Older adults (aged ≥65 years) comprise the majority of people diagnosed with cancer, yet they remain proportionally underrepresented in cancer research at every stage of the pathway. We call on funders, regulators, researchers and journals to make systematic inclusion of older adults the norm, across studies spanning from cancer prevention to end-of-life care.
The FDA recently approved daraxonrasib for patients with metastatic pancreatic adenocarcinoma who received at least one prior systemic therapy or who are not candidates for multiagent systemic therapy. Critics call the second clause non-evidence based. However, this imprecision enables access: trials generally enrol only patients with good performance status, which does not reflect the realities for most patients with metastatic pancreatic adenocarcinoma who never reach second-line therapy because their clinical condition deteriorates first. Real-world evidence should resolve any remaining uncertainty.
The availability of approved antibody–drug conjugates (ADCs) has rapidly expanded across oncology indications, yet biomarker development remains dominated by semi-quantitative immunohistochemistry. Robust biomarkers are needed to improve patient selection, guide therapeutic sequencing and identify resistance mechanisms that inform rational combinations. ADC activity depends on target antigen expression, linker chemistry and payload characteristics all within the context of the tumour microenvironment. Consequently, treatment response cannot be predicted solely by target expression. A more comprehensive biomarker framework is required that accounts for antigen abundance and accessibility, intracellular trafficking and linker cleavage, and tumour susceptibility to the payload. Furthermore, biomarkers of toxicity have been largely overlooked, even though toxicity can be equally determinant of clinical utility. In this Review, we outline a modular framework for ADC biomarker development organized around these components. We distinguish established evidence from emerging strategies and discuss technologies that could enable assessment of these determinants. We consider how modular biomarkers might inform patient selection, therapeutic sequencing, rational combinations, dose optimization and regulatory strategy while highlighting the various challenges that must be addressed before broad clinical adoption. Harmonized development across trials, tumour types and geographical regions will be essential to move biomarker development beyond empirical target-expression thresholds. Antibody–drug conjugates (ADCs) have transformed the management of various advanced-stage solid cancers. Nonetheless, and despite considerable development efforts, many of these agents lack reliable biomarkers of clinical benefit and/or are reliant on traditional methods of biomarker assessment, with biomarkers of resistance and/or toxicity largely overlooked. In this Review, the authors outline a modular ADC biomarker development strategy that considers the various components of these agents and discuss how biomarkers developed using this strategy might better inform patient selection, therapeutic sequencing, the development of rational combinations, dose optimization and regulatory strategy.
Human epidermal growth factor receptor 2 (HER2)-positive breast cancer has undergone one of the most profound therapeutic transformations in oncology. Once associated with poor outcomes, it is now a highly curable disease in the early-stage setting, and a substantial proportion of patients with metastatic disease survive beyond 5 years. This progress reflects the development of multiple HER2-targeted therapies, including monoclonal antibodies, antibody–drug conjugates and tyrosine-kinase inhibitors. Most notably, the HER2-targeted antibody–drug conjugate trastuzumab deruxtecan has rapidly been moved into earlier lines of therapy, with emerging roles in the first-line metastatic setting, adjuvant treatment of high-risk residual disease and neoadjuvant therapy. This expansion creates new opportunities, but also crucial evidence gaps regarding optimal sequencing, retreatment and selection of patients for treatment intensification. As treatment options expand, the central challenge is to right-size therapy across the disease continuum, which is the focus of this Review. In patients with early-stage disease, this right-sizing involves carefully de-intensifying treatment for those with low-risk tumours, optimizing neoadjuvant chemotherapy backbones and escalating therapy for those with residual disease; in patients with advanced-stage disease, it requires optimizing maintenance treatment strategies (for example, using palbociclib or tucatinib) after induction therapy, while integrating these maintenance regimens with the novel option of first-line trastuzumab deruxtecan plus pertuzumab, for which the optimal treatment duration and subsequent sequencing remain uncertain. Tissue, plasma and dynamic imaging-based biomarkers are beginning to inform this process, with several showing promising potential for clinical implementation. The iterative development of several highly effective treatments for HER2-positive breast cancer has transformed patient outcomes, but the now-crowded therapeutic landscape raises questions regarding the optimal approach for each patient. In this Review, the authors outline considerations for right-sizing therapy across the disease continuum, and discuss biomarkers that might facilitate this more individualized approach to treatment.
