Nature Reviews Clinical Oncology最新文献

{"title":"Exploring the next generation of antibody–drug conjugates","authors":"Kyoji Tsuchikama, Yasuaki Anami, Summer Y. Y. Ha, Chisato M. Yamazaki","doi":"10.1038/s41571-023-00850-2","DOIUrl":"10.1038/s41571-023-00850-2","url":null,"abstract":"Antibody–drug conjugates (ADCs) are a promising cancer treatment modality that enables the selective delivery of highly cytotoxic payloads to tumours. However, realizing the full potential of this platform necessitates innovative molecular designs to tackle several clinical challenges such as drug resistance, tumour heterogeneity and treatment-related adverse effects. Several emerging ADC formats exist, including bispecific ADCs, conditionally active ADCs (also known as probody–drug conjugates), immune-stimulating ADCs, protein-degrader ADCs and dual-drug ADCs, and each offers unique capabilities for tackling these various challenges. For example, probody–drug conjugates can enhance tumour specificity, whereas bispecific ADCs and dual-drug ADCs can address resistance and heterogeneity with enhanced activity. The incorporation of immune-stimulating and protein-degrader ADCs, which have distinct mechanisms of action, into existing treatment strategies could enable multimodal cancer treatment. Despite the promising outlook, the importance of patient stratification and biomarker identification cannot be overstated for these emerging ADCs, as these factors are crucial to identify patients who are most likely to derive benefit. As we continue to deepen our understanding of tumour biology and refine ADC design, we will edge closer to developing truly effective and safe ADCs for patients with treatment-refractory cancers. In this Review, we highlight advances in each ADC component (the monoclonal antibody, payload, linker and conjugation chemistry) and provide more-detailed discussions on selected examples of emerging novel ADCs of each format, enabled by engineering of one or more of these components. Antibody–drug conjugates (ADCs) are effective cancer drugs that have been approved for more than 20 specific indications. Nonetheless, acquired resistance and adverse events both limit the effectiveness of these agents. In this Review, the authors describe the development of novel ADC designs, including bispecific ADCs, probody–drug conjugates, immune-stimulating ADCs, protein-degrader ADCs and dual-drug ADCs. all of which have the potential to address these challenges and provide more effective ADCs.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139379476","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":"Management of patients with advanced-stage HER2-positive breast cancer: current evidence and future perspectives","authors":"Antonio Marra, Sarat Chandarlapaty, Shanu Modi","doi":"10.1038/s41571-023-00849-9","DOIUrl":"10.1038/s41571-023-00849-9","url":null,"abstract":"Amplification and/or overexpression of ERBB2, the gene encoding HER2, can be found in 15–20% of invasive breast cancers and is associated with an aggressive phenotype and poor clinical outcomes. Relentless research efforts in molecular biology and drug development have led to the implementation of several HER2-targeted therapies, including monoclonal antibodies, tyrosine-kinase inhibitors and antibody–drug conjugates, constituting one of the best examples of bench-to-bedside translation in oncology. Each individual drug class has improved patient outcomes and, importantly, the combinatorial and sequential use of different HER2-targeted therapies has increased cure rates in the early stage disease setting and substantially prolonged survival for patients with advanced-stage disease. In this Review, we describe key steps in the development of the modern paradigm for the treatment of HER2-positive advanced-stage breast cancer, including selecting and sequencing new-generation HER2-targeted therapies, and summarize efficacy and safety outcomes from pivotal studies. We then outline the factors that are currently known to be related to resistance to HER2-targeted therapies, such as HER2 intratumoural heterogeneity, activation of alternative signalling pathways and immune escape mechanisms, as well as potential strategies that might be used in the future to overcome this resistance and further improve patient outcomes. The discovery of ERBB2 as a gene frequently amplified and/or overexpressed in breast cancers and of its product HER2 as a biomarker has spurred the development of various targeted therapies. As a result, the prognosis of patients with advanced-stage HER2-positive breast cancer has greatly improved in the past decades. The authors of this Review describe the development of the current treatment landscape for these patients and discuss how to address resistance to further improve outcomes.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139379479","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":"‘Contribution of component’ and the perioperative immune-checkpoint inhibitor precedent","authors":"Garth W. Strohbehn, Bishal Gyawali","doi":"10.1038/s41571-023-00857-9","DOIUrl":"10.1038/s41571-023-00857-9","url":null,"abstract":"The FDA approval of perioperative pembrolizumab, an approach that combines neoadjuvant and adjuvant therapy with this agent, for patients with early stage non-small-cell lung cancer (NSCLC) contradicts its own stated standard for combination therapies. Given the large population of patients with early stage NSCLC and the high costs of pembrolizumab, whether the adjuvant component provides incremental benefit is an important question.