Drug development articles within Nature Reviews Clinical Oncology

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  • Comment |

    Drug regulators’ acceptance of any statistically significant improvement shown in a single randomized trial and lofty drug prices has created a situation where it is now, hypothetically, profitable for a company to run a clinical trials portfolio of chemically inert compounds. While the current cancer drug pipeline is certainly superior to inert drugs, we must rethink market incentives to encourage transformational drug development.

    • Vinay Prasad
    • , Christopher McCabe
    •  & Sham Mailankody

  • News & Views |

    After almost 20 years of negative trials of novel therapies for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), two androgen receptor antagonists have shown favourable outcomes in phase III trials involving patients with high-risk nmCRPC. Herein, the history of nmCRPC and clinical trials in this disease setting are discussed and a perspective on molecular imaging and clinical management of nmCRPC is offered.

    • Celestia S. Higano

  • Comment |

    According to the paradigm of precision medicine, the administration of agents targeting the molecular alteration detected in a particular patient’s tumour reduces uncertainty in the clinical management of that patient. We describe how approaches to precision medicine can lead, paradoxically, to increased levels of uncertainty. We offer recommendations for how physicians can better navigate new uncertainties in precision medicine.

    • Jonathan Kimmelman
    •  & Ian Tannock

  • Review Article |

    Both multiple myeloma and acute myeloid leukaemia are often preceded by defined precursor stages of neoplasia, which can aid efforts to unravel the mechanisms of disease progression. Herein, the authors review studies of the important roles of microenvironmental factors in promoting the development and progression of haematological cancers in these precursor conditions. Potential therapeutic strategies targeting the abnormal bone-marrow microenvironment are discussed.

    • Irene M. Ghobrial
    • , Alexandre Detappe
    •  & David P. Steensma

  • Review Article |

    Chimeric antigen receptor (CAR)-T-cell therapies are showing great promise in the treatment of cancer, particularly B-cell malignancies, but are associated with characteristic, potentially fatal toxicities, principally cytokine-release syndrome, CAR-T-cell-related encephalopathy syndrome, and haemophagocytic lymphohistiocytosis/macrophage-activation syndrome. Herein, the CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group, comprising multidisciplinary investigators from various institutions with clinical experience in the use of a range of CAR-T-cell platforms, review these acute toxicities and provide monitoring, grading, and management recommendations.

    • Sattva S. Neelapu
    • , Sudhakar Tummala
    •  & Elizabeth J. Shpall

  • Review Article |

    Cell-based immunotherapies are showing great promise in the treatment of even the most treatment-refractory of haematological malignancies. Herein, Jennifer Brudno and James Kochenderfer review the results obtained to date with CAR-T-cell therapies for lymphoma. They also discuss what has been learned regarding the limitations of CAR-T-cell therapies and areas for improvement relating to toxicity management, the design of CAR-T-cell products, conditioning regimens, and combination therapies.

    • Jennifer N. Brudno
    •  & James N. Kochenderfer

  • Comment |

    Scientific Advice meetings are a mechanism to improve communications between drug developers and regulators during the drug-development process. While standard practice for industry, the benefits provided by these meetings are under-utilised by academia. In the context of drug repurposing, can scientific advice, as part of a proposed new R&D tax credits scheme, help to unblock some of the obstacles in the way to clinical adoption?

    • Pan Pantziarka

  • Comment |

    In studies investigating the combination of two or more anticancer drugs that are already approved for independent use, or 'maintenance' regimens, the use of progression-free survival as the end point for approval is inadequate; sequential treatment with the same agents or existing salvage therapies, respectively, might provide an equivalent survival benefit, with lower toxicity, cost, and treatment burden, therefore, the use of an overall survival end point is essential to justify such interventions.

    • Bishal Gyawali
    •  & Vinay Prasad

  • News & Views |

    The success of cancer therapies is hampered by a paucity of suitable drug targets and the rapid development of therapy resistance. The concept of synthetic lethality provides a potential solution to these constraints via the identification of novel therapeutic vulnerabilities, as exemplified in two recent studies.

    • Diede Brunen
    •  & René Bernards

  • Comment |

    Over the past decade, many anticancer drugs have been approved for use only in combination regimens and only in palliative settings, despite having negligible single-agent activity in the same disease. We examine whether these agents provide any tangible clinical benefits and are worthy of continued development, or whether R&D efforts would be better focused elsewhere.

