Drug development articles within Nature Reviews Clinical Oncology

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  • 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

  • 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 |

    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

  • 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

  • Comment |

    In 2023, a decade after granting Accelerated Approval to the first-in-class BTK inhibitor ibrutinib for the treatment of mantle cell lymphoma, the FDA requested this indication be withdrawn. Herein, we discuss the seemingly inconsistent results from the SHINE and TRIANGLE trials, which relate to the distinct patient populations of these trials, and posit that regulatory approaches should take these nuances into account.

    • Edward R. Scheffer Cliff
    • , Talal Hilal
    •  & Aaron S. Kesselheim

  • Review Article |

    The TAM (TYRO3, AXL and MERTK) family receptor tyrosine kinases (RTKs) have diverse cancer-promoting functions in malignant cells as well as immune cells and other cell types in the tumour microenvironment, presenting an attractive opportunity for both direct and immune-mediated therapeutic activity manifest through inhibition of a single target. Accordingly, a variety of agents designed to selectively target TAM RTKs are entering clinical testing. This Review provides an essential guide to the TAM RTKs for clinicians. The authors comprehensively review the various roles of TAM RTKs in cancer, the evidence supporting their potential as therapeutic targets, and the translational development of TAM-targeted agents as cancer treatments.

    • Deborah DeRyckere
    • , Justus M. Huelse
    •  & Douglas K. Graham

  • Review Article |

    Despite improved outcomes owing to advances in systemic targeted therapies, patients with brain metastases from oncogene-driven non-small-cell lung cancer continue to have a poor prognosis. This situation largely reflects the limited central nervous system (CNS) penetrance of most targeted therapies, a limitation that is beginning to be addressed with the development of later-generation agents. In this Review, the authors describe the CNS activity of targeted therapies for patients with oncogene-driven non-small-cell lung cancers, including discussions of novel agents with improved CNS penetrance and the potential of intrathecal administration for patients with leptomeningeal disease.

    • Kelsey Pan
    • , Kyle Concannon
    •  & Xiuning Le

  • Review Article |

    In oncology, mRNA–lipid nanoparticles (LNPs) have been used either to achieve intratumoural expression of immune-stimulating cytokine combinations or as cancer vaccines, and new strategies are in development to enable the selective delivery of payloads into cancer cells previously considered unreachable. The authors of this Review present various approaches for delivering mRNA–LNPs to tumours and discuss improvements that will improve the selective targeting of cancer cells with mRNA–LNPs.

    • Edo Kon
    • , Nitay Ad-El
    •  & Dan Peer

  • News & Views |

    A recent report from the ATLAS trial comparing different maintenance strategies following haematopoeitic stem cell transplantation for multiple myeloma provides an opportunity to explore various themes of critical appraisal, including end points, the equipoise of trial design, and the part censoring can play in the validity of results.

    • Ghulam Rehman Mohyuddin
    •  & Tomer Meirson

  • Review Article |

    Advances in technology have enabled the development of several novel antibody–drug conjugates (ADCs) with encouraging clinical activity in patients with advanced-stage solid tumours. Indications for these therapies are expanding rapidly to earlier lines of therapy. Nonetheless, the toxicities of these various agents are not trivial and can be fatal, even in patients with early stage disease. In this Review, the authors summarize the toxicities of ADCs in patients with solid tumours both as monotherapies and in combination with other agents and discuss various ongoing research efforts attempting to optimize the therapeutic index of these agents.

    • Paolo Tarantino
    • , Biagio Ricciuti
    •  & Sara M. Tolaney

  • Comment |

    The FDA Accelerated Approval pathway, which has been pivotal in enabling early access to new oncology drugs over the past three decades, has recently come under increased scrutiny. New draft guidance published in March 2023 offers several possible solutions to improve this pathway, with the ultimate goal of improving outcomes for patients with cancer, but might also have important limitations.

    • David J. Benjamin
    •  & Mark P. Lythgoe

  • Comment |

    Recent FDA reviews of cemiplimab and sintilimab combined with chemotherapy for patients with advanced-stage non-small-cell lung cancer reached discordant outcomes, as cemiplimab was approved and sintilimab was rejected. The applications share many serious faults, including neither serving an unmet need nor enrolling any patients from the USA. We argue that the FDA criteria should be more transparent and consistent; moreover, the historical policy of the FDA to abstain from consideration of the cost of a drug perpetuates a crisis in oncology care and should be re-examined.

    • Aakash Desai
    • , Caleb J. Smith
    •  & Howard Jack West

  • Comment |

    In 2022, the FDA approved numerous new drug and biologic agents, including targeted small molecules, immunotherapeutics, a gene therapy and a radiopharmaceutical. Several drug development challenges were also addressed, and key focus areas for the FDA Oncology Center of Excellence included ongoing monitoring of the Accelerated Approval programme and drug dose optimization.

