New England Journal of Medicine最新文献

{"title":"Zongertinib in Previously Treated HER2-Mutant Non-Small-Cell Lung Cancer.","authors":"John V Heymach,Gerrina Ruiter,Myung-Ju Ahn,Nicolas Girard,Egbert F Smit,David Planchard,Yi-Long Wu,Byoung Chul Cho,Noboru Yamamoto,Joshua K Sabari,Yanqiu Zhao,Hai-Yan Tu,Kiyotaka Yoh,Ernest Nadal,Behbood Sadrolhefazi,Maren Rohrbacher,Ute von Wangenheim,Sabina Eigenbrod-Giese,Jon Zugazagoitia,","doi":"10.1056/nejmoa2503704","DOIUrl":"https://doi.org/10.1056/nejmoa2503704","url":null,"abstract":"BACKGROUNDInnovative oral targeted therapies are warranted for patients with human epidermal growth factor receptor 2 (HER2)-mutant non-small-cell lung cancer (NSCLC). Zongertinib is an oral, irreversible, HER2-selective tyrosine kinase inhibitor that has been shown to have efficacy in persons with advanced or metastatic solid tumors with HER2 alterations in a phase 1 study.METHODSWe evaluated zongertinib in a multicohort, phase 1a-1b trial involving patients with advanced or metastatic HER2-mutant NSCLC. Here we report the primary analysis of zongertinib in previously treated patients: those with tumors harboring a mutation in the tyrosine kinase domain (cohort 1), those with tumors harboring a mutation in the tyrosine kinase domain previously treated with a HER2-directed antibody-drug conjugate (cohort 5), and those with tumors harboring a non-tyrosine kinase domain mutation (cohort 3). In cohort 1, patients were initially randomly assigned to receive zongertinib at a dose of 120 mg or 240 mg once daily. Patients in cohorts 5 and 3 initially received 240 mg daily. After an interim analysis of data from cohort 1, subsequently recruited patients across all cohorts received zongertinib at a dose of 120 mg. The primary end point was an objective response assessed by blinded independent central review (cohorts 1 and 5) or by investigator review (cohort 3). Secondary end points included the duration of response and progression-free survival.RESULTSIn cohort 1, a total of 75 patients received zongertinib at a dose of 120 mg. At the data cutoff (November 29, 2024), 71% of these patients (95% confidence interval [CI], 60 to 80; P<0.001 against a ≤30% benchmark) had a confirmed objective response; the median duration of response was 14.1 months (95% CI, 6.9 to not evaluable), and the median progression-free survival was 12.4 months (95% CI, 8.2 to not evaluable). Grade 3 or higher drug-related adverse events occurred in 13 patients (17%). In cohort 5 (31 patients), 48% of the patients (95% CI, 32 to 65) had a confirmed objective response. Grade 3 or higher drug-related adverse events occurred in 1 patient (3%). In cohort 3 (20 patients), 30% of the patients (95% CI, 15 to 52) had a confirmed objective response. Grade 3 or higher drug-related adverse events occurred in 5 patients (25%). Across all three cohorts, no cases of drug-related interstitial lung disease occurred.CONCLUSIONSZongertinib showed clinical benefit with mainly low-grade adverse events in patients with previously treated HER2-mutant NSCLC. (Funded by Boehringer Ingelheim; Beamion LUNG-1 ClinicalTrials.gov number, NCT04886804.).","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"222 1","pages":""},"PeriodicalIF":158.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889244","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":"Nonoperative Management of Mismatch Repair-Deficient Tumors.","authors":"Andrea Cercek,Michael B Foote,Benoit Rousseau,J Joshua Smith,Jinru Shia,Jenna Sinopoli,Jill Weiss,Melissa Lumish,Lindsay Temple,Miteshkumar Patel,Callahan Wilde,Leonard B Saltz,Guillem Argiles,Zsofia Stadler,Oliver Artz,Steven Maron,Geoffrey Ku,Ping Gu,Yelena Y Janjigian,Daniela Molena,Gopa Iyer,Jonathan Coleman,Wassim Abida,Seth Cohen,Kevin Soares,Mark Schattner,Vivian E Strong,Rona Yaeger,Philip Paty,Marina Shcherba,Ryan Sugarman,Paul B Romesser,Alice Zervoudakis,Avni Desai,Neil H Segal,Imane El Dika,Maria Widmar,Iris Wei,Emmanouil Pappou,Gerard Fumo,Santiago Aparo,Mithat Gonen,Marc Gollub,Vetri S Jayaprakasham,Tae-Hyung Kim,Julio Garcia Aguilar,Martin Weiser,Luis A Diaz","doi":"10.1056/nejmoa2404512","DOIUrl":"https://doi.org/10.1056/nejmoa2404512","url":null,"abstract":"BACKGROUNDAmong patients with mismatch repair-deficient (dMMR), locally advanced rectal cancer, neoadjuvant checkpoint blockade eliminated the need for surgery in a high proportion of patients. Whether this approach can be extended to all early-stage dMMR solid tumors, regardless of tumor site, is unknown.METHODSWe conducted a phase 2 study in which patients with stage I, II, or III dMMR solid tumors that were amenable to curative-intent surgery were treated with neoadjuvant dostarlimab, a programmed cell death 1 (PD-1) blocking agent, for 6 months. The response to treatment was assessed in two cohorts: patients in cohort 1 had dMMR, locally advanced rectal cancer, and patients in cohort 2 had dMMR nonrectal solid tumors. Patients with a clinical complete response could elect to proceed with nonoperative management; those