Pub Date : 2024-11-29DOI: 10.1038/s41571-024-00971-2
Fei Zhou, Haoyue Guo, Yang Xia, Xiuning Le, Daniel S. W. Tan, Suresh S. Ramalingam, Caicun Zhou
The discovery of the association between EGFR 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 EGFR-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 EGFR-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 EGFR-mutant NSCLC on or after treatment with EGFR TKIs. In this Review, we describe the current first-line treatment options for EGFR-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. Third-generation EGFR tyrosine-kinase inhibitors (TKIs) are the standard-of-care first-line treatment for patients with advanced-stage EGFR-mutant NSCLC and their efficacy is being investigated in early stage and locally advanced disease. The authors of this Review describe the current first-line treatment options for EGFR-mutant NSCLC, discuss mechanisms of acquired resistance to third-generation EGFR TKIs and new promising treatment strategies, such as bispecific antibodies, next-generation TKIs, antibody–drug conjugates, immunotherapy approaches and targeted protein degraders.
{"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":"10.1038/s41571-024-00971-2","url":null,"abstract":"The discovery of the association between EGFR 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 EGFR-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 EGFR-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 EGFR-mutant NSCLC on or after treatment with EGFR TKIs. In this Review, we describe the current first-line treatment options for EGFR-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. Third-generation EGFR tyrosine-kinase inhibitors (TKIs) are the standard-of-care first-line treatment for patients with advanced-stage EGFR-mutant NSCLC and their efficacy is being investigated in early stage and locally advanced disease. The authors of this Review describe the current first-line treatment options for EGFR-mutant NSCLC, discuss mechanisms of acquired resistance to third-generation EGFR TKIs and new promising treatment strategies, such as bispecific antibodies, next-generation TKIs, antibody–drug conjugates, immunotherapy approaches and targeted protein degraders.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 2","pages":"95-116"},"PeriodicalIF":81.1,"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}
Pub Date : 2024-11-28DOI: 10.1038/s41571-024-00975-y
Diana Romero
{"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}
Pub Date : 2024-11-28DOI: 10.1038/s41571-024-00967-y
Klaus Pantel, Catherine Alix-Panabières
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.
{"title":"Minimal residual disease as a target for liquid biopsy in patients with solid tumours","authors":"Klaus Pantel, 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}
Pub Date : 2024-11-18DOI: 10.1038/s41571-024-00965-0
Paolo Ciracì, Vittorio Studiale, Ada Taravella, Carlotta Antoniotti, Chiara Cremolini
Over the past few years, several novel systemic treatments have emerged for patients with treatment-refractory metastatic colorectal cancer, thus making selection of the most effective later-line therapy a challenge for medical oncologists. Over the past decade, regorafenib and trifluridine–tipiracil were the only available drugs and often provided limited clinical benefit compared to best supportive care. Results from subsequent practice-changing trials opened several novel therapeutic avenues, both for unselected patients (such as trifluridine–tipiracil plus bevacizumab or fruquintinib) and for subgroups defined by the presence of actionable alterations in their tumours (such as HER2-targeted therapies or KRASG12C inhibitors) or with no acquired mechanisms of resistance to the previously received targeted agents in circulating tumour DNA (such as retreatment with anti-EGFR antibodies). In this Review, we provide a comprehensive overview of advances in the field over the past few years and offer a practical perspective on translation of the most relevant results into the daily management of patients with metastatic colorectal cancer using an evidence-based algorithm. Finally, we discuss some of the most appealing ongoing areas of research and highlight approaches with the potential to further expand the therapeutic armamentarium. Over the past few years, several novel therapies, including targeted therapies for specific subgroups as well as several non-targeted therapies, have been developed and approved for patients with chemorefractory metastatic colorectal cancer (CRC). Nonetheless, selecting patients who are most likely to benefit from one specific therapy is challenging owing to a lack of direct comparisons of the efficacy of these agents in specific settings. In this Review, the authors summarize the available evidence on the efficacy and safety of later-line therapies for patients with advanced-stage CRC and suggest an evidence-based treatment-selection algorithm.
