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Analysis of circulating tumour DNA (ctDNA) is commonly used for molecular profiling in patients with advanced-stage non-small-cell lung cancer (NSCLC). The authors of this Review summarize the available evidence on the potential utility of incorporating ctDNA in the management of those with early stage and locally advanced NSCLC and propose interventional studies to provide the necessary additional evidence.

Tumour-infiltrating lymphocytes (TILs) are crucial effectors of the anticancer immune response and are hypothesized to be key determinants the efficacy of immune-checkpoint inhibitors (ICIs). Herein, the authors review studies that have evaluated the roles of various TIL subsets as predictive biomarkers for ICIs, as well as opportunities, challenges and strategies for future research in this field.

Despite lower levels of most targetable alterations, a strong association with a history of smoking and generally higher levels of PD-L1 expression, patients with squamous non-small-cell lung cancer (LUSC) have inferior outcomes on immune-checkpoint inhibitors (ICIs) compared to those with non-squamous disease. In this Review, the authors describe the available evidence on the role of ICIs and of potential novel therapies in patients with LUSC, as well as highlighting important unresolved challenges and future research directions in this historically overlooked subtype.

In this Review, the authors discuss key clinical trials and therapeutic advances that have informed the current treatment landscape for cervical cancers of all stages, including refinement of surgical management approaches, the establishment of chemoradiotherapy, and the integration of anti-angiogenic agents, immune-checkpoint inhibitors and antibody–drug conjugates.

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.