with residual disease were to undergo resection. In this analysis, the primary end point, assessed in cohort 1, was a sustained clinical complete response at 12 months. Recurrence-free survival and safety were evaluated.RESULTSA total of 117 patients were included in the analysis. In cohort 1, all 49 patients who completed treatment had a clinical complete response and elected to proceed with nonoperative management. A total of 37 patients had a sustained clinical complete response at 12 months, a finding that met the criterion for efficacy. In cohort 2, a total of 35 of 54 patients who completed treatment had a clinical complete response, and 33 elected to proceed with nonoperative management. Among the 103 patients who completed treatment across both cohorts, 84 had a clinical complete response, and 82 did not undergo surgery. Among the 117 total patients, recurrence-free survival at 2 years was 92% (95% confidence interval, 86 to 99); the median follow-up for recurrence was 20.0 months (range, 0 to 60.8). The majority of patients (95%) had reversible, grade 1 or 2 adverse events (60%) or had no adverse events (35%). The option for curative resection was not compromised during or after treatment in any of the patients.CONCLUSIONSAmong patients with early-stage dMMR solid tumors that were amenable to curative-intent surgery, neoadjuvant PD-1 blockade led to organ preservation in a high proportion of patients. (Funded by Swim Across America and others; ClinicalTrials.gov number, NCT04165772.).","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"8 1","pages":""},"PeriodicalIF":158.5,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889232","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":"Clonal Hematopoiesis as a Driver of Solid Tumors.","authors":"Lachelle D Weeks,Benjamin L Ebert","doi":"10.1056/nejme2504775","DOIUrl":"https://doi.org/10.1056/nejme2504775","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"7 1","pages":"1654-1656"},"PeriodicalIF":158.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143871969","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":"Efficacy of Baloxavir Treatment in Preventing Transmission of Influenza.","authors":"Arnold S Monto,Klaus Kuhlbusch,Corrado Bernasconi,Bin Cao,Herman Avner Cohen,Emily Graham,Aeron C Hurt,Laurie Katugampola,Takashi Kamezawa,Adam S Lauring,Barry McLean,Takahiro Takazono,Andreas Widmer,Steffen Wildum,Benjamin J Cowling","doi":"10.1056/nejmoa2413156","DOIUrl":"https://doi.org/10.1056/nejmoa2413156","url":null,"abstract":"BACKGROUNDBaloxavir marboxil (baloxavir) rapidly reduces influenza virus shedding, which suggests that it may reduce transmission. Studies of treatment with neuraminidase inhibitors have not shown sufficient evidence that they prevent transmission to contacts.METHODSWe conducted a multicountry, phase 3b trial to assess the efficacy of single-dose baloxavir treatment to reduce influenza transmission from index patients to household contacts. Influenza-positive index patients 5 to 64 years of age were randomly assigned in a 1:1 ratio to receive baloxavir or placebo within 48 hours after symptom onset. The primary end point was transmission of influenza virus from an index patient to a household contact by day 5. The first secondary end point was transmission of influenza virus by day 5 that resulted in symptoms.RESULTSOverall, 1457 index patients and 2681 household contacts were enrolled across the 2019-2024 influenza seasons; 726 index patients were assigned to the baloxavir group, and 731 to the placebo group. By day 5, transmission of laboratory-confirmed influenza was significantly lower with baloxavir than with placebo (adjusted incidence, 9.5% vs. 13.4%; adjusted odds ratio, 0.68; 95.38% confidence interval [CI], 0.50 to 0.93; P = 0.01), with an adjusted relative risk reduction of 29% (95.38% CI, 12 to 45). The adjusted incidence of transmission of influenza virus by day 5 that resulted in symptoms was 5.8% with baloxavir and 7.6% with placebo; however, the difference was not significant (adjusted odds ratio, 0.75; 95.38% CI, 0.50 to 1.12; P = 0.16). Emergence of drug-resistant viruses during the follow-up period occurred in 7.2% (95% CI, 4.1 to 11.6) of the index patients in the baloxavir group; no resistant viruses were detected in household contacts. No new safety signals were identified.CONCLUSIONSTreatment with a single oral dose of baloxavir led to a lower incidence of transmission of influenza virus to close contacts than placebo. (Funded by F. Hoffmann-La Roche and others; CENTERSTONE ClinicalTrials.gov number, NCT03969212.).","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"24 1","pages":"1582-1593"},"PeriodicalIF":158.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872070","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":"Tirzepatide for Heart Failure and Obesity.","authors":"Jesse C Krakauer, Nir Y Krakauer","doi":"10.1056/NEJMc2502743","DOIUrl":"https://doi.org/10.1056/NEJMc2502743","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"392 16","pages":"1660"},"PeriodicalIF":96.