Baseline circulating growth differentiation factor-15 and the cancer phenotype in the PROACC-1 phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia.
Authors: Eric Roeland, Susie M. Collins, Shelley des Etages-Wong, Shannon L. Lubaczewski, Tateaki Naito, Andrew Hendifar, Marie T. Fallon, Koichi Takayama, Timothy R. Asmis, Richard Francis Dunne, Ira A. Jacobs, Michelle I. Rossulek, Ruolun Qiu, Jeffrey Crawford, Aditi Saxena, John Groarke
Journal: Journal of Clinical Oncology (2025)

12060 Background: Growth differentiation factor-15 (GDF-15) is an emerging therapeutic target in cancer cachexia. However, the association of circulating GDF-15 with the cancer cachexia phenotype remains poorly characterized. Methods: Serum GDF-15 was measured using the Roche Elecsys GDF-15 assay at screening in a phase 2, randomized trial of ponsegromab (an investigational anti-GDF-15 monoclonal antibody) in patients with cancer cachexia, and an elevated serum GDF-15 (≥ 1500 pg/mL) (NCT05546476). Cachexia was defined by international consensus criteria and sarcopenia by standardized sex-specific cut-off values for lumbar skeletal muscle index. Cross-sectional associations of GDF-15 with various demographic and clinical parameters were explored post-hoc using summary statistics and Pearson’s correlation (with GDF-15 on the log 10 scale). Results: A total of 187 patients were enrolled in this study with a median (IQR) age of 67 (60-74) years and 37% were female. Baseline median GDF-15 values were higher among patients with cachexia and colorectal and pancreatic cancers, compared to NSCLC. GDF-15 elevation was higher in patients with stage IV disease, sarcopenia, and worse performance status (Table). Higher GDF-15 levels were associated with lower serum albumin (r = -0.31 [95% CI: -0.44, -0.177]) and pre-albumin (r = -0.17 [95% CI: -0.31, -0.03]). No significant associations were observed between GDF-15 levels and appetite or fatigue assessments. Conclusions: Among patients with cancer cachexia, GDF-15 elevation was more pronounced in those with more advanced cancer, sarcopenia, and worse performance status. In addition, GDF-15 levels were negatively correlated with markers of nutritional status. Clinical trial information: NCT05546476 . Demographic or Clinical Characteristic n Median (IQR) serum GDF-15, pg/ml Age, years- 18-44- 45-64- ≥65 670111 2718 (2461, 8117)4197 (2366, 9425)3849 (2310, 7125) Type of cancer- NSCLC- Pancreatic- Colorectal 745954 2701 (2114, 4094)4714 (2408, 9561)6468 (4106, 10052) Interval from cancer diagnosis- &lt;1 year- ≥1 year 9691 4259 (2447, 8919)3781 (2259, 6997) Stage of cancer- I/II- III- IV 1634137 3551 (2264, 6320)3232 (2461, 5704)4365 (2387, 8117) Body mass index (BMI), kg/m2- &lt;20- ≥20 9988 3254 (2220, 6801)5052 (2712, 8749) % weight loss in 6 months prior to screening- &lt; 10%- ≥ 10% 9988 3849 (2290, 7677)4118 (2381, 7595) Sarcopenia status- Yes- No 14440 4259 (2402, 7672)2928 (2136, 8052) ECOG Performance Status- 0- 1- 2/3 3312331 2842 (2408, 5673)4094 (2366, 8623)5119 (2272, 7667) Systemic anticancer therapy- Platinum-based therapy- Antimetabolite agents- Biological agents- Antimicrotubule agents- PD-1 or PD-L1 inhibitors 68100407330 5760 (3053, 10008)5914 (2847, 10768)5744 (3317, 9644)4891 (2762, 9425)2744 (2149, 4787)