Nature Reviews Clinical Oncology最新文献

{"title":"Adding blinatumomab to chemotherapy reduces recurrence risk in standard-risk paediatric B-ALL","authors":"Peter Sidaway","doi":"10.1038/s41571-024-00980-1","DOIUrl":"https://doi.org/10.1038/s41571-024-00980-1","url":null,"abstract":"<p>Despite considerable progress, B-cell acute lymphoblastic leukaemia (B-ALL) remains a major cause of cancer-related death in children. Now, data from the phase III AALL1731 trial demonstrate that adding the CD19 × CD3 bispecific T cell engager blinatumomab to chemotherapy significantly improves the outcomes of patients with standard-risk B-ALL with an average or high risk of disease relapse.</p><p>In this trial, 1,440 children (1–10 years of age) with standard-risk B-ALL with an average (<i>n</i> = 835) or high (<i>n</i> = 605) risk of relapse, based on cytogenetic features and minimal residual disease (MRD) status on completion of induction therapy, were randomly assigned (1:1) to receive two cycles of post-induction (for average-risk patients) or post-consolidation (for high-risk patients) chemotherapy with versus without blinatumomab. Disease-free survival (DFS) was the primary endpoint.</p>","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"11 1","pages":""},"PeriodicalIF":78.8,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841021","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":"Ipilimumab plus nivolumab efficacious in patients with dMMR/MSI-H disease","authors":"Peter Sidaway","doi":"10.1038/s41571-024-00978-9","DOIUrl":"https://doi.org/10.1038/s41571-024-00978-9","url":null,"abstract":"<p>The combination of the anti-PD-1 antibody nivolumab plus the anti-CTLA4 antibody ipilimumab showed promising efficacy outcomes as first-line therapy in 45 patients with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer (CRC) as part of the single-arm, phase II CheckMate 142 trial. Now, data from the phase III CheckMate 8HW trial confirm the efficacy of this combination in this setting.</p><p>A total of 303 patients who had not received systemic therapy for unresectable or metastatic dMMR/MSI-H CRC were randomly assigned (2:1) to receive either ipilimumab plus nivolumab or investigator’s choice of chemotherapy, with or without targeted therapy. Patients were also randomly assigned to a nivolumab monotherapy arm, although data from this arm were not reported at this cutoff. Progression-free survival (PFS) in those with centrally confirmed dMMR/MSI-H status (255 patients) was the primary end point.</p>","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"90 1","pages":""},"PeriodicalIF":78.8,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809629","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":"T cell dynamics with neoadjuvant immunotherapy in head and neck cancer","authors":"Maryann Zhao, Jonathan D. Schoenfeld, Ann Marie Egloff, Glenn J. Hanna, Robert I. Haddad, Douglas R. Adkins, Ravindra Uppaluri","doi":"10.1038/s41571-024-00969-w","DOIUrl":"https://doi.org/10.1038/s41571-024-00969-w","url":null,"abstract":"<p>Immune-checkpoint inhibitors (ICIs) are being tested as neoadjuvant therapies in various solid tumours, including in patients with head and neck squamous cell carcinoma (HNSCC), with promising results. Key findings thus far include that this approach is well-tolerated with favourable clinical outcomes including promising pathological response rates in initial studies. Pathological responses are likely to be increased by combining other agents with anti-PD-(L)1 antibodies. Comparisons of baseline biopsy samples with post-treatment surgical specimens have enabled correlative studies utilizing multiomic and immunogenomic methods. Data from these studies suggest that pretreatment intratumoural tissue-resident memory CD8⁺ T cells are key drivers of tumour regression and give rise to both local and systemic antitumour immune responses. Analyses of systemic responses have defined a PD-1⁺KLRG1⁻ circulating CD8⁺ T cell subpopulation that is highly predictive of response, and revealed the interrelationships between intratumoural clones and circulating CD8⁺ T cells. Lastly, interrogation of T cell populations within lymph nodes is beginning to delineate the immune crosstalk between the primary tumour and tumour-draining lymph nodes and how this relationship might be disrupted with tumour infiltration of the latter. In this Review, we examine data from trials testing neoadjuvant ICIs in patients with HNSCC, focusing on human papillomavirus-unrelated disease, and highlight correlative immunogenomic findings from these trials.</p>","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"48 10 1","pages":""},"PeriodicalIF":78.8,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796987","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":"Leptomeningeal metastatic disease: new frontiers and future directions","authors":"Ahmad Ozair, Hannah Wilding, Debarati Bhanja, Nicholas Mikolajewicz, Michael Glantz, Stuart A. Grossman, Arjun Sahgal, Emilie Le Rhun, Michael Weller, Tobias Weiss, Tracy T. Batchelor, Patrick Y. Wen, Daphne A. Haas-Kogan, Mustafa Khasraw, Roberta Rudà, Riccardo Soffietti, Philipp Vollmuth, Vivek Subbiah, Chetan Bettegowda, Lily C. Pham, Graeme F. Woodworth, Manmeet S. Ahluwalia, Alireza Mansouri","doi":"10.1038/s41571-024-00970-3","DOIUrl":"https://doi.org/10.1038/s41571-024-00970-3","url":null,"abstract":"<p>Leptomeningeal metastatic disease (LMD), encompassing entities of ‘meningeal carcinomatosis’, neoplastic meningitis’ and ‘leukaemic/lymphomatous meningitis’, arises secondary to the metastatic dissemination of cancer cells from extracranial and certain intracranial malignancies into the leptomeninges