Advancing Cancer Cachexia Drug Development: Leveraging Biomarkers and Functional Endpoints to Optimize Trial Design

Cancer-associated cachexia is a complex, multistage metabolic disorder that markedly contributes to morbidity and mortality in patients with advanced cancer, yet effective pharmacological interventions are lacking. Cachexia drug development has expanded significantly in recent years, with multiple repurposed agents and novel therapies targeting specific pathways entering clinical trials. However, clinical benefit has been limited not only by a lack of promising agents but also, to a large extent, by suboptimal trial design.

This article reviews the current evidence to highlight the core principles required to modernize cachexia clinical trials. We emphasize that both repurposed drugs and novel agents have a role, but multimodal approaches integrating pharmacologic intervention with nutritional support and exercise are essential for therapeutic success. Early intervention, guided by predictive biomarkers such as C-reactive protein and Interleukin-6, and relatively short study durations focused on rapid clinical benefit are critical considerations.

We demonstrate the importance of moving beyond weight-based endpoints alone toward functional primary endpoints. Selection of appropriate control arms is crucial and should include multimodal interventions, while trial designs must account for patient heterogeneity and concurrent anticancer therapies.