor further attempts to reconcile the human rights of patients with the property claims of investors will suffice. Reforms must, instead, decommercialise insurance and care provision.</p>","PeriodicalId":18014,"journal":{"name":"The Lancet","volume":" ","pages":"2588-2600"},"PeriodicalIF":88.5,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367680","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 : 2025-11-22Epub Date: 2025-10-22DOI: 10.1016/S0140-6736(25)01533-8
Jessica R Biesiekierski, Daisy Jonkers, Carolina Ciacci, Imran Aziz
Non-coeliac gluten sensitivity (NCGS) refers to individuals who report intestinal and extraintestinal symptoms related to the ingestion of gluten-based or wheat-based foods, in the absence of coeliac disease or wheat allergy. Gluten is found in multiple cereals, including wheat, rye, and barley, although the precise trigger of symptoms in NCGS remains unclear. Although approximately 10% of adults worldwide self-report gluten or wheat sensitivity, meta-analyses suggest that, during controlled challenge studies, 16-30% of these individuals have symptoms specifically triggered by gluten. However, methodological variability-including the presence of fermentable carbohydrates in challenge preparations-limits interpretation. Current evidence suggests that fermentable carbohydrates and nocebo effects contribute considerably to symptom generation in many cases. The substantial size of the gluten-free market raises questions about commercial and media influences on how NCGS is portrayed, and on the direction of related research. Definitive diagnosis of NCGS remains elusive due to the absence of biomarkers, significant overlap with disorders of gut-brain interaction, and methodological challenges in dietary evaluation. Until causative agents are identified and diagnostic tests developed, NCGS remains a diagnosis of exclusion, requiring careful systematic evaluation. Management approaches should balance dietary modification with recognition of psychological factors while ensuring nutritional adequacy. This Review critically examines current evidence regarding NCGS as a distinct entity, explores potential mechanisms, and provides practical guidance for assessment and management, while acknowledging major uncertainties in the field.
{"title":"Non-coeliac gluten sensitivity.","authors":"Jessica R Biesiekierski, Daisy Jonkers, Carolina Ciacci, Imran Aziz","doi":"10.1016/S0140-6736(25)01533-8","DOIUrl":"10.1016/S0140-6736(25)01533-8","url":null,"abstract":"<p><p>Non-coeliac gluten sensitivity (NCGS) refers to individuals who report intestinal and extraintestinal symptoms related to the ingestion of gluten-based or wheat-based foods, in the absence of coeliac disease or wheat allergy. Gluten is found in multiple cereals, including wheat, rye, and barley, although the precise trigger of symptoms in NCGS remains unclear. Although approximately 10% of adults worldwide self-report gluten or wheat sensitivity, meta-analyses suggest that, during controlled challenge studies, 16-30% of these individuals have symptoms specifically triggered by gluten. However, methodological variability-including the presence of fermentable carbohydrates in challenge preparations-limits interpretation. Current evidence suggests that fermentable carbohydrates and nocebo effects contribute considerably to symptom generation in many cases. The substantial size of the gluten-free market raises questions about commercial and media influences on how NCGS is portrayed, and on the direction of related research. Definitive diagnosis of NCGS remains elusive due to the absence of biomarkers, significant overlap with disorders of gut-brain interaction, and methodological challenges in dietary evaluation. Until causative agents are identified and diagnostic tests developed, NCGS remains a diagnosis of exclusion, requiring careful systematic evaluation. Management approaches should balance dietary modification with recognition of psychological factors while ensuring nutritional adequacy. This Review critically examines current evidence regarding NCGS as a distinct entity, explores potential mechanisms, and provides practical guidance for assessment and management, while acknowledging major uncertainties in the field.</p>","PeriodicalId":18014,"journal":{"name":"The Lancet","volume":" ","pages":"2494-2508"},"PeriodicalIF":88.5,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370373","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 : 2025-11-22Epub Date: 2025-10-24DOI: 10.1016/S0140-6736(25)01430-8
Ghaith Noaiseh, Kathy L Sivils, Kim Campbell, Jada Idokogi, Kim Hung Lo, Sophia G Liva, Jocelyn H Leu, Harman Dhatt, Keying Ma, Steven Leonardo, He Li, Jonathan J Hubbard, Jacques-Eric Gottenberg