{"title":"Late-line options for patients with metastatic colorectal cancer: a review and evidence-based algorithm","authors":"Paolo Ciracì, Vittorio Studiale, Ada Taravella, Carlotta Antoniotti, Chiara Cremolini","doi":"10.1038/s41571-024-00965-0","DOIUrl":"10.1038/s41571-024-00965-0","url":null,"abstract":"Over the past few years, several novel systemic treatments have emerged for patients with treatment-refractory metastatic colorectal cancer, thus making selection of the most effective later-line therapy a challenge for medical oncologists. Over the past decade, regorafenib and trifluridine–tipiracil were the only available drugs and often provided limited clinical benefit compared to best supportive care. Results from subsequent practice-changing trials opened several novel therapeutic avenues, both for unselected patients (such as trifluridine–tipiracil plus bevacizumab or fruquintinib) and for subgroups defined by the presence of actionable alterations in their tumours (such as HER2-targeted therapies or KRASG12C inhibitors) or with no acquired mechanisms of resistance to the previously received targeted agents in circulating tumour DNA (such as retreatment with anti-EGFR antibodies). In this Review, we provide a comprehensive overview of advances in the field over the past few years and offer a practical perspective on translation of the most relevant results into the daily management of patients with metastatic colorectal cancer using an evidence-based algorithm. Finally, we discuss some of the most appealing ongoing areas of research and highlight approaches with the potential to further expand the therapeutic armamentarium. Over the past few years, several novel therapies, including targeted therapies for specific subgroups as well as several non-targeted therapies, have been developed and approved for patients with chemorefractory metastatic colorectal cancer (CRC). Nonetheless, selecting patients who are most likely to benefit from one specific therapy is challenging owing to a lack of direct comparisons of the efficacy of these agents in specific settings. In this Review, the authors summarize the available evidence on the efficacy and safety of later-line therapies for patients with advanced-stage CRC and suggest an evidence-based treatment-selection algorithm.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 1","pages":"28-45"},"PeriodicalIF":81.1,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665319","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 : 2024-11-15DOI: 10.1038/s41571-024-00959-y
Caroline Diorio, David T. Teachey, Stephan A. Grupp
Chimeric antigen receptor (CAR) T cells are revolutionizing cancer therapy, particularly for haematological malignancies, conferring durable and sometimes curative responses in patients with advanced-stage disease. The CAR T cell products currently approved for clinical use are all autologous and are often effective; however, in patients who are lymphopenic and/or heavily pretreated with chemotherapy, autologous T cells can be difficult to harvest in sufficient numbers or have functional impairments that might ultimately render them less efficacious. Moreover, autologous products take several weeks to produce, and each product can be used in only one patient. By contrast, allogeneic CAR T cells can be produced for many patients using T cells from a single healthy donor, can be optimized for safety and efficacy, can be instantly available for ‘off-the-shelf’ use and, therefore, might also be more cost-effective. Despite these potential advantages, the development of allogeneic CAR T cells has lagged behind that of autologous products, owing to the additional challenges such as avoiding graft-versus-host disease and host-mediated graft rejection. Over the past few years, the development of advanced genome-editing techniques has facilitated the generation of novel allogeneic CAR T cell products. Furthermore, CAR cell products derived from other cell types such as induced pluripotent stem cells and natural killer cells are being investigated for clinical use. In this Review, we discuss the potential of allogeneic CAR cell products to expand life-saving immunotherapy to a much broader population of patients in the coming years, the progress made to date and strategies to overcome remaining hurdles. Several chimeric antigen receptor (CAR) T cell therapies are approved for the treatment of various haematological cancers; however, they are all autologous products requiring individualized manufacturing for each patient, which presents technical, logistical and resource challenges that limits scalability and implementation, and even raises certain ethical questions. Allogeneic products have the potential to address many of these issues, but come with their own challenges. This Review summarizes the advantages and disadvantages of allogeneic CAR cell products derived from T cells or other immune cells, their engineering and progress towards clinical implementation, as well as hurdles that remain to be overcome.