    • Deepti Telaraja
    • , Nicole Gormley
    •  & Richard Pazdur

  • Review Article |

    Protein degraders constitute a new class of agents that eliminate, rather than just inhibit, their target proteins. These novel agents have recently entered testing in oncology trials, with initial data providing clinical proof of concept for the mechanism of action as well as the antitumour activity of heterobifunctional protein degraders. In this Review, the authors outline the progress in the development of such protein degraders for the treatment of cancer and consider prospects and potential challenges for these agents.

    • Deborah Chirnomas
    • , Keith R. Hornberger
    •  & Craig M. Crews

  • Comment |

    The development of modern immune-based therapies for multiple myeloma has expanded rapidly over the past several years, and GPRC5D has been identified as a viable immunotherapeutic target. Herein, we discuss data and provide future perspectives on GPRC5D-directed CAR T cells and bispecific antibodies for patients with relapsed and/or refractory multiple myeloma.

    • Karthik Nath
    • , Bruno A. Costa
    •  & Sham Mailankody

  • Comment |

    Around 100 new cancer drugs, defined as new molecular entities, were approved in China between 2005 and 2021. More than half of these new cancer drugs do not constitute innovations in mechanism of action or therapy and do not have documented meaningful clinical benefit. Approaches are needed to promote meaningful innovation for patients with cancer.

    • Yichen Zhang
    • , Anita K. Wagner
    •  & Xiaodong Guan

  • Review Article |

    Oncolytic viruses (OVs) provide a novel cancer treatment strategy, with a mechanism of action and toxicity profiles that are distinctly different to those of more traditional therapies. Thus far, four OVs have entered clinical use globally, yet only talimogene laherparepvec (T-VEC) has entered widespread clinical use. In this Review, the authors describe the clinical and regulatory experience with T-VEC thus far, and how this can guide the development of novel OVs. Discussions of a range of novel OVs with the potential for clinical implementation in the near future are also provided.

    • Sophia Z. Shalhout
    • , David M. Miller
    •  & Howard L. Kaufman

  • Review Article |

    Immunotherapies have dramatically improved the outcomes of a subset of patients with advanced-stage cancers. Nonetheless, most patients will not respond to these agents and adverse events can be severe. In this Review, the authors describe the potential to address these challenges by combining immunotherapies with currently available thermal therapies as well as by using thermal immuno-nanomedicines.

    • Zhe Yang
    • , Di Gao
    •  & Xingcai Zhang

  • Review Article |

    Chimeric antigen receptor (CAR) T cells are effective therapies for patients with relapsed and/or refractory B cell malignancies, partly owing to the ability to target B cell-specific antigens. However, CAR T cells targeting solid tumour antigens are likely to carry a higher risk of on-target, off-tumour toxicity (OTOT). Here, the authors summarize the available data on OTOT in the context of CAR T cells targeting solid tumour antigens and describe novel CAR T cell designs that might overcome such toxicities.

    • Christian L. Flugel
    • , Robbie G. Majzner
    •  & Mohamed Abou-el-Enein

  • Review Article |

    Owing to several limitations, including elimination by the immune system and a lack of tumour specificity, systemically administered synthetic nanoparticles are used for a limited range of cancer indications. In this Review, the authors describe the potential of cellular nanoparticles (comprising a cell membrane coating around a synthetic core) to overcome these issues as well as their application in drug delivery, phototherapy and immunotherapy.

    • Ronnie H. Fang
    • , Weiwei Gao
    •  & Liangfang Zhang

  • Review Article |

    Systemic therapies for early-stage disease have been tested in clinical trials for decades. The authors of this Review provide an overview of the evolution of (neo)adjuvant trials from the pre-genomic to the post-genomic era, focusing on design, end points and biomarkers that, together, could enable the delivery of more personalized treatment.

    • Elisa Agostinetto
    • , Joseph Gligorov
    •  & Martine Piccart

  • Perspective |

    Glioblastoma, the most common form of brain cancer in adults, has a dismal prognosis and has proven recalcitrant to novel targeted therapies and immunotherapies. Extrachromosomal DNAs (ecDNAs) harbouring oncogenes are increasingly recognized as important drivers of tumour development, evolution and resistance to treatment, particularly in patients with glioblastoma. In this Perspective, the authors summarize key reasons for the failed clinical translation of new therapies for glioblastoma, highlighting the important contributions of ecDNAs. They then focus on the opportunities and challenges of utilizing ecDNAs to improve the likelihood of success in the development of precision medicines for this disease.

    • Imran Noorani
    • , Paul S. Mischel
    •  & Charles Swanton

  • News & Views |

    The development of covalent, allele-specific inhibitors of KRASG12C represents a major breakthrough in precision oncology. Herein we discuss recent data from the phase II KRYSTAL-1 trial of adagrasib in KRASG12C-mutated non-small-cell lung cancer (NSCLC). This trial showed responses in a subset of patients, including among those with brain metastases, and offers exploratory insights into potential biomarkers of response.

