Pub Date : 2024-04-25DOI: 10.1038/s41571-024-00896-w
Christopher Nevala-Plagemann, Ignacio Garrido-Laguna
The FDA has approved nanoliposomal irinotecan, 5-fluorouracil, leucovorin and oxaliplatin (NALIRIFOX) for patients with metastatic pancreatic adenocarcinoma on the basis of results from the NAPOLI 3 trial, in which this four-drug regimen improved overall survival relative to a doublet regimen. Here we discuss how, in the context of prior results from the PRODIGE 4 trial testing 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (modified FOLFIRINOX), NALIRIFOX does not seem to raise the bar, but rather exposes patients and health-care systems to financial toxicities.
{"title":"NALIRIFOX for metastatic pancreatic adenocarcinoma: hope or hype?","authors":"Christopher Nevala-Plagemann, Ignacio Garrido-Laguna","doi":"10.1038/s41571-024-00896-w","DOIUrl":"10.1038/s41571-024-00896-w","url":null,"abstract":"The FDA has approved nanoliposomal irinotecan, 5-fluorouracil, leucovorin and oxaliplatin (NALIRIFOX) for patients with metastatic pancreatic adenocarcinoma on the basis of results from the NAPOLI 3 trial, in which this four-drug regimen improved overall survival relative to a doublet regimen. Here we discuss how, in the context of prior results from the PRODIGE 4 trial testing 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (modified FOLFIRINOX), NALIRIFOX does not seem to raise the bar, but rather exposes patients and health-care systems to financial toxicities.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"21 8","pages":"567-568"},"PeriodicalIF":81.1,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140642393","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 : 2024-04-22DOI: 10.1038/s41571-024-00895-x
Ghulam Rehman Mohyuddin, Aaron M. Goodman
Certain subsets of patients with multiple myeloma or its precursor conditions are overtreated with current approaches to therapy. Herein, we highlight several key areas where we believe de-escalation of treatment is needed. Dedicated trials to assess these de-escalation approaches and urgent changes to current clinical practices are needed.
{"title":"Overtreatment of multiple myeloma and its precursor states: de-escalation is an urgent need in clinical practice and trials","authors":"Ghulam Rehman Mohyuddin, Aaron M. Goodman","doi":"10.1038/s41571-024-00895-x","DOIUrl":"10.1038/s41571-024-00895-x","url":null,"abstract":"Certain subsets of patients with multiple myeloma or its precursor conditions are overtreated with current approaches to therapy. Herein, we highlight several key areas where we believe de-escalation of treatment is needed. Dedicated trials to assess these de-escalation approaches and urgent changes to current clinical practices are needed.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"21 8","pages":"561-562"},"PeriodicalIF":81.1,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140632300","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 : 2024-04-19DOI: 10.1038/s41571-024-00891-1
Emily Hoffmann, Max Masthoff, Wolfgang G. Kunz, Max Seidensticker, Stefanie Bobe, Mirjam Gerwing, Wolfgang E. Berdel, Christoph Schliemann, Cornelius Faber, Moritz Wildgruber
Our understanding of tumour biology has evolved over the past decades and cancer is now viewed as a complex ecosystem with interactions between various cellular and non-cellular components within the tumour microenvironment (TME) at multiple scales. However, morphological imaging remains the mainstay of tumour staging and assessment of response to therapy, and the characterization of the TME with non-invasive imaging has not yet entered routine clinical practice. By combining multiple MRI sequences, each providing different but complementary information about the TME, multiparametric MRI (mpMRI) enables non-invasive assessment of molecular and cellular features within the TME, including their spatial and temporal heterogeneity. With an increasing number of advanced MRI techniques bridging the gap between preclinical and clinical applications, mpMRI could ultimately guide the selection of treatment approaches, precisely tailored to each individual patient, tumour and therapeutic modality. In this Review, we describe the evolving role of mpMRI in the non-invasive characterization of the TME, outline its applications for cancer detection, staging and assessment of response to therapy, and discuss considerations and challenges for its use in future medical applications, including personalized integrated diagnostics. By combining multiple MRI sequences, each providing different but complementary information about the tumour microenvironment (TME), multiparametric MRI (mpMRI) enables non-invasive assessment of the heterogeneous features of the TME components. The authors of this Review describe the role of mpMRI in the non-invasive characterization of the TME, presenting examples of its utility in cancer detection, staging and assessment of response to therapy, and considering future applications for personalized integrated diagnostics.