<p><strong>Background: </strong>Sjögren's disease is characterised by mucosal dryness, fatigue, chronic pain, systemic organ involvement, and elevated autoreactive IgG antibodies. There are no approved disease-modifying treatments. Therefore, we aimed to evaluate nipocalimab, a neonatal Fc receptor blocker that reduces circulating IgG, including autoantibodies, in patients with Sjögren's disease.</p><p><strong>Methods: </strong>This phase 2, double-blind, multicentre trial enrolled individuals with moderate-to-severe, active Sjögren's disease (ie, Clinical European League Against Rheumatism Sjögren's Syndrome Disease Activity Index [ClinESSDAI] of at least 6) who were seropositive for anti-Ro IgG autoantibodies. Participants were recruited from 69 centres across France, Germany, Italy, Japan, the Netherlands, Poland, Portugal, Spain, Taiwan, and the USA. These centres included rheumatology centres, hospitals, and clinical research centres with experience conducting pharmaceutical company-sponsored phase 2 and phase 3 studies, which reported an ability to enrol eligible patients. Central randomisation assigned participants to one of three treatment groups using an Interactive Web Response System. Randomised (1:1:1) participants received intravenous nipocalimab 5 mg/kg, intravenous nipocalimab 15 mg/kg, or placebo every 2 weeks for 22 weeks. Schedules for administering the study intervention were the same across treatment groups, and labels on the study interventions were prepared by an unmasked pharmacist and were identical to maintain masking for the participants, investigators, site staff, and sponsor. The primary endpoint was change from baseline in ClinESSDAI score at week 24. The primary endpoint and other efficacy and safety analyses included participants who were randomly assigned and who received at least one dose of study intervention. For the primary endpoint, data from the time of discontinuation and onward were considered missing. The primary analysis approach used a mixed model for repeated measures to estimate the average outcome, taking into account the non-missing data and variability. DAHLIAS was registered with EudraCT (2021-000665-32) and ClinicalTrials.gov (NCT04968912) and has been completed.</p><p><strong>Findings: </strong>163 participants were recruited between Sept 21, 2021, and April 3, 2023, (53 participants to nipocalimab 5 mg/kg, 54 to nipocalimab 15 mg/kg, and 56 to the placebo). The mean age of participants was 48·1 years (SD 12·12); 151 (93%) participants were female and 12 (7%) were male. The nipocalimab 15 mg/kg group had a significant reduction in ClinESSDAI score at week 24 versus the placebo group (least squares mean difference -2·65, 90% CI -4·03 to -1·28; p=0·0018), and the nipocalimab 5 mg/kg group had a non-significant reduction versus placebo (-0·34, -1·71 to 1·03; p=0·68). The safety profile of nipocalimab was comparable, for both doses, with that of placebo, with generally similar rates of adverse events
{"title":"Efficacy and safety of nipocalimab in patients with moderate-to-severe Sjögren's disease (DAHLIAS): a randomised, phase 2, placebo-controlled, double-blind trial.","authors":"Ghaith Noaiseh, Kathy L Sivils, Kim Campbell, Jada Idokogi, Kim Hung Lo, Sophia G Liva, Jocelyn H Leu, Harman Dhatt, Keying Ma, Steven Leonardo, He Li, Jonathan J Hubbard, Jacques-Eric Gottenberg","doi":"10.1016/S0140-6736(25)01430-8","DOIUrl":"10.1016/S0140-6736(25)01430-8","url":null,"abstract":"<p><strong>Background: </strong>Sjögren's disease is characterised by mucosal dryness, fatigue, chronic pain, systemic organ involvement, and elevated autoreactive IgG antibodies. There are no approved disease-modifying treatments. Therefore, we aimed to evaluate nipocalimab, a neonatal Fc receptor blocker that reduces circulating IgG, including autoantibodies, in patients with Sjögren's disease.</p><p><strong>Methods: </strong>This phase 2, double-blind, multicentre trial enrolled individuals with moderate-to-severe, active Sjögren's disease (ie, Clinical European League Against Rheumatism Sjögren's Syndrome Disease Activity Index [ClinESSDAI] of at least 6) who were seropositive for anti-Ro IgG autoantibodies. Participants were recruited from 69 centres across France, Germany, Italy, Japan, the Netherlands, Poland, Portugal, Spain, Taiwan, and the USA. These centres included rheumatology centres, hospitals, and clinical research centres with experience conducting pharmaceutical company-sponsored phase 2 and phase 3 studies, which reported an ability to enrol eligible patients. Central randomisation assigned participants to one of three treatment groups using an Interactive Web Response System. Randomised (1:1:1) participants received intravenous nipocalimab 5 mg/kg, intravenous nipocalimab 15 mg/kg, or placebo every 