    • Bishal Gyawali
    •  & Vinay Prasad

  • Comment |

    The 69 National Cancer Institute-designated Cancer Centers are premier academic institutions that place significant value on research integrity and an ethic that rigorous evidence should guide patient care and define expectations. Recent patient-focused advertising has strayed from these values, obscuring valid reasons for seeking care at these centres.

    • David Rubenson
    •  & Daniel S. Kapp

  • Opinion |

    Clinical trial design has dramatically evolved with the advent of precision medicine. As a result, expedited drug-approval decisions have been made on the basis of evidence obtained in uncontrolled clinical trials. Herein, Saad et al. discuss the need to conduct randomized controlled trials at all phases of drug development in oncology, and present strategies to facilitate a seamless transition between phases of drug and/or biomarker development.

    • Everardo D. Saad
    • , Xavier Paoletti
    •  & Marc Buyse

  • Opinion |

    Assessment of tumour burden has become an integral part of most oncology clinical trials, and enables the evaluation of the activity and efficacy of new cancer therapeutics in solid tumours. Although RECIST was developed to assess treatment activity in early phase II trials with tumour response as the primary end point, it is now applied across the spectrum from early phase I trials through to confirmatory phase III trials. Several questions regarding the role of RECIST in the rapidly changing landscape of oncology therapeutics, and the challenges faced in its evaluation, are highlighted.

    • Saskia Litière
    • , Sandra Collette
    •  & Jan Bogaerts

  • Review Article |

    Immune-checkpoint inhibitors are revolutionizing the treatment of many types of solid cancer. Expression of the inhibitory immune-checkpoint proteins programmed cell-death 1 (PD-1) and its ligands (PD-L1 and PD-L2) are frequently detected in haematological malignancies, and agents targeting these proteins have activity in such diseases, notably Hodgkin lymphoma. Herein, the current evidence supporting the roles of PD-1–PD-L1 blockade in the treatment of various B-cell malignancies is reviewed.

    • Aaron Goodman
    • , Sandip P. Patel
    •  & Razelle Kurzrock

  • Review Article |

    Intrinsic pathophysiological barriers limit the delivery of drugs to pancreatic cancers, contributing to the limited effectiveness of treatment. Nanomedicine approaches have the potential to overcome many of these drug-delivery challenges, and two nanoparticle therapies are now approved for the treatment of this disease. The authors discuss the key pathobiological barriers that must be overcome, the approaches to nanomedicine that have been pursued to date, and those that are the focus of ongoing research.

    • Pavan P. Adiseshaiah
    • , Rachael M. Crist
    •  & Scott E. McNeil

  • News & Views |

    In a recent study, the addition of olaratumab to doxorubicin chemotherapy for patients with soft-tissue sarcoma resulted in prolongation of progression-free survival by only 2.5 months, but an overall survival benefit of 11.8 months; the large disparity between these outcomes raises important questions. We discuss these results in relation to those of other trials, and the implications for sarcoma therapy.

    • Ian Judson
    •  & Winette T. van der Graaf

  • News & Views |

    Escalating costs of cancer treatments are threatening access to high-quality care. This economic trend comes at a time of unprecedented opportunity for translational research, but an alarmingly low level of patient participation in clinical trials. Patients' concerns about costs are a barrier to trial enrolment, and addressing these concerns is a moral and practical imperative if we are to accelerate progress against cancer.

    • Neal J. Meropol

  • Review Article |

    Metabolic reprogramming to support tumour growth is a near universal characteristic of cancer, and thus targeting cancer metabolism has been, and continues to be, a focus for drug-development efforts. In this Review, the authors describe the various metabolic alterations and vulnerabilities of tumours that are potentially important targets for anticancer agents, highlighting both the challenges and opportunities.

    • Ubaldo E. Martinez-Outschoorn
    • , Maria Peiris-Pagés
    •  & Michael P. Lisanti

  • Review Article |

    Advances in our understanding of thyroid cancer biology have led to the regulatory approval of a number of molecularly targeted therapies for advanced-stage disease. Herein, the authors summarize the progress made to date in molecular medicine for the different histotypes of thyroid cancer, and highlight the questions for future research focused on treatment of the various disease subtypes.

    • Keith C. Bible
    •  & Mabel Ryder

  • News & Views |

    The recent FDA approval of MM-398 as a second-line treatment of metastatic pancreatic cancer, based on a 1.9-month overall survival benefit observed in the NAPOLI-1 trial, adds a new therapeutic option for this notoriously difficult-to-treat disease; however, by discouraging clinical trial enrolment, this approval might have negative consequences for the development of novel agents, which remain an essential unmet need.