{"title":"Multiparametric MRI for characterization of the tumour microenvironment","authors":"Emily Hoffmann, Max Masthoff, Wolfgang G. Kunz, Max Seidensticker, Stefanie Bobe, Mirjam Gerwing, Wolfgang E. Berdel, Christoph Schliemann, Cornelius Faber, Moritz Wildgruber","doi":"10.1038/s41571-024-00891-1","DOIUrl":"10.1038/s41571-024-00891-1","url":null,"abstract":"Our understanding of tumour biology has evolved over the past decades and cancer is now viewed as a complex ecosystem with interactions between various cellular and non-cellular components within the tumour microenvironment (TME) at multiple scales. However, morphological imaging remains the mainstay of tumour staging and assessment of response to therapy, and the characterization of the TME with non-invasive imaging has not yet entered routine clinical practice. By combining multiple MRI sequences, each providing different but complementary information about the TME, multiparametric MRI (mpMRI) enables non-invasive assessment of molecular and cellular features within the TME, including their spatial and temporal heterogeneity. With an increasing number of advanced MRI techniques bridging the gap between preclinical and clinical applications, mpMRI could ultimately guide the selection of treatment approaches, precisely tailored to each individual patient, tumour and therapeutic modality. In this Review, we describe the evolving role of mpMRI in the non-invasive characterization of the TME, outline its applications for cancer detection, staging and assessment of response to therapy, and discuss considerations and challenges for its use in future medical applications, including personalized integrated diagnostics. By combining multiple MRI sequences, each providing different but complementary information about the tumour microenvironment (TME), multiparametric MRI (mpMRI) enables non-invasive assessment of the heterogeneous features of the TME components. The authors of this Review describe the role of mpMRI in the non-invasive characterization of the TME, presenting examples of its utility in cancer detection, staging and assessment of response to therapy, and considering future applications for personalized integrated diagnostics.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"21 6","pages":"428-448"},"PeriodicalIF":78.8,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140621568","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 : 2024-04-18DOI: 10.1038/s41571-024-00893-z
David Killock
{"title":"ALND can be safely omitted for patients with sentinel-node macrometastases","authors":"David Killock","doi":"10.1038/s41571-024-00893-z","DOIUrl":"10.1038/s41571-024-00893-z","url":null,"abstract":"","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"21 6","pages":"402-402"},"PeriodicalIF":78.8,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140607604","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 : 2024-04-15DOI: 10.1038/s41571-024-00890-2
David H. Aggen, Jonathan E. Rosenberg
T cell infiltration in the tumour microenvironment (TME) is a prerequisite for sustained antitumour immune responses. However, identifying predictive biomarkers that quantify T cell infiltration and the presence of proinflammatory TMEs associated with immune-checkpoint inhibitor (ICI) response for clinical implementation has proved challenging. Here, we highlight a study that validates a T cell-to-stroma enrichment score generated from RNA sequencing data as a novel biomarker for ICI response in patients with urothelial carcinoma.
肿瘤微环境（TME）中的 T 细胞浸润是持续抗肿瘤免疫反应的先决条件。然而，为临床应用确定量化 T 细胞浸润的预测性生物标记物以及与免疫检查点抑制剂 (ICI) 反应相关的促炎 TME 的存在已被证明具有挑战性。在此，我们重点介绍一项研究，该研究验证了从 RNA 测序数据中生成的 T 细胞-间质富集评分是尿路上皮癌患者 ICI 反应的新型生物标记物。
{"title":"Lighting the torch: intratumoural T cell-to-stroma enrichment score as a predictor of immunotherapy response in urothelial carcinoma","authors":"David H. Aggen, Jonathan E. Rosenberg","doi":"10.1038/s41571-024-00890-2","DOIUrl":"10.1038/s41571-024-00890-2","url":null,"abstract":"T cell infiltration in the tumour microenvironment (TME) is a prerequisite for sustained antitumour immune responses. However, identifying predictive biomarkers that quantify T cell infiltration and the presence of proinflammatory TMEs associated with immune-checkpoint inhibitor (ICI) response for clinical implementation has proved challenging. Here, we highlight a study that validates a T cell-to-stroma enrichment score generated from RNA sequencing data as a novel biomarker for ICI response in patients with urothelial carcinoma.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"21 7","pages":"487-488"},"PeriodicalIF":81.1,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140553400","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 : 2024-04-10DOI: 10.1038/s41571-024-00886-y
