Cancer therapy articles within Nature Reviews Clinical Oncology

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  • News & Views |

    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.

    • Christopher Nevala-Plagemann
    •  & Ignacio Garrido-Laguna

  • Comment |

    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.

    • Ghulam Rehman Mohyuddin
    •  & Aaron M. Goodman

  • News & Views |

    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.

    • David H. Aggen
    •  & Jonathan E. Rosenberg

  • Review Article |

    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.

    • Sebastian G. Huayamares
    • , David Loughrey
    •  & Eric J. Sorscher

  • News & Views |

    The composition of the gut microbiota has emerged as a tumour-extrinsic factor that modulates response to immune-checkpoint inhibitors (ICIs), although the lack of consistency in microbiota signatures across studies has limited their value as reliable biomarkers. Herein, we discuss a recent study in which longitudinal microbiome profiling identified several taxa that are persistently enriched in patients with melanoma and a favourable response to ICIs.

    • Saman Maleki Vareki
    •  & Diwakar Davar

  • Review Article |

    FGFR inhibitors are now approved for use in patients with advanced-stage urothelial carcinoma, cholangiocarcinoma and myeloid or lymphoid neoplasms that harbour certain FGFR alterations. Nonetheless, challenges such as tolerability and acquired resistance limit the clinical potential of these agents. In this Review, the authors summarize the available clinical data on FGFR inhibitors, describe promising novel agents and highlight future research directions that might optimize the efficacy of FGFR-targeted therapies.

    • Masuko Katoh
    • , Yohann Loriot
    •  & Masaru Katoh

  • Review Article |

    Patients with early stage hepatocellular carcinoma typically undergo resection, liver transplantation or local ablation; however, 30–50% will have disease recurrence at 3 years. The authors of this Review describe the tumour immune microenvironment and mechanism of action of immunotherapies, and discuss the available evidence from phase II/III trials of neoadjuvant and adjuvant treatment approaches in this setting.

    • Josep M. Llovet
    • , Roser Pinyol
    •  & Richard S. Finn

  • Review Article |

    Increasing evidence indicates that signalling networks activated downstream of oncogenic alterations contribute fundamentally to cancer immune evasion, including by promoting the accumulation of regulatory T (Treg) cells and other immunosuppressive cells in the tumour microenvironment (TME). Herein, the authors discuss the mechanisms via which cancers engage Treg cells to evade antitumour immunity, as well as the characteristics of Treg cells in the TME and their roles in resistance to immune-checkpoint inhibitors. Considering these aspects, they propose the concept of ‘immuno-genomic cancer evolution’ for tumorigenesis and the related paradigm of ‘immuno-genomic precision medicine’, postulating that the specific characteristics of cancer, especially genetic profiles that correlate with particular immunosuppressive networks in the TME, are likely to inform individualized strategies for combining molecularly targeted agents with immunotherapies.

    • Shogo Kumagai
    • , Kota Itahashi
    •  & Hiroyoshi Nishikawa

  • Comment |

    In 2023, the US FDA approved several new cancer drugs and biologic agents, including seven small-molecule inhibitors, four bispecific T cell engagers, two anti-PD-1 antibodies and one cell therapy product. Regulatory focus areas included analyses of biomarker-positive subgroups that drive efficacy, equipoise in randomized controlled trials and a new authority to require confirmatory trials be underway before accelerated approval.

    • Kelly J. Norsworthy
    • , Rosa J. Lee-Alonzo
    •  & Richard Pazdur

  • Review Article |

    Ataxia telangiectasia and Rad3-related protein serine/threonine kinase (ATR) is a mediator of the cellular replication stress response that, upon activation, initiates a cascade of coordinated reactions that ultimately enables DNA repair. This biological function makes ATR an attractive therapeutic target in cancers with elevated replication stress or DNA-repair deficiency. This Review discusses the currently available results from clinical trials testing ATR inhibitors as well as challenges and solutions in the development of this therapeutic class.

    • Natalie Y. L. Ngoi
    • , Patrick G. Pilié
    •  & Timothy A. Yap

  • Review Article |

    Dendritic cells (DCs) are antigen-presenting cells that function at the interface between innate and adaptive immunity, thereby acting as key mediators of antitumour immune responses and immunotherapy efficacy. In this Review, the authors outline the emerging complexity of intratumoural DC states that is being revealed through single-cell analyses as well as the contributions of different DC subsets to anticancer immunity and the activity of immune-checkpoint inhibitors. The authors also discuss advances in the development of DC-based cancer therapies and considerations for their potential combination with other anticancer therapies.

    • Ignacio Heras-Murillo
    • , Irene Adán-Barrientos
    •  & David Sancho

  • News & Views |

    Durable responses with first-line platinum-based chemotherapy for advanced-stage urothelial carcinoma are rare, and patient outcomes are poor. Recently, CheckMate 901 became the first phase III trial to establish a significant overall survival benefit from a combined chemoimmunotherapy approach in this disease setting. Herein, we discuss key findings from CheckMate 901 and their implications in the context of a rapidly evolving treatment landscape.

