Articles in 2024

Neoadjuvant administration of immune-checkpoint inhibitors (ICIs) has substantially improved the outcomes in patients with various solid tumours, including those with head and neck cancer. However, not all patients derive benefit, indicating a need for biomarkers that enable accurate predictions of a response to these agents. In this Review the authors describe changes in both intratumour and circulating T cells in patients with locally advanced head and neck cancer receiving neoadjuvant ICIs, and consider the role of specific T cell subsets as biomarkers in this setting.

Leptomeningeal metastatic disease (LMD) arises secondary to the metastatic dissemination of cancer cells into the leptomeninges and cerebrospinal fluid. Novel therapies against systemic disease have not yet translated into improved outcomes for patients with LMD, in whom median survival after diagnosis remains at 2–6 months. The authors of this Review, a multidisciplinary group of experts, describe the emerging evidence and areas of active investigation in LMD and provide directed recommendations for future research.

As one of the first studies testing perioperative anti-PD-(L)1 antibodies in resectable non-small-cell lung cancer (NSCLC), NADIM now confirms, in its final report, impressive 5-year clinical outcomes and that a pCR following neoadjuvant therapy translates into improved long-term survival. These data support the development of novel, personalized treatments for locally advanced resectable NSCLC.

The experience with PARP inhibitors provides evidence of the clinical utility of synthetic lethality, whereby the simultaneous presence of two specific alterations is required for antitumour activity. In this Review, the authors describe attempts to identify novel synthetic lethal interactions, including the role of emerging technologies in identifying new synthetic lethal relationships as well as novel agents that are currently being tested in clinical trials that might extend the clinical relevance of synthetic lethality beyond PARP inhibitors.

Increased recognition of the roles of epigenetic reprogramming in cancer has spurred the development of epigenetic therapies, although these drugs have meaningful efficacy as single agents in only a narrow range of malignancies. In this Review, the authors discuss advances and pitfalls in the use of epigenetic drugs combined with chemotherapies, immunotherapies or other targeted agents, including epigenetic–epigenetic combinations.

Third-generation EGFR tyrosine-kinase inhibitors (TKIs) are the standard-of-care first-line treatment for patients with advanced-stage EGFR-mutant NSCLC and their efficacy is being investigated in early stage and locally advanced disease. The authors of this Review describe the current first-line treatment options for EGFR-mutant NSCLC, discuss mechanisms of acquired resistance to third-generation EGFR TKIs and new promising treatment strategies, such as bispecific antibodies, next-generation TKIs, antibody–drug conjugates, immunotherapy approaches and targeted protein degraders.

Liquid biopsy, or the analysis of tumour-derived or tumour-induced cells or cellular products in the blood or other body fluids, is a promising approach to assess minimal residual disease (MRD; also known as measurable or molecular residual disease). The authors of this Review discuss the available evidence on the use of circulating tumour DNA to detect and monitor MRD in patients with solid tumours to enable treatment decisions before terminal metastatic disease is evident on imaging.

Over the past few years, several novel therapies, including targeted therapies for specific subgroups as well as several non-targeted therapies, have been developed and approved for patients with chemorefractory metastatic colorectal cancer (CRC). Nonetheless, selecting patients who are most likely to benefit from one specific therapy is challenging owing to a lack of direct comparisons of the efficacy of these agents in specific settings. In this Review, the authors summarize the available evidence on the efficacy and safety of later-line therapies for patients with advanced-stage CRC and suggest an evidence-based treatment-selection algorithm.

Several chimeric antigen receptor (CAR) T cell therapies are approved for the treatment of various haematological cancers; however, they are all autologous products requiring individualized manufacturing for each patient, which presents technical, logistical and resource challenges that limits scalability and implementation, and even raises certain ethical questions. Allogeneic products have the potential to address many of these issues, but come with their own challenges. This Review summarizes the advantages and disadvantages of allogeneic CAR cell products derived from T cells or other immune cells, their engineering and progress towards clinical implementation, as well as hurdles that remain to be overcome.

The DESTINY-Breast06 trial investigated earlier and broader use of trastuzumab deruxtecan in patients with metastatic hormone-receptor-positive breast cancer, and demonstrated improvements in progression-free survival over standard chemotherapy. These data provide a meaningful advance; however, this strategy might not be right for all patients, and careful consideration is recommended before blanket use.

A number of therapeutics that target mediators of signalling in the hypothalamic and brainstem regions that control appetite, ingestive behaviour, satiety, nausea and vomiting are starting to move the needle on cancer cachexia. However, clarification of meaningful clinical benefits for patients and the primary end points that should support regulatory approval of cachexia treatments is needed.

In several B cell malignancies, BTK is a crucial mediator of oncogenic signalling pathways and inhibitors of this kinase have substantially improved patient outcomes. This Review discusses the currently approved indications for covalent and non-covalent BTK inhibitors, as well as mechanisms of resistance, and novel BTK-targeted agents and treatment strategies that have the potential to further improve outcomes.