Hung-Yang Kuo, Kabir A. Khan, Robert S. Kerbel
Antiangiogenic agents, generally antibodies or tyrosine-kinase inhibitors that target the VEGF–VEGFR pathway, are currently among the few combination partners clinically proven to improve the efficacy of immune-checkpoint inhibitors (ICIs). This benefit has been demonstrated in pivotal phase III trials across different cancer types, some with practice-changing results; however, numerous phase III trials have also had negative results. The rationale for using antiangiogenic drugs as partners for ICIs relies primarily on blocking the multiple immunosuppressive effects of VEGF and inducing several different vascular-modulating effects that can stimulate immunity, such as vascular normalization leading to increased intratumoural blood perfusion and flow, and inhibition of pro-apoptotic effects of endothelial cells on T cells, among others. Conversely, VEGF blockade can also cause changes that suppress antitumour immunity, such as increased tumour hypoxia, and reduced intratumoural ingress of co-administered ICIs. As a result, the net clinical benefits from antiangiogenic–ICI combinations will be determined by the balance between the opposing effects of VEGF signalling and its inhibition on the antitumour immune response. In this Perspective, we summarize the results from the currently completed phase III trials evaluating antiangiogenic agent–ICI combinations. We also discuss strategies to improve the efficacy of these combinations, focusing on aspects that include the deleterious functions of VEGF–VEGFR inhibition on antitumour immunity, vessel co-option as a driver of non-angiogenic tumour growth, clinical trial design, or the rationale for drug selection, dosing and scheduling. The benefit of combining antiangiogenic agents with immune-checkpoint inhibitors has been demonstrated in pivotal phase III trials across different cancer types, some with practice-changing results; however, other phase III trials have had negative results. The authors of this Perspective discuss the variable outcomes of these trials, considering factors that account for these differences and suggesting future initiatives for improving the outcomes in patients receiving these combinations.
抗血管生成药物（通常是针对血管内皮生长因子-血管内皮生长因子受体通路的抗体或酪氨酸激酶抑制剂）是目前少数几种经临床证实可提高免疫检查点抑制剂（ICIs）疗效的联合用药。这种益处已在不同癌症类型的关键性 III 期试验中得到证实，其中一些试验的结果改变了临床实践；然而，许多 III 期试验也出现了负面结果。使用抗血管生成药物作为 ICIs 伴侣的主要理由是阻断血管内皮生长因子的多种免疫抑制作用，并诱导多种不同的血管调节作用，从而刺激免疫，如血管正常化导致瘤内血液灌注和流动增加，以及抑制内皮细胞对 T 细胞的促凋亡作用等。相反，血管内皮生长因子阻断也会导致抑制抗肿瘤免疫的变化，如增加肿瘤缺氧、减少合用 ICIs 的瘤内摄取等。因此，抗血管生成-ICI 联合疗法的净临床获益将取决于血管内皮生长因子信号传递及其抑制对抗肿瘤免疫反应的对立效应之间的平衡。在本透视中，我们总结了目前已完成的抗血管生成剂-ICI 联合疗法 III 期临床试验的评估结果。我们还讨论了提高这些组合疗效的策略，重点关注的方面包括 VEGF-VEGFR 抑制对抗肿瘤免疫的有害作用、作为非血管生成性肿瘤生长驱动因素的血管增生、临床试验设计或药物选择、剂量和时间安排的合理性。
{"title":"Antiangiogenic–immune-checkpoint inhibitor combinations: lessons from phase III clinical trials","authors":"Hung-Yang Kuo, Kabir A. Khan, Robert S. Kerbel","doi":"10.1038/s41571-024-00886-y","DOIUrl":"10.1038/s41571-024-00886-y","url":null,"abstract":"Antiangiogenic agents, generally antibodies or tyrosine-kinase inhibitors that target the VEGF–VEGFR pathway, are currently among the few combination partners clinically proven to improve the efficacy of immune-checkpoint inhibitors (ICIs). This benefit has been demonstrated in pivotal phase III trials across different cancer types, some with practice-changing results; however, numerous phase III trials have also had negative results. The rationale for using antiangiogenic drugs as partners for ICIs relies primarily on blocking the multiple immunosuppressive effects of VEGF and inducing several different vascular-modulating effects that can stimulate immunity, such as vascular normalization leading to increased intratumoural blood perfusion and flow, and inhibition of pro-apoptotic effects of endothelial cells on T cells, among others. Conversely, VEGF blockade can also cause changes that suppress antitumour immunity, such as increased tumour hypoxia, and reduced intratumoural ingress of co-administered ICIs. As a result, the net clinical benefits from antiangiogenic–ICI combinations will be determined by the balance between the opposing effects of VEGF signalling and its inhibition on the antitumour immune response. In this Perspective, we summarize the results from the currently completed phase III trials evaluating antiangiogenic agent–ICI combinations. We also discuss strategies to improve the efficacy of these combinations, focusing on aspects that include the deleterious functions of VEGF–VEGFR inhibition on antitumour immunity, vessel co-option as a driver of non-angiogenic tumour growth, clinical trial design, or the rationale for drug selection, dosing and scheduling. The benefit of combining antiangiogenic agents with immune-checkpoint inhibitors has been demonstrated in pivotal phase III trials across different cancer types, some with practice-changing results; however, other phase III trials have had negative results. The authors of this Perspective discuss the variable outcomes of these trials, considering factors that account for these differences and suggesting future initiatives for improving the outcomes in patients receiving these combinations.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"21 6","pages":"468-482"},"PeriodicalIF":78.8,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140544844","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 : 2024-04-08DOI: 10.1038/s41571-024-00883-1
