Drug discovery articles within Nature Reviews Clinical Oncology

Featured

  • Comment |

    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.

    • Garth W. Strohbehn
    •  & Bishal Gyawali

  • Comment |

    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Herein, we discuss approaches that will enable the implementation of this initiative as well as some concerns that the draft guidance has raised in the oncology community.

    • Simon Rodney
    •  & Udai Banerji

  • News & Views |

    Recent results from the FLAURA2 and MARIPOSA-2 trials underline the continued role of chemotherapy in the treatment of patients with EGFR-mutated non-small-cell lung cancer in the era of targeted therapies. Herein, we argue that the most appropriate and rational sequence and/or combination of therapies remains a matter of discussion.

    • Rafael Rosell
    •  & María González-Cao

  • Review Article |

    Dysregulation of N6-methyladenosine (m6A), the most prevalent internal modification in eukaryotic mRNA, is common in various cancer types. The authors of this Review provide an overview of the mechanisms of m6A-dependent RNA regulation, summarize current knowledge of their pathological effects and potential utility as biomarkers in cancer, and describe ongoing efforts to develop small-molecule inhibitors of oncogenic m6A modifiers.

    • Xiaolan Deng
    • , Ying Qing
    •  & Jianjun Chen

  • Review Article |

    Preclinical models that faithfully recapitulate interactions between the human immune system and tumours are necessary to evaluate human-specific immunotherapies in vivo; however, their number is currently limited. The authors of this Review discuss the currently available humanized mouse models, which are immunodeficient mice co-engrafted with human tumours and immune components, with a focus on their applicability in translational research.

    • Jane Chuprin
    • , Hannah Buettner
    •  & Michael A. Brehm

  • News & Views |

    Data on a new treatment approach utilizing bispecific monoclonal antibodies targetting B-cell maturation antigen (BCMA) were recently published, yielding very encouraging results in the setting of relapsed and/or refractory multiple myeloma (RRMM). How to safely and effectively deliver this treatment to patients and where it fits in the RRMM treatment paradigm are important questions for the future.

    • Krina Patel
    •  & Sagar Lonial

  • Review Article |

    Vaccination against COVID-19 confers robust protection from severe disease. However, the extent to which this applies to patients with cancer remains uncertain given that these patients were excluded from most of the pivotal studies. In this Review, the authors provide an overview of the efficacy and immunogenicity of COVID-19 vaccines in patients with cancer, and discuss alternatives to vaccination for those who might be unable to develop a proficient immune response following vaccination.

    • Annika Fendler
    • , Elisabeth G. E. de Vries
    •  & Marie von Lilienfeld-Toal

  • Perspective |

    In oncology, a definition of drug value that patients, payers, regulators and clinicians agree upon on does not exist. The authors of this Perspective discuss different approaches to measuring value, such as assessments of benefit–risk balance and cost-effectiveness, individual attitudes to risk, and use of scales developed to measure value objectively. They also explain how regulators can help to inform different decision makers.

    • Francesco Pignatti
    • , Ulla Wilking
    •  & Jonas Bergh

  • Comment |

    Recent FDA draft guidance for sponsors of oncology clinical trials encourages enrolment of patients with incurable cancer and no potential for prolonged and/or near-normal survival, regardless of whether they have received existing treatment options. This guidance constitutes a substantial departure from current standards, with potentially profound implications for trial participants as well as drug regulation and reimbursement.

    • Mark P. Lythgoe
    •  & Vinay Prasad

  • Review Article |

    The blood–brain barrier regulates the movement of various substances between the blood and the brain and therefore has a crucial role in ensuring normal brain function. In both primary brain tumours and brain metastases, the blood–brain barrier is modified to the blood–tumour barrier (BTB), resulting in altered permeability; however, the BTB continues to restrict the penetration of many therapeutic agents into intracranial tumours. Here, Patricia Steeg describes the current knowledge of BTB structure and function and discusses how this knowledge can be translated into improvements in cancer therapy and patient outcomes.

    • Patricia S. Steeg

  • News & Views |

    Randomized controlled trials designed to test cancer therapies often fail to clarify effectiveness in real-world settings. Herein, we explore lessons for trial development in oncology that can be learnt from the large-cohort, pragmatic RECOVERY trial involving patients hospitalized with COVID-19.

    • Rahul Banerjee
    •  & Vinay Prasad

  • Comment |

    Informative censoring occurs when progression-free survival is the primary end point of a randomized clinical trial and unequal patient dropout is observed between treatment arms owing to poorer tolerance of experimental treatment. Herein we discuss how informative censoring in the experimental arm before criteria for disease progression are met causes bias towards a positive result.

    • Arnoud J. Templeton
    • , Eitan Amir
    •  & Ian F. Tannock

  • Viewpoint |

    Regulatory approval of new cancer medicines can have important consequence for patients with advanced-stage and/or rare cancers who have exhausted all standard-of-care therapies. However, evidence that new medicines are safe and effective can also take time to accrue, and approval with a lack of evidence may cause unnecessary harm to patients. In this Viewpoint, we asked two leading oncologists involved in clinical drug development, an expert in regulatory science and prescription drug policy, and a prominent patient advocate, to provide their opinions on the current approach to cancer drug approvals.

    • Razelle Kurzrock
    • , Hagop M. Kantarjian
    •  & Ellen V. Sigal

  • Editorial |

    Phase I trials form the foundations of evidence-based oncology. Here, we explore the ethical controversies surrounding how participation in such trials should be presented to patients.

