Martin Harutyunyan for the Supportive CARE DIGEST
Cancer cachexia remains one of the most challenging and clinically significant syndromes in oncology. It affects most patients with advanced cancer and contributes to weight loss, anorexia, reduced physical function, and decreased tolerance to systemic therapy. Despite its impact, there are still no approved pharmacologic treatments that reliably reverse the syndrome. This makes the emerging science around GDF‑15 inhibition particularly important, as it offers a biologically grounded approach to a condition that has long lacked effective options.
In this episode of MASCC’s Supportive CARE DIGEST, Dr. Martin Harutyunyan, medical oncologist, palliative care specialist, and Director of OncoDaily LA, reviews the recent Phase 2 trial of ponsegromab published in the New England Journal of Medicine. The study evaluated ponsegromab in patients with advanced cancer and documented cachexia. GDF‑15, a cytokine that drives anorexia through the GFRAL receptor in the brainstem, has emerged as a central mediator of cancer‑related weight loss. Targeting GDF‑15 with ponsegromab represents a shift toward addressing the underlying biology of cachexia rather than managing its downstream symptoms.
Clinical Findings and the Role of GDF‑15
The Phase 2 trial demonstrated clear, dose‑dependent improvements in body weight, appetite, anorexia symptoms, physical activity, and skeletal muscle index. These outcomes were supported by objective measurements, including ActiGraph data and CT‑based muscle analysis. Importantly, the degree of GDF‑15 suppression correlated with clinical benefit, reinforcing the role of GDF‑15 as a mechanistic driver of cachexia. The safety profile was favorable, with fewer nausea‑related symptoms compared with placebo. Together, these findings highlight GDF‑15 inhibition as a promising therapeutic strategy and position ponsegromab as a potential future option in supportive oncology.
Ongoing Development and Future Directions
Dr. Harutyunyan also discusses the broader development program. The open‑label extension is evaluating durability and long‑term safety, including sustained suppression of GDF‑15 over time. The RIVER-mPDAC Phase 2b and 3 trial is underway in metastatic pancreatic cancer, a setting where GDF‑15 levels are often markedly elevated. Additional studies are exploring the relevance of GDF‑15 inhibition in heart failure, reflecting the expanding interest in this pathway across multiple disease states. These efforts underscore the potential of targeting GDF‑15 to improve outcomes in conditions characterized by anorexia, weight loss, and metabolic disruption.