Sebastian G. Huayamares, David Loughrey, Hyejin Kim, James E. Dahlman, Eric J. Sorscher
The treatment of patients with advanced-stage solid tumours typically involves a multimodality approach (including surgery, chemotherapy, radiotherapy, targeted therapy and/or immunotherapy), which is often ultimately ineffective. Nucleic acid-based drugs, either as monotherapies or in combination with standard-of-care therapies, are rapidly emerging as novel treatments capable of generating responses in otherwise refractory tumours. These therapies include those using viral vectors (also referred to as gene therapies), several of which have now been approved by regulatory agencies, and nanoparticles containing mRNAs and a range of other nucleotides. In this Review, we describe the development and clinical activity of viral and non-viral nucleic acid-based treatments, including their mechanisms of action, tolerability and available efficacy data from patients with solid tumours. We also describe the effects of the tumour microenvironment on drug delivery for both systemically administered and locally administered agents. Finally, we discuss important trends resulting from ongoing clinical trials and preclinical testing, and manufacturing and/or stability considerations that are expected to underpin the next generation of nucleic acid agents for patients with solid tumours. Nucleic acid-based therapies offer an alternative to traditional cancer treatment modalities, with promising data beginning to emerge. In this Review, the authors describe the design and development of nucleic acid-based therapies administered virally and non-virally, including discussions of the advantages and disadvantage of each approach, as well as the role of patient-specific factors such as the tumour microenvironment, and consider the most promising future research directions.
{"title":"Nucleic acid-based drugs for patients with solid tumours","authors":"Sebastian G. Huayamares, David Loughrey, Hyejin Kim, James E. Dahlman, Eric J. Sorscher","doi":"10.1038/s41571-024-00883-1","DOIUrl":"10.1038/s41571-024-00883-1","url":null,"abstract":"The treatment of patients with advanced-stage solid tumours typically involves a multimodality approach (including surgery, chemotherapy, radiotherapy, targeted therapy and/or immunotherapy), which is often ultimately ineffective. Nucleic acid-based drugs, either as monotherapies or in combination with standard-of-care therapies, are rapidly emerging as novel treatments capable of generating responses in otherwise refractory tumours. These therapies include those using viral vectors (also referred to as gene therapies), several of which have now been approved by regulatory agencies, and nanoparticles containing mRNAs and a range of other nucleotides. In this Review, we describe the development and clinical activity of viral and non-viral nucleic acid-based treatments, including their mechanisms of action, tolerability and available efficacy data from patients with solid tumours. We also describe the effects of the tumour microenvironment on drug delivery for both systemically administered and locally administered agents. Finally, we discuss important trends resulting from ongoing clinical trials and preclinical testing, and manufacturing and/or stability considerations that are expected to underpin the next generation of nucleic acid agents for patients with solid tumours. Nucleic acid-based therapies offer an alternative to traditional cancer treatment modalities, with promising data beginning to emerge. In this Review, the authors describe the design and development of nucleic acid-based therapies administered virally and non-virally, including discussions of the advantages and disadvantage of each approach, as well as the role of patient-specific factors such as the tumour microenvironment, and consider the most promising future research directions.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"21 6","pages":"407-427"},"PeriodicalIF":78.8,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140534349","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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