嵌合抗原受体（CAR）T 细胞正在彻底改变癌症治疗，尤其是血液恶性肿瘤的治疗，它能为晚期患者带来持久的、有时甚至是治愈性的治疗效果。目前获准用于临床的 CAR T 细胞产品都是自体细胞，而且通常都很有效；但是，对于淋巴细胞减少和/或接受大量化疗预处理的患者，自体 T 细胞可能很难获得足够的数量，或者存在功能障碍，最终可能导致疗效降低。此外，自体产品的生产需要数周时间，而且每种产品只能用于一名患者。相比之下，异体 CAR T 细胞可以使用来自单一健康供体的 T 细胞为许多患者生产，其安全性和有效性可以得到优化，可以立即 "现成 "使用，因此可能更具成本效益。尽管有这些潜在优势，但异体 CAR T 细胞的开发一直落后于自体产品，原因是要避免移植物抗宿主疾病和宿主介导的移植物排斥反应等额外挑战。过去几年中，先进基因组编辑技术的发展促进了新型异体 CAR T 细胞产品的产生。此外，从诱导多能干细胞和自然杀伤细胞等其他细胞类型中提取的 CAR 细胞产品也正被研究用于临床。在这篇综述中，我们将讨论异体 CAR 细胞产品在未来几年将拯救生命的免疫疗法扩展到更广泛患者群体的潜力、迄今为止取得的进展以及克服剩余障碍的策略。
{"title":"Allogeneic chimeric antigen receptor cell therapies for cancer: progress made and remaining roadblocks","authors":"Caroline Diorio, David T. Teachey, Stephan A. Grupp","doi":"10.1038/s41571-024-00959-y","DOIUrl":"10.1038/s41571-024-00959-y","url":null,"abstract":"Chimeric antigen receptor (CAR) T cells are revolutionizing cancer therapy, particularly for haematological malignancies, conferring durable and sometimes curative responses in patients with advanced-stage disease. The CAR T cell products currently approved for clinical use are all autologous and are often effective; however, in patients who are lymphopenic and/or heavily pretreated with chemotherapy, autologous T cells can be difficult to harvest in sufficient numbers or have functional impairments that might ultimately render them less efficacious. Moreover, autologous products take several weeks to produce, and each product can be used in only one patient. By contrast, allogeneic CAR T cells can be produced for many patients using T cells from a single healthy donor, can be optimized for safety and efficacy, can be instantly available for ‘off-the-shelf’ use and, therefore, might also be more cost-effective. Despite these potential advantages, the development of allogeneic CAR T cells has lagged behind that of autologous products, owing to the additional challenges such as avoiding graft-versus-host disease and host-mediated graft rejection. Over the past few years, the development of advanced genome-editing techniques has facilitated the generation of novel allogeneic CAR T cell products. Furthermore, CAR cell products derived from other cell types such as induced pluripotent stem cells and natural killer cells are being investigated for clinical use. In this Review, we discuss the potential of allogeneic CAR cell products to expand life-saving immunotherapy to a much broader population of patients in the coming years, the progress made to date and strategies to overcome remaining hurdles. Several chimeric antigen receptor (CAR) T cell therapies are approved for the treatment of various haematological cancers; however, they are all autologous products requiring individualized manufacturing for each patient, which presents technical, logistical and resource challenges that limits scalability and implementation, and even raises certain ethical questions. Allogeneic products have the potential to address many of these issues, but come with their own challenges. This Review summarizes the advantages and disadvantages of allogeneic CAR cell products derived from T cells or other immune cells, their engineering and progress towards clinical implementation, as well as hurdles that remain to be overcome.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 1","pages":"10-27"},"PeriodicalIF":81.1,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637134","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 : 2024-11-06DOI: 10.1038/s41571-024-00963-2
Joshua Drago, Shanu Modi
The DESTINY-Breast06 trial investigated earlier and broader use of trastuzumab deruxtecan in patients with metastatic hormone-receptor-positive breast cancer, and demonstrated improvements in progression-free survival over standard chemotherapy. These data provide a meaningful advance; however, this strategy might not be right for all patients, and careful consideration is recommended before blanket use.
{"title":"Expanding the use of T-DXd in metastatic HR-positive breast cancer: where are we now?","authors":"Joshua Drago, Shanu Modi","doi":"10.1038/s41571-024-00963-2","DOIUrl":"10.1038/s41571-024-00963-2","url":null,"abstract":"The DESTINY-Breast06 trial investigated earlier and broader use of trastuzumab deruxtecan in patients with metastatic hormone-receptor-positive breast cancer, and demonstrated improvements in progression-free survival over standard chemotherapy. These data provide a meaningful advance; however, this strategy might not be right for all patients, and careful consideration is recommended before blanket use.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 1","pages":"6-7"},"PeriodicalIF":81.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588704","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 : 2024-11-05DOI: 10.1038/s41571-024-00964-1
Vickie E. Baracos
A number of therapeutics that target mediators of signalling in the hypothalamic and brainstem regions that control appetite, ingestive behaviour, satiety, nausea and vomiting are starting to move the needle on cancer cachexia. However, clarification of meaningful clinical benefits for patients and the primary end points that should support regulatory approval of cachexia treatments is needed.
{"title":"On the cusp of targeted therapy for cancer cachexia — what clinical benefits might we promise our patients?","authors":"Vickie E. Baracos","doi":"10.1038/s41571-024-00964-1","DOIUrl":"10.1038/s41571-024-00964-1","url":null,"abstract":"A number of therapeutics that target mediators of signalling in the hypothalamic and brainstem regions that control appetite, ingestive behaviour, satiety, nausea and vomiting are starting to move the needle on cancer cachexia. However, clarification of meaningful clinical benefits for patients and the primary end points that should support regulatory approval of cachexia treatments is needed.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 1","pages":"8-9"},"PeriodicalIF":81.1,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580740","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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