  • Comment |

    New molecular insights occasionally lead to the rapid development of therapeutic agents that improve the outcomes of patients with cancer; however, these breakthroughs can be followed by extensive, empirically driven and often unsuccessful efforts at extending the drug to other indications or combinations. Herein, we describe the clinical development of imatinib, a paradigm of rapid molecularly driven drug development, and advocate for a balanced portrayal of the potential of molecularly targeted therapies for cancer.

    • Benjamin G. Carlisle
    • , Tiger Zheng
    •  & Jonathan Kimmelman

  • Perspective |

    Oncology phase I trials have been traditionally referred to as ‘toxicity trials’. The distinction of clinical trials into three phases has been challenged in the past few years, leading to the current situation in which response rates are increasingly reported from phase I trials. The authors dissect the ethical dilemmas surrounding the therapeutic intent of phase I trials and provide evidence of contemporary phase I trials as a therapeutic option for patients with cancer.

    • Jacob J. Adashek
    • , Patricia M. LoRusso
    •  & Razelle Kurzrock

  • Comment |

    Many argue that phase I cancer trials are a therapeutic option for eligible patients. I question this position and offer a more nuanced view that differentiates between types of trials. Patients seeking treatment might legitimately pursue phase I trials, although labelling all phase I trials as therapeutic contradicts the spirit of evidence-based medicine.

    • Jonathan Kimmelman

  • Comment |

    The FDA grants Accelerated Approval when deemed necessary to address an unmet need, with a promise that post-marketing research commitments will be fulfilled and that the approvals will be revisited and eventually changed if clinically meaningful results are reported. Herein, we present a timeline of all Accelerated Approvals granted to immune-checkpoint inhibitors to illustrate three ways in which the FDA has failed to fulfil their part in this social contract.

    • Jennifer Gill
    •  & Vinay Prasad

  • News & Views |

    Inhibition of the NKG2A immune checkpoint restores natural killer cell and T cell effector function in preclinical cancer models. In addition, NKG2A blockade in combination with other therapeutic antibodies is showing encouraging responses in a subset of patients with metastatic colorectal or head and neck cancer. However, established biomarkers of response are lacking, and larger trials are needed to enable firm conclusions to be drawn about whether NKG2A inhibition complements existing immunotherapies.

    • Benjamin C. Creelan
    •  & Scott J. Antonia

  • Perspective |

    Many clinical trials are testing the safety and/or efficacy of combining radiotherapy with immunotherapy, nearly all using a single-site irradiation (or ‘abscopal’) approach, but emerging evidence suggests that this approach likely produces suboptimal results. The authors of this Perspective provide a biological rationale supporting the abandonment of the abscopal approach, and instead advocate exploring comprehensive irradiation of multiple/all lesions.

    • Eric D. Brooks
    •  & Joe Y. Chang

  • News & Views |

    In a cohort of 100 patients with neuroendocrine cancer, the use of NETest enabled earlier prediction of tumour progression and resulted in a reduction in the frequency of follow-up procedures. These outcomes are exciting and promising, but limited in value by the heterogeneity of the study cohort and by suboptimal assay sensitivity and specificity.

    • Guido Rindi
    •  & Bertram Wiedenmann

  • Review Article |

    FGFR alterations can be detected in a small subset of many different cancer types. Inspired by the successes with other targeted therapies, preliminary attempts to target FGFR-altered cancers have been hampered by low response rates and acquired resistance. In this Review, the author describes the development of FGFR inhibitors thus far, and provides guidance on future research priorities.

    • Masaru Katoh

  • News & Views |

    The ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) will be useful as a common language to harmonize discussions in precision oncology and could also guide policy and reimbursement decisions, but it is far from perfect. Herein, we highlight how ESCAT can be further improved to increase its utility in clinical and policy decisions.

    • Bishal Gyawali
    •  & Aaron S. Kesselheim

  • News & Views |

    A minority of patients with gastroesophageal adenocarcinoma derive benefit from immune-checkpoint inhibition (ICI). In a large-cohort phase III study, the nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) arm (which was based on promising preliminary data from CheckMate 032) was closed owing to unacceptably high levels of mortality and morbidity. Our quest for better biomarkers than programmed cell death 1 ligand 1 (PD-L1) and safer dual ICI strategies must continue.

    • Kazuto Harada
    • , Ahmed A. F. Abdelhakeem
    •  & Jaffer A. Ajani

  • Perspective |

    With the expansion of the precision medicine paradigm, seamless trial approaches to drug development hold great promise for accelerating the accessibility of novel therapeutic agents but are also accompanied by important trade-offs. The authors describe several opportunities to improve the efficiency of drug development in oncology, as well as new mechanisms to obtain information about anticancer therapies throughout their life cycle.

    • Sharyl J. Nass
    • , Mace L. Rothenberg
    •  & Richard L. Schilsky

  • Review Article |

    Androgen receptor (AR) splice variants (AR-Vs) are truncated isoforms of the AR, of which a subset remain constitutively active in the absence of circulating androgens. AR-Vs have been proposed to contribute to therapeutic resistance. The authors of this Review outline the current understanding of the role of the spliceosome in prostate cancer progression and explore the therapeutic utility of manipulating alternative splicing.

    • Alec Paschalis
    • , Adam Sharp
    •  & Johann. S. de Bono

  • News & Views |

    Accelerated approval enables investigational drugs to reach the US market on the basis of their demonstrated effects in unvalidated surrogate measures, only reasonably likely to predict clinical response. To fulfil the social compromise, regulators should ensure that confirmatory trials testing clinically meaningful end points are already underway at the time of approval.

    • Bishal Gyawali
    •  & Aaron S. Kesselheim

Browse broader subjects

Browse narrower subjects

Browse Drug discovery across other nature.com journals