Research Highlight |
Featured
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Research Highlight |
Activity of selpercatinib in RET fusion-positive cancers confirmed
- Diana Romero
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Review Article |
The current state of the art and future trends in RAS-targeted cancer therapies
The RAS oncogenes are among the most common drivers of tumour development and progression but have historically been considered undruggable. The development of direct KRAS inhibitors has changed this paradigm, although currently clinical use of these novel therapeutics is limited to a select subset of patients, and intrinsic or acquired resistance presents an inevitable challenge to cure. Herein, the authors provide an overview of the RAS pathway in cancer and review the ongoing efforts to develop effective therapeutic strategies for RAS-mutant cancers. They also discuss the current understanding of mechanisms of resistance to direct KRAS inhibitors and strategies by which they might be overcome.
- Salman R. Punekar
- , Vamsidhar Velcheti
- & Kwok-Kin Wong
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News & Views |
The KRYSTAL-1 study of adagrasib — a new trial for KRASG12C-mutated non-small-cell lung cancer
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
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News & Views |
When an embarrassment of riches isn’t enough
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
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Review Article |
Radiotheranostics in oncology: current challenges and emerging opportunities
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
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Review Article |
Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management
Patients with non-small-cell lung cancers (NSCLCs) harbouring oncogenic EGFR or ALK alterations can benefit from therapies targeting these alterations, although acquired resistance to these agents is common. Third-generation inhibitors have extended the response durations of many patients with NSCLCs harbouring these alterations, albeit with differing patterns of resistance to those associated with earlier-generation agents. Here, the authors describe the mechanisms of acquired resistance to third-generation EGFR and ALK inhibitors and provide insights into future research directions in this area.
- Alissa J. Cooper
- , Lecia V. Sequist
- & Jessica J. Lin
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Review Article |
At a crossroads: how to translate the roles of PI3K in oncogenic and metabolic signalling into improvements in cancer therapy
Several PI3K pathway inhibitors are currently approved as cancer treatments; however, finding an acceptable therapeutic window to target this key signalling cascade linking cancer growth with metabolism has proven challenging and the clinical results to date have arguably been disappointing. In this Review, Vasan and Cantley discuss the effects of PI3K pathway alterations on signalling and metabolism in solid tumours as well as past and present efforts to improve the somewhat limited clinical efficacy of PI3K pathway inhibitors, with a particular focus on PI3Kα in breast cancers.
- Neil Vasan
- & Lewis C. Cantley
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Review Article |
Preparing for CAR T cell therapy: patient selection, bridging therapies and lymphodepletion
Chimeric antigen receptor T cells have revolutionized the treatment of patients with certain haematological malignancies. Nonetheless, an optimal approach to lymphodepleting chemotherapy and/or bridging therapies has yet to be defined in patients receiving these agents. In this Review, the authors describe the various lymphodepletion and/or bridging therapy strategies used, and highlight the need for prospective comparisons in order to determine the safest and most effective approach.
- Leila Amini
- , Sara K. Silbert
- & Mohamed Abou-el-Enein
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Research Highlight |
Amivantamab is effective in NSCLC harbouring EGFR exon 20 insertions
- Diana Romero
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News & Views |
Whole-genome sequencing for myeloid disease: one assay to stratify them all?
Whole-genome sequencing of samples from patients with myeloid malignancies can enable more accurate risk stratification than is possible with conventional cytogenetics. Research by Duncavage et al. demonstrates that such an approach can now be delivered within several days using a highly streamlined and automated workflow.
- Karilyn T. M. Larkin
- & John C. Byrd
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Review Article |
Towards precision medicine for AML
Advances in sequencing technology have rapidly improved our understanding of the biology of acute myeloid leukaemia and led to the development of several novel targeted therapies. In this Review, the authors summarize the landscape of novel targeted therapies for patients with acute myeloid leukaemia and provide guidance on future research directions.
- Hartmut Döhner
- , Andrew H. Wei
- & Bob Löwenberg
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Review Article |
Evolution of systemic therapy for stages I–III non-metastatic non-small-cell lung cancer
The authors of this Review present the current considerations in the treatment of patients with early-stage lung cancer, discussing the critical determination of resectability by thoracic surgical oncologists and the management of both resectable and unresectable disease with a focus on systemic therapy selection. They also address innovations in drug development, trial design and efforts to identify early-stage cancers.
- Jamie E. Chaft
- , Andreas Rimner
- & Tina Cascone
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Review Article |
Precision oncology in metastatic colorectal cancer — from biology to medicine
Progress in precision medicine for colorectal cancer continues to lag behind the rapid improvements seen in patients with certain other solid tumour types. Nonetheless, owing largely to the availability of better translational models, novel and effective targeted therapy strategies based on tumour biology are beginning to be developed for subsets of patients. In this Review, the authors summarize these developments and discuss future directions in this rapidly evolving area of research.
- Federica Di Nicolantonio
- , Pietro Paolo Vitiello
- & Alberto Bardelli
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Comment |
Registration trials in countries without access to US standards of care — pitfalls of interpretation
Data from several trials support the efficacy of first-line tyrosine-kinase inhibitors combined with immune-checkpoint inhibitors (ICIs) in metastatic renal cell carcinoma. However, whether combining these drugs is preferable to using them sequentially remains unclear. Here, we assess the implications for patients and payers of limited access to second-line ICIs in the control arms of trials.
- Garth W. Strohbehn
- & Daniel A. Goldstein
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Review Article |
Biomarker-targeted therapies for advanced-stage gastric and gastro-oesophageal junction cancers: an emerging paradigm
Despite considerable progress in the development of targeted therapies, only three biomarkers are currently used to guide the treatment of patients with gastric or gastro-oesophageal junction cancers using approved targeted therapies. Nonetheless, owing to advances in our understanding of tumour biology and sequencing technologies, several novel therapies are expected to soon become available. In this Review, the authors describe current and future biomarker-guided therapies for patients with G/GEJ cancers.
- Yoshiaki Nakamura
- , Akihito Kawazoe
- & Kohei Shitara
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Review Article |
The clinical development of antibody–drug conjugates — lessons from leukaemia
Antibody–drug conjugates (ADCs) were originally developed for patients with haematological malignancies. In light of the recent increase in interest in this type of therapy, this Review describes the clinical experience with two ADCs — gemtuzumab ozogamicin and inotuzumab ozogamicin — in patients with haematological malignancies and provides guidance on the future directions for the development of novel ADCs for patients with leukaemias.
- Elias Jabbour
- , Shilpa Paul
- & Hagop Kantarjian
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Review Article |
Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide
The discovery that the anticancer activity of thalidomide and its analogues, such as lenalidomide, reflects drug-induced degradation of specific target proteins has heightened interest in novel ‘degrader’ drugs. Herein, the authors review the wide and expanding use of thalidomide analogues in the treatment of multiple cancers and outline how lessons learned from this experience, particularly with lenalidomide, can guide the clinical development of new targeted protein degradation platforms.
- Max Jan
- , Adam S. Sperling
- & Benjamin L. Ebert