    • Susan E. Bates
    •  & Tito Fojo

  • News & Views |

    Henderson and colleagues previously highlighted the need for more-rigorous standards of preclinical experimental design and reporting metrics. They now build on their earlier work with a meta-analysis of preclinical experiments that examined the efficacy of sunitinib. Their results demonstrate how suboptimal preclinical study designs can prompt unwarranted clinical expectations.

    • Eric E. Gardner
    •  & Charles M. Rudin

  • Review Article |

    As the numbers of available anticancer drugs and thus possible drug combinations continues to grow, determining the optimal toxicity–efficacy balance of treatment regimens becomes increasingly complex, and the utility of standard empirical approaches to optimizing drug dosing and scheduling is becoming increasingly limited. Mathematical modelling can substantially advance the development of effective treatment regimens through improved rationalization of therapeutic strategies. In this Review, the authors highlight the achievements that have been made to date in computational modelling of drug regimens, as well as the limitations of this approach. They also discuss the potential future implementation of this strategy to achieve precision medicine in oncology.

    • Dominique Barbolosi
    • , Joseph Ciccolini
    •  & Nicolas André

  • News & Views |

    Pancreatic cancer remains a difficult-to-treat malignancy, yet nab-paclitaxel plus gemcitabine prolongs survival. Closer examination of the mechanism of action of nab-paclitaxel hints at a role for targeting KRAS. We discuss how nab-paclitaxel may be active in pancreatic cancer and how this informs the way forward to better treat patients with pancreatic cancer.

    • Agnes Basseville
    • , Susan Bates
    •  & Tito Fojo

  • Review Article |

    Cancer stem cell (CSC) populations are increasingly recognized in most malignancies and are hypothesized to contribute to cancer proliferation, relapse, and metastasis. Thus, the highly conserved stem-cell signal transduction pathways involved in development and tissue homeostasis that are frequently active in CSCs represent prime targets for targeted therapies against this characteristically treatment-resistant and highly tumorigenic cell population. This Review provides a update on the clinical development of therapies targeting Wnt, Notch, and Hedgehog, three prominent stem-cell signalling pathways that are upregulated in CSCs.

    • Naoko Takebe
    • , Lucio Miele
    •  & S. Percy Ivy

  • Review Article |

    The survival rates of patients with pancreatic cancer are low and have not improved significantly over the past three or four decades. Thus, effective treatments for this disease are an urgent unmet need. Novel treatment paradigms will probably be required, and many new therapeutic approaches are being tested in this setting. This Review outlines the state-of-the-art therapies for patients with pancreatic cancer, as well as the novel treatment strategies that are the focus of drug-development efforts.

    • Ignacio Garrido-Laguna
    •  & Manuel Hidalgo

  • Review Article |

    The landscape of translational oncology has shifted dramatically over the past 10 years, characterized by the introduction of more-sophisticated molecular tools into the clinic and advances are being employed in genomic clinical trials that will examine the feasibility of matching a broad range of systemic therapies to specific molecular tumour characteristics. The authors review selected developments in translational cancer biology, diagnostics, and therapeutics that have occurred over the past decade and offer our thoughts on future prospects for the next few years.

    • James H. Doroshow
    •  & Shivaani Kummar

  • Viewpoint |

    In this Viewpoint, four of our Advisory Board members discuss the key challenges in clinical cancer research that need to be overcome to achieve tangible progress in the next decade. The issues and challenges include clinical development and testing of multiple agents in combination, design of clinical trials, tumour heterogeneity, drug development and trial design, and funding for cancer research. What have we learnt over the past 10 years and how should we progress in the next decade?

    • Vincent T. DeVita Jr
    • , Alexander M. M. Eggermont
    •  & David J. Kerr

  • News & Views |

    Cytotoxic agents are conventionally dosed on the basis of the maximum tolerated dose defined in phase I trials. A study assessing adverse events in over 2,000 patients treated with molecularly targeted agents suggests a need to redefine criteria for dosing of molecularly targeted agents, which should be based on randomized, dose-ranging phase II trials.

    • Mark J. Ratain

  • News & Views |

    Hepatocellular carcinoma is a difficult-to-treat cancer and, after numerous phase III trials assessing kinase inhibitors have failed to meet their end points, sorafenib is the only accepted treatment for advanced stages of the disease. Now, the trial EVOLVE-1 has shown a lack of benefit for everolimus in the second-line treatment setting.

    • Josep M. Llovet

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