    • Yonina R. Murciano-Goroff
    •  & Piro Lito

  • Comment |

    Median overall survival for patients with newly diagnosed multiple myeloma may surpass ten years. Nonetheless, many patients face considerable treatment-related morbidity and relapsed disease. Owing to this typically long overall survival, most multiple myeloma trials now use progression-free survival as their primary end point. In this Comment, we highlight circumstances in which this end point does not best answer the questions that various trials seek to investigate.

    • Edward R. Scheffer Cliff
    •  & Ghulam Rehman Mohyuddin

  • Review Article |

    Radiotheranostics enables the clinician to image and then target lesions using the same probe. Despite this appealing potential, interest in the field of radiotheranostics has long been constrained by a lack of expertise, high infrastructure costs and the availability of non-radioactive alternative approaches. Nonetheless, several recent successes have led to renewed research interest. In this Review, the authors summarize the current challenges and opportunities in this rapidly emerging area.

    • Lisa Bodei
    • , Ken Herrmann
    •  & Jason S. Lewis

  • Comment |

    Timely and comprehensive updating of treatment guidelines remains a challenge and necessity in medical oncology. Herein we discuss our assessment of how trial results with four off-patent drugs have been considered for integration into major guidelines in the absence of a commercial sponsor, in which we found reasons for concern.

    • Gauthier Bouche
    •  & Lydie Meheus

  • News & Views |

    Immune-checkpoint inhibitors have revolutionized the treatment of patients with non-small-cell lung cancer (NSCLC). Recently, indications for immune-checkpoint inhibitors have expanded from advanced-stage NSCLC to adjuvant, and now neoadjuvant, therapy for resectable NSCLC, with three cycles of preoperative chemoimmunotherapy achieving superior pathological complete response rates and event-free survival compared with chemotherapy alone in the phase III CheckMate 816 trial.

    • Boris Sepesi
    •  & Stephen G. Swisher

  • Perspective |

    In this Perspective, Nathan Cherny appraises the FDA approvals of therapeutic agents granted for use in adult patients with solid tumours during the 5 years 2017–2021 against the aspirations of the Cancer Moonshot, in terms of sheer number of approvals, the strength of the supporting evidence and the magnitude of clinical benefit. He also outlines areas where improvements are needed to more confidently ensure that the clinical benefits of approved treatments justify the associated risks.

    • Nathan I. Cherny

  • Review Article |

    Antibodies targeting PD-1 or its ligand PD-L1 have revolutionized cancer therapy. Increased understanding of the mechanisms regulating PD-L1 has revealed links with several important oncogenic signalling pathways. Herein, the authors review the transcriptional, post-transcriptional and translational regulation of PD-L1 expression in cancers as well as the diverse post-translational modifications, including phosphorylation, palmitoylation, glycosylation, acetylation and ubiquitination, that affect PD-L1 stability and activity. They also discuss the possibility to simultaneously target key oncogenic pathways and modulate PD-L1 expression using small-molecule agents, which have potential advantages over or might synergize with anti-PD-1/PD-L1 antibodies.

    • Hirohito Yamaguchi
    • , Jung-Mao Hsu
    •  & Mien-Chie Hung

  • 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

  • News & Views |

    Efforts are being made to incorporate immune-checkpoint inhibitors into therapy for early stage non-small-cell lung cancer. The IMpower010 trial of adjuvant atezolizumab has recently become the first study to demonstrate that this strategy can improve disease-free survival in a subset of patients. This trial opens a new area of research in the quest for the optimal perioperative strategy to increase overall survival.

    • Jordi Remon
    •  & Benjamin Besse

  • Review Article |

    Immune-checkpoint inhibitors have dramatically improved the outcomes in patients with advanced-stage cancers, although the majority of patients will not respond to these agents. Here, the authors describe the potential of targeting emerging immunomodulatory pathways, with a focus on alternative immune checkpoints and tumour metabolism as approaches that might enable further improvements in the outcomes of patients with cancer, either as monotherapies or in combination with existing agents.

    • Lukas Kraehenbuehl
    • , Chien-Huan Weng
    •  & Taha Merghoub

  • 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 |

    Cancer-associated fibroblasts (CAFs) are inherently linked with cancers and have long been considered attractive therapeutic targets. However, the existence of several CAF subpopulations with substantial phenotypic and functional heterogeneity and plasticity is increasingly recognized. This Review provides an overview of the heterogeneity of CAFs and its implications with regard to the tumour-promoting and tumour-restraining roles of these cells as well as their clinical relevance in terms of prognostic value and therapeutic potential. The authors also provide insights and perspectives on future research and clinical studies involving CAFs.

    • Yang Chen
    • , Kathleen M. McAndrews
    •  & Raghu Kalluri

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