and cerebrospinal fluid. The clinical burden of LMD has been increasing secondary to more sensitive diagnostics, aggressive local therapies for discrete brain metastases, and improved management of extracranial disease with targeted and immunotherapeutic agents, resulting in improved survival. However, owing to drug delivery challenges and the unique microenvironment of LMD, novel therapies against systemic disease have not yet translated into improved outcomes for these patients. Underdiagnosis and misdiagnosis are common, response assessment remains challenging, and the prognosis associated with this disease of whole neuroaxis remains extremely poor. The dearth of effective therapies is further challenged by the difficulties in studying this dynamic disease state. In this Review, a multidisciplinary group of experts describe the emerging evidence and areas of active investigation in LMD and provide directed recommendations for future research. Drawing upon paradigm-changing advances in mechanistic science, computational approaches, and trial design, the authors discuss domain-specific and cross-disciplinary strategies for optimizing the clinical and translational research landscape for LMD. Advances in diagnostics, multi-agent intrathecal therapies, cell-based therapies, immunotherapies, proton craniospinal irradiation and ongoing clinical trials offer hope for improving outcomes for patients with LMD.</p>","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"83 1","pages":""},"PeriodicalIF":78.8,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793290","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":"Synthetic lethal strategies for the development of cancer therapeutics","authors":"Natalie Y. L. Ngoi,&nbsp;David Gallo,&nbsp;Carlos Torrado,&nbsp;Mirella Nardo,&nbsp;Daniel Durocher,&nbsp;Timothy A. Yap","doi":"10.1038/s41571-024-00966-z","DOIUrl":"10.1038/s41571-024-00966-z","url":null,"abstract":"Synthetic lethality is a genetic phenomenon whereby the simultaneous presence of two different genetic alterations impairs cellular viability. Importantly, targeting synthetic lethal interactions offers potential therapeutic strategies for cancers with alterations in pathways that might otherwise be considered undruggable. High-throughput screening methods based on modern CRISPR–Cas9 technologies have emerged and become crucial for identifying novel synthetic lethal interactions with the potential for translation into biologically rational cancer therapeutic strategies as well as associated predictive biomarkers of response capable of guiding patient selection. Spurred by the clinical success of PARP inhibitors in patients with BRCA-mutant cancers, novel agents targeting multiple synthetic lethal interactions within DNA damage response pathways are in clinical development, and rational strategies targeting synthetic lethal interactions spanning alterations in epigenetic, metabolic and proliferative pathways have also emerged and are in late preclinical and/or early clinical testing. In this Review, we provide a comprehensive overview of established and emerging technologies for synthetic lethal drug discovery and development and discuss promising therapeutic strategies targeting such interactions. The experience with PARP inhibitors provides evidence of the clinical utility of synthetic lethality, whereby the simultaneous presence of two specific alterations is required for antitumour activity. In this Review, the authors describe attempts to identify novel synthetic lethal interactions, including the role of emerging technologies in identifying new synthetic lethal relationships as well as novel agents that are currently being tested in clinical trials that might extend the clinical relevance of synthetic lethality beyond PARP inhibitors.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 1","pages":"46-64"},"PeriodicalIF":81.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41571-024-00966-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760331","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}

{"title":"Perioperative nivolumab results in favourable long-term outcomes in patients with locally advanced resectable non-small-cell lung cancer","authors":"Tina Cascone, William N. William","doi":"10.1038/s41571-024-00976-x","DOIUrl":"https://doi.org/10.1038/s41571-024-00976-x","url":null,"abstract":"As one of the first studies testing perioperative anti-PD-(L)1 antibodies in resectable non-small-cell lung cancer (NSCLC), NADIM now confirms, in its final report, impressive 5-year clinical outcomes and that a pCR following neoadjuvant therapy translates into improved long-term survival. These data support the development of novel, personalized treatments for locally advanced resectable NSCLC.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"18 1","pages":""},"PeriodicalIF":78.8,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760484","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":"Getting the right combination to break the epigenetic code","authors":"Seda S. Tolu, Aaron D. Viny, Jennifer E. Amengual, Barbara Pro, Susan E. Bates","doi":"10.1038/s41571-024-00972-1","DOIUrl":"https://doi.org/10.1038/s41571-024-00972-1","url":null,"abstract":"<p>Rapid advances in the field of epigenetics have facilitated the development of novel therapeutics targeting epigenetic mechanisms that are hijacked by cancer cells to support tumour growth and progression. Several epigenetic agents have been approved by the FDA for the treatment of cancer; however, the efficacy of these drugs is dependent on the underlying biology and drivers of the disease, with inherent differences between solid tumours and haematological