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139101253","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 MRD-guided treatment in CLL","authors":"Diana Romero","doi":"10.1038/s41571-023-00858-8","DOIUrl":"10.1038/s41571-023-00858-8","url":null,"abstract":"","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139076685","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":"Optimizing the FDA’s Project Optimus: opportunities and challenges","authors":"Simon Rodney, Udai Banerji","doi":"10.1038/s41571-023-00853-z","DOIUrl":"10.1038/s41571-023-00853-z","url":null,"abstract":"Through Project Optimus, the FDA calls for radical changes in the design of early phase trials to identify the optimal doses of oncology drugs to achieve maximal efficacy with better tolerability and patient acceptability. Herein, we discuss approaches that will enable the implementation of this initiative as well as some concerns that the draft guidance has raised in the oncology community.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138823045","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":"PERSEUS triumphs — efficacy of daratumumab confirmed in transplant-eligible NDMM","authors":"David Killock","doi":"10.1038/s41571-023-00856-w","DOIUrl":"10.1038/s41571-023-00856-w","url":null,"abstract":"","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138822878","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":"Mirvetuximab soravtansine superior to chemotherapy in platinum-resistant epithelial ovarian cancer","authors":"Peter Sidaway","doi":"10.1038/s41571-023-00851-1","DOIUrl":"10.1038/s41571-023-00851-1","url":null,"abstract":"","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138808028","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":"Pyrotinib in combination with first-line trastuzumab and docetaxel for patients with HER2-positive metastatic breast cancer: a new therapeutic option?","authors":"Pier Paolo M. Berton Giachetti, Giuseppe Curigliano","doi":"10.1038/s41571-023-00854-y","DOIUrl":"10.1038/s41571-023-00854-y","url":null,"abstract":"Recent results from the phase III PHILA trial demonstrate a benefit in terms of progression-free survival derived from the addition of pyrotinib to first-line chemotherapy plus trastuzumab in patients with metastatic HER2-positive breast cancer. Dual HER2 blockade with pyrotinib and trastuzumab is an effective therapeutic strategy but might increase the risk of gastrointestinal toxicity; therefore, the risk-to-benefit ratio should be carefully evaluated.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138808034","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":"Neoadjuvant chemoimmunotherapy is effective in locally advanced cervical cancer","authors":"Diana Romero","doi":"10.1038/s41571-023-00855-x","DOIUrl":"10.1038/s41571-023-00855-x","url":null,"abstract":"","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138808031","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":"Pharmacological reactivation of p53 in the era of precision anticancer medicine","authors":"Amos Tuval, Charlotte Strandgren, Angelos Heldin, Mireia Palomar-Siles, Klas G. Wiman","doi":"10.1038/s41571-023-00842-2","DOIUrl":"10.1038/s41571-023-00842-2","url":null,"abstract":"p53, which is encoded by the most frequently mutated gene in cancer, TP53, is an attractive target for novel cancer therapies. Despite major challenges associated with this approach, several compounds that either augment the activity of wild-type p53 or restore all, or some, of the wild-type functions to p53 mutants are currently being explored. In wild-type TP53 cancer cells, p53 function is often abrogated by overexpression of the negative regulator MDM2, and agents that disrupt p53–MDM2 binding can trigger a robust p53 response, albeit potentially with induction of p53 activity in non-malignant cells. In TP53-mutant cancer cells, compounds that promote the refolding of missense mutant p53 or the translational readthrough of nonsense mutant TP53 might elicit potent cell death. Some of these compounds have been, or are being, tested in clinical trials involving patients with various types of cancer. Nonetheless, no p53-targeting drug has so far been approved for clinical use. Advances in our understanding of p53 biology provide some clues as to the underlying reasons for the variable clinical activity of p53-restoring therapies seen thus far. In this Review, we discuss the intricate interactions between p53 and its cellular and microenvironmental contexts and factors that can influence p53’s activity. We also propose several strategies for improving the clinical efficacy of these agents through the complex perspective of p53 functionality. p53, encoded by TP53, the commonest mutated gene in cancer, is an appealing target for systemic anticancer therapies including those designed to restore p53 function. Thus far, and despite promising preclinical data and several clinical trials, no p53-restoring systemic therapy has been approved for therapeutic use. Despite this limited success, several research efforts are ongoing. In this Review, the authors summarize the role of p53 in cancer with a focus on the complexity of p53 function and how this relates to clinical attempts to restore at least some of these functions.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":78.8,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138657424","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}