    • Nimira Alimohamed
    •  & Srikala S. Sridhar

  • Review Article |

    Various BRAF alterations are found and function as oncogenic drivers across diverse cancer types. BRAF inhibitor-based therapy has improved outcomes for patients with cancers harbouring BRAFV600 mutations, although resistance develops in most, and the current inhibitors are not effective against other types of BRAF alterations. In this Review, the authors describe the mechanisms underlying oncogenic BRAF signalling, as well as pan-cancer and lineage-specific mechanisms of intrinsic, adaptive and acquired resistance to BRAF inhibitors. They also discuss novel RAF inhibitors and drug combinations designed to overcome these resistance mechanisms and/or expand the applicability of molecularly targeted therapy to a broader range of BRAF-mutant cancers.

    • Aphrothiti J. Hanrahan
    • , Ziyu Chen
    •  & David B. Solit

  • News & Views |

    Several novel personalized therapies focus on targeting neoantigens. Such strategies require the identification of suitable vaccine neoepitopes or neoantigen-specific T cell receptor (TCR) clonotypes. Herein, we discuss a recently published report that describes a combined transcriptional and phenotype signature, NeoTCRPBL, that enables the minimally invasive identification of rare neoantigen-specific TCRs from peripheral blood that might enable more-effective T cell-based therapies against cancer.

    • Marco Donia
    •  & Inge Marie Svane

  • Review Article |

    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.

    • Kyoji Tsuchikama
    • , Yasuaki Anami
    •  & Chisato M. Yamazaki

  • Review Article |

    Despite dramatic progress over the past decade, only around 50% of patients with advanced-stage melanoma derive durable benefit from immune-checkpoint inhibitors (ICIs) and/or BRAF and MEK (BRAF/MEK) inhibitors. Over the past few years, adoptive cell therapy with tumour-infiltrating lymphocytes (TILs) has demonstrated encouraging efficacy including in patients with disease progression on ICIs or BRAF/MEK inhibitors. In this Review, the authors summarize the role of TIL therapies in the management of these patients and describe future research strategies that might improve safety or efficacy.

    • Sebastian Klobuch
    • , Tom T. P. Seijkens
    •  & John B. A. G. Haanen

  • Review Article |

    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.

    • Antonio Marra
    • , Sarat Chandarlapaty
    •  & Shanu Modi

  • News & Views |

    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.

    • Pier Paolo M. Berton Giachetti
    •  & Giuseppe Curigliano

  • Review Article |

    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.

    • Amos Tuval
    • , Charlotte Strandgren
    •  & Klas G. Wiman

  • Review Article |

    Patients with advanced-stage urothelial cancer (aUC) continue to have poor long-term survival outcomes. However, developments in the past 5 years, most notably the availability of maintenance therapy with the anti-PD-1 antibody avelumab, are beginning to change this issue. In this Review, the authors provide an overview of the treatment of patients with aUC, including considerations of the various promising new therapeutic modalities and how they might improve clinical outcomes.

    • Rosa Nadal
    • , Begoña P. Valderrama
    •  & Joaquim Bellmunt

  • Perspective |

    Despite some success in patients with certain B cell malignancies and relapsed and/or refractory multiple myeloma, studies testing chimeric antigen receptor (CAR) T cells in patients with advanced-stage solid tumours have been largely unsuccessful, with a few notable exceptions. In this Perspective, the author provides some possible reasons for the failures of most CAR T cell-based approaches and suggests strategies that might address some of these challenges.

    • Steven M. Albelda

  • Comment |

    Projected increases of cancer-attributable health-care costs, accompanied by staff shortages, will impose future economic and operational challenges on national health-care systems. Herein, we highlight a series of clinical and health economic rationales in support of publicly funded clinical trial teams that conduct real-world dose-reduction trials aiming for adjustment of cancer drug label doses to reduce not only the financial burden on payers, but also the toxicity burden on patients.

    • Kim Theilgaard-Mönch
    •  & Lars Holger Ehlers

  • Review Article |

    According to the precision oncology paradigm, cancer therapies are increasingly being matched to specific sensitizing alterations using a biomarker-directed approach. However, the criteria for determining the actionability of molecular alterations and selecting matched treatments evolve over time. Molecular tumour boards (MTBs) have emerged as means to capitalize on the collective knowledge of various experts to interpret molecular-profiling data and to eliminate subjectivity in treatment selection. This Review describes the components, processes and increasingly important role of MTBs in optimizing the implementation of precision oncology in both clinical trials and clinical practice, as well as current and future considerations for ensuring the sustainability of MTBs and expanding their outreach to underserved populations.

    • Apostolia M. Tsimberidou
    • , Michael Kahle
    •  & Funda Meric-Bernstam

  • Review Article |

    Ovarian carcinoma is a highly heterogeneous tumour type, both spatially and temporally. As a consequence, these carcinomas are often associated with poor outcomes. Ovarian carcinoma comprises various subtypes with distinct complex molecular features. The authors of this Review discuss the molecular, cellular and anatomical heterogeneity of ovarian carcinoma, and outline the current and future treatment strategies for this malignancy.

    • Ana C. Veneziani
    • , Eduardo Gonzalez-Ochoa
    •  & Amit M. Oza

  • Perspective |

    Despite improved effectiveness, most systemic cancer therapies are not curative and most patients will develop acquired resistance that often cannot be explained by the emergence of specific genomic alterations. In this Perspective, the authors describe the potential role of a small population of tumour cells, termed drug-tolerant persister cells, that are able to survive therapy and, on continued treatment exposure, develop stable mechanisms of resistance to systemic therapies.

    • Yi Pu
    • , Lu Li
    •  & Shensi Shen

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