malignancies. The efficacy of epigenetic drugs as single agents remains limited across most cancer types, which has spurred the clinical development of combination therapies, with the hope of attaining synergistic activity and/or overcoming treatment resistance. In this Review we discuss clinical advances that have been achieved with the use of epigenetic agents in combination with chemotherapies, immunotherapies or other targeted agents, including epigenetic–epigenetic combinations, as well as limitations and challenges associated with these combinatorial strategies. So far, the success of combination therapies targeting epigenetic mechanisms has generally been confined to haematological malignancies, with limited efficacy observed in patients with solid tumours. Nevertheless, this Review captures the field of epigenetic combination therapies across the spectra of haematology and oncology, highlighting opportunities for precision therapy to effectively harness the potential of epigenetic agents and produce meaningful improvements in clinical outcomes.</p>","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"37 1","pages":""},"PeriodicalIF":78.8,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760314","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":"The changing treatment landscape of EGFR-mutant non-small-cell lung cancer","authors":"Fei Zhou, Haoyue Guo, Yang Xia, Xiuning Le, Daniel S. W. Tan, Suresh S. Ramalingam, Caicun Zhou","doi":"10.1038/s41571-024-00971-2","DOIUrl":"https://doi.org/10.1038/s41571-024-00971-2","url":null,"abstract":"<p>The discovery of the association between <i>EGFR</i> mutations and the efficacy of EGFR tyrosine-kinase inhibitors (TKIs) has revolutionized the treatment paradigm for patients with non-small-cell lung cancer (NSCLC). Currently, third-generation EGFR TKIs, which are often characterized by potent central nervous system penetrance, are the standard-of-care first-line treatment for advanced-stage <i>EGFR</i>-mutant NSCLC. Rational combinations of third-generation EGFR TKIs with anti-angiogenic drugs, chemotherapy, the EGFR–MET bispecific antibody amivantamab or local tumour ablation are being investigated as strategies to delay drug resistance and increase clinical benefit. Furthermore, EGFR TKIs are being evaluated in patients with early stage or locally advanced <i>EGFR</i>-mutant NSCLC, with the ambitious aim of achieving cancer cure. Despite the inevitable challenge of acquired resistance, emerging treatments such as new TKIs, antibody–drug conjugates, new immunotherapeutic approaches and targeted protein degraders have shown considerable promise in patients with progression of <i>EGFR</i>-mutant NSCLC on or after treatment with EGFR TKIs. In this Review, we describe the current first-line treatment options for <i>EGFR</i>-mutant NSCLC, provide an overview of the mechanisms of acquired resistance to third-generation EGFR TKIs and explore novel promising treatment strategies. We also highlight potential avenues for future research that are aimed at improving the survival outcomes of patients with this disease.</p>","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"58 1","pages":""},"PeriodicalIF":78.8,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142753222","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":"Benefit with glofitamab plus chemotherapy in transplant-ineligible R/R DLBCL","authors":"Diana Romero","doi":"10.1038/s41571-024-00975-y","DOIUrl":"10.1038/s41571-024-00975-y","url":null,"abstract":"","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 1","pages":"2-2"},"PeriodicalIF":81.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735665","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":"Minimal residual disease as a target for liquid biopsy in patients with solid tumours","authors":"Klaus Pantel,&nbsp;Catherine Alix-Panabières","doi":"10.1038/s41571-024-00967-y","DOIUrl":"10.1038/s41571-024-00967-y","url":null,"abstract":"Metastasis is the leading cause of cancer-related death in patients with solid tumours. Current imaging technologies are not sufficiently sensitive to detect minimal residual disease (MRD; also known as measurable or molecular residual disease) after initial surgery or chemotherapy, pointing to the need for more sensitive tests to detect remaining traces of cancer in the body. Liquid biopsy, or the analysis of tumour-derived or tumour-induced cells or cellular products in the blood or other body fluids, has opened a new diagnostic avenue to detect and monitor MRD. Liquid biopsy is already used in clinical decision making for patients with haematological malignancies. Here, we review current knowledge on the use of circulating tumour DNA (ctDNA) to detect and monitor MRD in patients with solid tumours. We also discuss how ctDNA-guided MRD detection and characterization could herald a new era of novel ‘post-adjuvant therapies’ with the potential to eliminate MRD and cure patients before terminal metastatic disease is evident on imaging. Liquid biopsy, or the analysis of tumour-derived or tumour-induced cells or cellular products in the blood or other body fluids, is a promising approach to assess minimal residual disease (MRD; also known as measurable or molecular residual disease). The authors of this Review discuss the available evidence on the use of circulating tumour DNA to detect and monitor MRD in patients with solid tumours to enable treatment decisions before terminal metastatic disease is evident on imaging.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 1","pages":"65-77"},"PeriodicalIF":81.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735723","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}