Chimeric antigen receptor (CAR) T cells have become standard-of-care therapies for patients with certain relapsed and/or refractory haematological malignancies over the past decade. However, this approach remains largely ineffective in patients with solid tumours, in part owing to limited CAR T cell persistence, the immunosuppressive tumour microenvironment of many solid tumours and limited trafficking of CAR T cells into tumours. Central nervous system (CNS) tumours, many of which are associated with a poor prognosis and require new treatment approaches, present additional challenges such as the presence of the blood-brain barrier as well as concerns over treatment-related neurotoxicities. Despite these difficulties, clinical trials involving both adult and paediatric patients with primary CNS tumours have provided signals of efficacy. In this Review, we discuss completed, ongoing and anticipated trials testing CAR T cells in patients with CNS tumours. We also highlight the most promising preclinical developments that might lead to novel clinical approaches in this area.

Historically, systemic therapy for hormone-sensitive prostate cancer (HSPC) was predicated on androgen-deprivation therapy (ADT) alone. However, in the past decade, substantial improvements have been made by intensifying treatment based on a better understanding of the broad underlying biology of these cancers. The addition of androgen receptor pathway inhibitors (ARPIs), docetaxel and/or radiotherapy to ADT is of proven benefit in certain patient subgroups, whereas AKT inhibitors, radioligand therapies and poly ADP-ribose polymerase (PARP) inhibitors are being evaluated in patients with metastatic HSPC. The clinical states of HSPC are determined by a history of localized prostate cancer versus presentation with de novo metastatic disease, as well as the extent of disease on conventional computed tomography imaging and whole-body bone scintigraphy. However, modern nuclear imaging modalities such as prostate-specific membrane antigen PET can visualize metastases below the limit of detection of computed tomography and whole-body bone scintigraphy; this earlier and more precise detection of metastases has identified new subgroups of patients for which certain treatment approaches, such as adding docetaxel to ADT plus an ARPI, might or might not apply. In this Review, we discuss the personalized management of both non-metastatic and metastatic HSPC, including how to select patients for docetaxel, choice of ARPI and use of radiotherapy to primary and metastatic disease sites. We also discuss emerging novel therapies and important principles of toxicity mitigation for HSPC.

Oesophageal adenocarcinoma (OAC) and its precursor condition, Barrett oesophagus, are characterized by phenotypic and molecular intertumoural and intratumoural heterogeneity. This heterogeneity arises in space and time through a complex and still poorly understood interplay between cancer-cell-intrinsic factors, the tumour microenvironment and external influences, such as exposure to anticancer therapies. Together, these elements contribute to a high degree of resistance to therapy while limiting the development of novel targeted therapies and the identification of predictive biomarkers. This situation is exacerbated both in Barrett oesophagus and OAC by a historical clinical reliance on biopsy samples that reflect disease status only at a single location and timepoint. A better understanding of heterogeneity is therefore vital to improve efforts to intercept the development of and optimize treatments for OAC. In this Review, we provide an overview of current and future directions of research on the heterogeneity of Barrett oesophagus and OAC, summarizing our knowledge of the factors that influence heterogeneity, and its consequences across the spectrum of these diseases.

Resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a major obstacle in the clinical management of EGFR-mutant non-small-cell lung cancer (NSCLC). Despite the transformative therapeutic activity of the multiple iterations of EGFR TKIs, spanning from first-generation reversible inhibitors such as erlotinib and gefitinib to the current standard-of-care third-generation covalent inhibitor osimertinib, primary or acquired resistance to these agents inevitably emerges via diverse mechanisms. The advent of combination therapies that incorporate chemotherapy, anti-angiogenic agents, bispecific antibodies or antibody-drug conjugates has increased clinical benefit but introduced new resistance phenotypes, underscoring the dynamic plasticity and complexity of tumour evolution under therapeutic pressure. In this Review, we provide a comprehensive synthesis of the molecular mechanisms that underlie resistance to third-generation EGFR TKIs, describe biomarker-guided and biomarker-unselected therapeutic strategies to overcome these mechanisms, and discuss emerging approaches to pre-empt resistance through early application of combination therapies. We highlight the paradigm shift from radiological to molecular monitoring of resistance to therapy and explore how advances in circulating tumour DNA analysis, artificial intelligence and multi-omics might facilitate adaptive treatment strategies. As the therapeutic landscape evolves, a more complete mechanistic understanding of resistance will be essential to guide rational treatment sequencing, inform trial design and improve long-term outcomes for patients with EGFR-mutant NSCLC.

Molecularly targeted agents and immune checkpoint inhibitors (ICIs) are transforming the treatment landscape for patients with advanced-stage urothelial carcinoma (aUC), although trials testing these novel agents have shown mixed results. In this context, the identification of biomarkers has seen limited success: while activating mutations in FGFR3 are now established as an actionable biomarker to guide treatment with FGFR inhibitors, PD-L1 expression has shown inconsistent value as a predictive biomarker of response to ICIs. The identification of prognostic and predictive biomarkers for ICIs, antibody-drug conjugates and targeted therapies is an active area of research; promising candidates include tumour mutational burden and HER2 overexpression. In the past few years, circulating tumour DNA has emerged as a minimally invasive biomarker, with increasing data supporting its prognostic value and utility for monitoring clinical responses. In this Review, we address these developments and discuss biomarkers that could have clinical utility in patients with aUC.