Reviews & Analysis

PRO-TECT is a randomized trial that innovatively integrated financial toxicity screening into a pre-existing digital symptom-monitoring programme, enabling longitudinal detection of financial toxicity. Such a strategy provides an unobtrusive and cost-effective method for early detection and mitigation of financial toxicity by aligning the needs of patients and carers with the resources available in community clinical practices.

According to the precision oncology paradigm, cancer therapies are increasingly being matched to specific sensitizing alterations using a biomarker-directed approach. However, the criteria for determining the actionability of molecular alterations and selecting matched treatments evolve over time. Molecular tumour boards (MTBs) have emerged as means to capitalize on the collective knowledge of various experts to interpret molecular-profiling data and to eliminate subjectivity in treatment selection. This Review describes the components, processes and increasingly important role of MTBs in optimizing the implementation of precision oncology in both clinical trials and clinical practice, as well as current and future considerations for ensuring the sustainability of MTBs and expanding their outreach to underserved populations.

The use of composite end points in clinical trials can expedite drug development and approval, and thus improve patient access to novel treatments, but are often vaguely and heterogeneously defined, with considerable inter-study variation in the component events that are included. The different component events can vary in clinical significance and be differentially affected by treatment but, nevertheless, are rarely reported separately. In this Perspective, Walia et al. define composite outcomes that are commonly used in oncology, discuss the advantages and challenges of using composite end points, and advocate for transparent reporting including a full breakdown of the component events to facilitate accurate interpretation of trial results and the true benefit of an intervention.

Epstein–Barr virus (EBV)-based biomarkers are used for nasopharyngeal carcinoma (NPC) screening in endemic regions. A recent prospective study describes the use of a new serological biomarker, antibodies targeting the EBV protein BNLF2b, for NPC screening in >20,000 participants. This biomarker yielded both higher sensitivity and specificity for NPC detection in the screening cohort compared with the conventionally used antibodies. Herein, we highlight the key findings of this study and discuss the implications of these results.

Ovarian carcinoma is a highly heterogeneous tumour type, both spatially and temporally. As a consequence, these carcinomas are often associated with poor outcomes. Ovarian carcinoma comprises various subtypes with distinct complex molecular features. The authors of this Review discuss the molecular, cellular and anatomical heterogeneity of ovarian carcinoma, and outline the current and future treatment strategies for this malignancy.

Despite improved effectiveness, most systemic cancer therapies are not curative and most patients will develop acquired resistance that often cannot be explained by the emergence of specific genomic alterations. In this Perspective, the authors describe the potential role of a small population of tumour cells, termed drug-tolerant persister cells, that are able to survive therapy and, on continued treatment exposure, develop stable mechanisms of resistance to systemic therapies.

The availability of regimens containing one or more immune-checkpoint inhibitors (ICIs) has improved the outcomes in patients with advanced-stage hepatocellular carcinoma. However, clinical benefit from these regimens is difficult to predict, indicating the need for novel biomarkers. In this Review, the authors describe the available evidence on biomarkers to guide the use of ICIs in these patients and discuss promising future research directions.

Following the recent FDA Accelerated Approval of enfortumab vedotin (EV) plus pembrolizumab for patients with advanced-stage urothelial carcinoma who are cisplatin-ineligible, herein we highlight key clinical outcomes with this combination based on results from Cohort K of the pivotal phase Ib/II EV-103 trial. We also discuss treatment sequencing, de-escalation strategies and toxicity management as EV–pembrolizumab becomes widely used in clinical practice.

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.

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.

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.

Advances over the past decade have established a prominent role of the gut microbiota in the modulation of immune homeostasis and function, including in patients with cancer receiving immune-checkpoint inhibitors. In this Review, the authors summarize current knowledge of the role of the microbiota in this context, describe several methods of modulating the microbiota clinically to improve patient outcomes, and highlight important future directions in this expanding area of research.

Several trials are testing immune-checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, in patients with resectable non-small-cell lung cancer as an adjuvant, neoadjuvant or perioperative approach. However, the optimal use of ICIs with curative intent in patients with early stage non-small-cell lung cancer remains unclear. The authors of this Review discuss the current trial landscape and discuss challenges and opportunities.

Advances in the treatment of childhood cancers have substantially improved cure rates, although the gains in survival are offset by an elevated burden of morbidities and an excess risk of early death owing predominantly to the adverse effects of therapy. In this Review, the authors summarize the evolution of paediatric cancer therapies over the past five decades as well as the associated landscape of treatment-related late and/or long-term health conditions experienced by childhood cancer survivors. In addition, they discuss strategies that are being explored to reduce the overall burden and consequences of these morbidities with the ultimate aim of improving not only the quantity but also the quality of life-years gained for this large, medically vulnerable population.

Lung cancer is the commonest cancer globally. Reflecting patterns of smoking and other risk factor exposures, both the incidence of and mortality from lung cancer are highest in economically developed countries. Nonetheless, developing and less economically developed countries are likely to have the biggest increases in lung cancer in the coming years. In this Review, the authors describe the global epidemiology of lung cancer, and how changes in exposures, socioeconomic status, public health interventions and better treatment strategies are influencing both the incidence of and mortality from lung cancer.

Hotspot point mutations in IDH1 occur in the vast majority of adult grade 2–3 gliomas. The understanding of their role in tumour biology continues to evolve. Therapeutic targeting of mutant IDH1 with vorasidenib demonstrated highly encouraging efficacy and minimal toxicity in a recent, randomized phase III trial involving patients with low-grade gliomas.

Despite advances in drug development for patients with lymphoma over the past decades, the identification of biomarkers for treatment selection remains an unmet need. The authors of this Review provide an overview of quantitative PET-based biomarkers in this patient population and discuss the challenges and opportunities in the integration of these biomarkers in clinical trials and the routine management of patients with lymphoma.

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.

Planning for a pregnancy in patients receiving adjuvant endocrine therapy following a diagnosis of hormone receptor (HR)-positive early stage breast cancer is challenging. Recent data from the POSITIVE trial provide reassuring prospective evidence that a temporary interruption of endocrine therapy for women with HR-positive breast cancer who are trying to conceive can be considered safe in the short term for selected patients.

Many studies attempting to identify biomarkers for predicting of immune-checkpoint inhibitor (ICI) efficacy have led to the description of Gut OncoMicrobiome Signatures (GOMS). Several GOMS support an association between oncogenesis and intestinal dysbiosis, and other GOMS are shared between patients with several cancer subtypes and individuals with seemingly unrelated chronic inflammatory disorders. The authors of this Review discuss these patterns as well as the findings from a meta-analysis of GOMS associated with clinical benefit from ICIs, and propose practical guidelines to incorporate GOMS in decision-making in immuno-oncology.