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144052541","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":"Tirzepatide for Heart Failure and Obesity.","authors":"Jeffrey Wagner","doi":"10.1056/NEJMc2502743","DOIUrl":"https://doi.org/10.1056/NEJMc2502743","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"392 16","pages":"1659-1660"},"PeriodicalIF":96.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143995703","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":"APOL1 Bi- and Monoallelic Variants and Chronic Kidney Disease in West Africans. Reply.","authors":"Rasheed A Gbadegesin, Dwomoa Adu, Akinlolu Ojo","doi":"10.1056/NEJMc2502038","DOIUrl":"https://doi.org/10.1056/NEJMc2502038","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"392 16","pages":"1664"},"PeriodicalIF":96.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144040691","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":"Tirzepatide for Heart Failure and Obesity.","authors":"Joseph E Marine,John Mandrola,Vinay Prasad","doi":"10.1056/nejmc2502743","DOIUrl":"https://doi.org/10.1056/nejmc2502743","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"14 1","pages":"1660"},"PeriodicalIF":158.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143871970","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":"Case 12-2025: A 56-Year-Old Woman with Sore Throat and Rash.","authors":"John Trinidad,Kimon C Zachary,Ting Zhao","doi":"10.1056/nejmcpc2412522","DOIUrl":"https://doi.org/10.1056/nejmcpc2412522","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"5 1","pages":"1637-1645"},"PeriodicalIF":158.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143871991","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":"Tumor-Infiltrating Clonal Hematopoiesis.","authors":"Oriol Pich, Elsa Bernard, Maria Zagorulya, Andrew Rowan, Constandina Pospori, Ramy Slama, Hector Huerga Encabo, Jennifer O'Sullivan, Despoina Papazoglou, Panayiotis Anastasiou, Chrysante S Iliakis, Sally-Ann Clark, Krijn K Dijkstra, Vittorio Barbè, Chris Bailey, Aaron J Stonestrom, Katey S S Enfield, Mary Green, Charlotte K Brierley, Alastair Magness, David R Pearce, Robert E Hynds, Rija Zaidi, Jayant K Rane, Ángel F Álvarez-Prado, Kerstin Thol, Rachel Scott, Supreet Kaur Bola, Elena Hoxha, Steve K Harris, Karl S Peggs, Sergio A Quezada, Allan Hackshaw, Simone Zaccaria, Johanna A Joyce, Ilaria Malanchi, Michael F Berger, Mariam Jamal-Hanjani, Andreas Wack, Julian Downward, William Grey, Cristina Lo Celso, Eva Grönroos, Charles M Rudin, Adam J Mead, Dominique Bonnet, Elli Papaemmanuil, Charles Swanton","doi":"10.1056/NEJMoa2413361","DOIUrl":"https://doi.org/10.1056/NEJMoa2413361","url":null,"abstract":"<p><strong>Background: </strong>Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with increased mortality among patients with cancer. CHIP mutations with high variant-allele frequencies can be detected in tumors, a phenomenon we term tumor-infiltrating clonal hematopoiesis (TI-CH). The frequency of TI-CH and its effect on tumor evolution are unclear.</p><p><strong>Methods: </strong>We characterized CHIP and TI-CH in 421 patients with early-stage non-small-cell lung cancer (NSCLC) from the TRACERx study and in 49,351 patients from the MSK-IMPACT pan-cancer cohort. We studied the association of TI-CH with survival and disease recurrence and evaluated the functional effect of <i>TET2</i>-mutant CHIP on the biologic features of lung tumors.</p><p><strong>Results: </strong>Among patients with NSCLC, 42% of those with CHIP had TI-CH. TI-CH independently predicted an increased risk of death or recurrence, with an adjusted hazard ratio of 1.80 (95% confidence interval [CI], 1.23 to 2.63) as compared with the absence of CHIP and an adjusted hazard ratio of 1.62 (95% CI, 1.02 to 2.56) as compared with CHIP in the absence of TI-CH. Among patients with solid tumors, 26% of those with CHIP had TI-CH. TI-CH conferred a risk of death from any cause that was 1.17 times (95% CI, 1.06 to 1.29) as high as the risk with CHIP in the absence of TI-CH. <i>TET2</i> mutations were the strongest genetic predictor of TI-CH; such mutations enhanced monocyte migration to lung tumor cells, fueled a myeloid-rich tumor microenvironment in mice, and resulted in the promotion of tumor organoid growth.</p><p><strong>Conclusions: </strong>TI-CH increased the risk of disease recurrence or death among patients with NSCLC and the risk of death from any cause among patients with solid tumors. TI-CH remodeled the tumor immune microenvironment and accelerated tumor organoid growth, findings that support a role for an aging-related hematologic clonal proliferation in cancer evolution. (Funded by the Royal Society and others.).</p>","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"392 16","pages":"1594-1608"},"PeriodicalIF":96.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12021423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041248","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}