2 weeks for 22 weeks. Schedules for administering the study intervention were the same across treatment groups, and labels on the study interventions were prepared by an unmasked pharmacist and were identical to maintain masking for the participants, investigators, site staff, and sponsor. The primary endpoint was change from baseline in ClinESSDAI score at week 24. The primary endpoint and other efficacy and safety analyses included participants who were randomly assigned and who received at least one dose of study intervention. For the primary endpoint, data from the time of discontinuation and onward were considered missing. The primary analysis approach used a mixed model for repeated measures to estimate the average outcome, taking into account the non-missing data and variability. DAHLIAS was registered with EudraCT (2021-000665-32) and ClinicalTrials.gov (NCT04968912) and has been completed.</p><p><strong>Findings: </strong>163 participants were recruited between Sept 21, 2021, and April 3, 2023, (53 participants to nipocalimab 5 mg/kg, 54 to nipocalimab 15 mg/kg, and 56 to the placebo). The mean age of participants was 48·1 years (SD 12·12); 151 (93%) participants were female and 12 (7%) were male. The nipocalimab 15 mg/kg group had a significant reduction in ClinESSDAI score at week 24 versus the placebo group (least squares mean difference -2·65, 90% CI -4·03 to -1·28; p=0·0018), and the nipocalimab 5 mg/kg group had a non-significant reduction versus placebo (-0·34, -1·71 to 1·03; p=0·68). The safety profile of nipocalimab was comparable, for both doses, with that of placebo, with generally similar rates of adverse events","PeriodicalId":18014,"journal":{"name":"The Lancet","volume":"406 10518","pages":"2435-2448"},"PeriodicalIF":88.5,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596723","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 : 2025-11-22Epub Date: 2025-10-24DOI: 10.1016/S0140-6736(25)01810-0
Benjamin A Fisher
{"title":"Nipocalimab for Sjögren's disease-the importance of autoantibodies.","authors":"Benjamin A Fisher","doi":"10.1016/S0140-6736(25)01810-0","DOIUrl":"https://doi.org/10.1016/S0140-6736(25)01810-0","url":null,"abstract":"","PeriodicalId":18014,"journal":{"name":"The Lancet","volume":"406 10518","pages":"2397-2398"},"PeriodicalIF":88.5,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596726","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 : 2025-11-15Epub Date: 2025-10-20DOI: 10.1016/S0140-6736(25)02025-2
J Randolph Hecht, Young Suk Park, Josep Tabernero, Myung-Ah Lee, Soohyeon Lee, Anna C Virgili, Marc Van den Eynde, Elisa Fontana, Marwan Fakih, Gholamreza Asghari, Jane So, Alexander Stein, Olivier Dubreuil, Lubomir Bodnar, Cixin Steven He, Guan Wang, Robina Smith, Cathy Eng, Anwaar Saeed
<p><strong>Background: </strong>Zanzalintinib is a multitargeted tyrosine-kinase inhibitor that, when combined with atezolizumab, showed promising antitumour activity and manageable toxicity in a phase 1 study. We aimed to compare the efficacy and safety of zanzalintinib-atezolizumab versus regorafenib in patients with previously treated metastatic colorectal cancer.</p><p><strong>Methods: </strong>STELLAR-303 is a global, randomised, open-label, phase 3 trial done at 121 centres (including hospitals, academic medical centres, and specialised cancer research facilities) in 16 countries. Patients aged 18 years and older with confirmed metastatic adenocarcinoma of the colon or rectum, who had previously received standard-of-care therapy, and did not have microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumours were randomly assigned (1:1) in blocks of four to oral zanzalintinib (100 mg daily) plus intravenous atezolizumab (1200 mg every 3 weeks) or oral regorafenib (160 mg daily on days 1-21 of each 28-day cycle) using an interactive response technology system, stratified by geographical region, RAS status, and presence of liver metastases. Dual primary endpoints were overall survival in the intention-to-treat (ITT) population and in the subset of patients without liver metastases. Safety was assessed in all patients who received at least one dose of study drug. This report is based on a planned overall survival analysis (data cutoff April 30, 2025); the trial is active but not recruiting, and continues to the final overall survival analysis in the subset of patients without liver metastases. This trial is registered with ClinicalTrials.gov (NCT05425940).</p><p><strong>Findings: </strong>1325 patients were screened for eligibility; between Sept 7, 2022, and July 15, 2024, 901 patients were randomly assigned to zanzalintinib-atezolizumab (n=451) or regorafenib (n=450). 528 (59%) patients were male and 373 (41%) were female; 485 (54%) were White, 338 (38%) were Asian, 18 (2%) were Black, 24 (3%) were other races, and 36 (4%) had race not reported. At a median follow-up of 18·0 months (IQR 14·6-21·5), zanzalintinib-atezolizumab showed a significant overall survival benefit versus regorafenib in the ITT population (stratified hazard ratio [HR] 0·80 [95% CI 0·69-0·93]; p=0·0045) with a median overall survival of 10·9 months (95% CI 9·9-12·1) versus 9·4 months (8·5-10·2). At the interim analysis of overall survival in the subset of patients without liver metastases, the stratified HR for zanzalintinib-atezolizumab versus regorafenib was 0·79 (95% CI 0·61-1·03); p=0·087 (median overall survival 15·9 months [95% CI 13·5-17·6] vs 12·7 months [10·9-15·5]). Grade 3 or worse treatment-related adverse events occurred in 268 (60%) of 446 patients receiving zanzalintinib-atezolizumab and 161 (37%) of 434 patients receiving regorafenib. There were five (1%) treatment-related deaths in the zanzalintinib-atezolizumab group and one (<1%) in
{"title":"Zanzalintinib plus atezolizumab versus regorafenib in refractory colorectal cancer (STELLAR-303): a randomised, open-label, phase 3 trial.","authors":"J Randolph Hecht, Young Suk Park, Josep Tabernero, Myung-Ah Lee, Soohyeon Lee, Anna C Virgili, Marc Van den Eynde, Elisa Fontana, Marwan Fakih, Gholamreza Asghari, Jane So, Alexander Stein, Olivier Dubreuil, Lubomir Bodnar, Cixin Steven He, Guan Wang, Robina Smith, Cathy Eng, Anwaar Saeed","doi":"10.1016/S0140-6736(25)02025-2","DOIUrl":"10.1016/S0140-6736(25)02025-2","url":null,"abstract":"<p><strong>Background: </strong>Zanzalintinib is a multitargeted tyrosine-kinase inhibitor that, when combined with atezolizumab, showed promising antitumour activity and manageable toxicity in a phase 1 study. We aimed to compare the efficacy and safety of zanzalintinib-atezolizumab versus regorafenib in patients with previously treated metastatic colorectal cancer.</p><p><strong>Methods: </strong>STELLAR-303 is a global, randomised, open-label, phase 3 trial done at 121 centres (including hospitals, academic medical centres, and specialised cancer research facilities) in 16 countries. Patients aged 18 years and older with confirmed metastatic adenocarcinoma of the colon or rectum, who had previously received standard-of-care therapy, and did not have microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumours were randomly assigned (1:1) in blocks of four to oral zanzalintinib (100 mg daily) plus intravenous atezolizumab (1200 mg every 3 weeks) or oral regorafenib (160 mg daily on days 1-21 of each 28-day cycle) using an interactive response technology system, stratified by geographical region, RAS status, and presence of liver metastases. Dual primary endpoints were overall survival in the intention-to-treat (ITT) population and in the subset of patients without liver metastases. Safety was assessed in all patients who received at least one dose of study drug. This report is based on a planned overall survival analysis (data cutoff April 30, 2025); the trial is active but not recruiting, and continues to the final overall survival analysis in the subset of patients without liver metastases. This trial is registered with ClinicalTrials.gov (NCT05425940).</p><p><strong>Findings: </strong>1325 patients were screened for eligibility; between Sept 7, 2022, and July 15, 2024, 901 patients were randomly assigned to zanzalintinib-atezolizumab (n=451) or regorafenib (n=450). 528 (59%) patients were male and 373 (41%) were female; 485 (54%) were White, 338 (38%) were Asian, 18 (2%) were Black, 24 (3%) were other races, and 36 (4%) had race not reported. At a median follow-up of 18·0 months (IQR 14·6-21·5), zanzalintinib-atezolizumab showed a significant overall survival benefit versus regorafenib in the ITT population (stratified hazard ratio [HR] 0·80 [95% CI 0·69-0·93]; p=0·0045) with a median overall survival of 10·9 months (95% CI 9·9-12·1) versus 9·4 months (8·5-10·2). At the interim analysis of overall survival in the subset of patients without liver metastases, the stratified HR for zanzalintinib-atezolizumab versus regorafenib was 0·79 (95% CI 0·61-1·03); p=0·087 (median overall survival 15·9 months [95% CI 13·5-17·6] vs 12·7 months [10·9-15·5]). Grade 3 or worse treatment-related adverse events occurred in 268 (60%) of 446 patients receiving zanzalintinib-atezolizumab and 161 (37%) of 434 patients receiving regorafenib. There were five (1%) treatment-related deaths in the zanzalintinib-atezolizumab group and one (<1%) in","PeriodicalId":18014,"journal":{"name":"The Lancet","volume":" ","pages":"2360-2370"},"PeriodicalIF":88.5,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145355136","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}
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