Ponsegromab Reduces Symptoms Linked to Cancer Cachexia, Elevated GDF-15
Patients in the ponsegromab group had significantly greater weight gain and physical activity than those in the placebo arm in a phase 2 trial.
Patients in the ponsegromab group had significantly greater weight gain and physical activity than those in the placebo arm in a phase 2 trial.
Ponsegromab (PF-06946860), a monoclonal antibody that inhibits GDF-15 levels, was found to increase weight gain and overall activity levels while reducing cachexia symptoms among patients with cancer cachexia and an elevated serum GDF-15 level, according to data from a phase 2 trial (NCT05546476) published in The New England Journal of Medicine.
Data from the trial reveal that across 3 ponsegromab dose levels (100 mg, 200 mg, 400 mg), the increases in weight were significantly higher vs placebo at 12 weeks. The between-group differences between the 100 mg, 200 mg, and 400 mg groups, respectively, and placebo were 1.22 kg (95% CI, 0.37-2.25; P <.05), 1.92 kg (95% CI, 0.92-2.97; P <.05), and 2.81 kg (95% CI, 1.55-4.08; P <.05). Additionally, more patients in the 200-mg ponsegromab group reported no appetite loss at baseline (39%) than in the 400-mg group (28%), 100-mg group (26%), and the placebo group (21%).
Furthermore, regarding Functional Assessment of Anorexia Cachexia Treatment–Anorexia Cachexia Subscale (FAACT-ACS) scores, patients in the 100-mg and 400-mg groups had improvements from baseline over placebo, at increases of 4.12 (95% CI, 0.86-7.34) and 4.50 (95% CI, 1.29-7.77), respectively. Furthermore, for the FAACT 5-Item Anorexia Symptom Scale (FAACT-5IASS), similar improvements were observed in the 100-mg and 400-mg groups, at increases of 2.20 (95% CI, 0.36-3.99) and 2.39 (95% CI, 0.61-4.15), respectively.
“Ponsegromab-mediated inhibition of GDF-15 resulted in a reduction in cachexia symptoms and increases in body weight, appetite, overall activity, and skeletal muscle mass as compared with placebo in patients with cancer cachexia and an elevated circulating GDF-15 level,” John D. Groarke, MBBCh, MSc, MPH, executive director of Cardiometabolic Clinical Research and Development at Pfizer, wrote in the publication with study coinvestigators. “These findings support the hypothesis that GDF-15 is a primary driver of cachexia and establish this cytokine as a potential therapeutic target for further evaluation in clinical trials.”
Patients with cancer cachexia and a serum GDF-15 level of 1500 pg per mL or higher in the 12-week, randomized, double-blind phase 2 trial were randomly assigned (1:1:1:1) to receive either 100 mg, 200 mg, or 400 mg of ponsegromab or placebo, administered subcutaneously every 4 weeks for 3 doses. A total of 187 patients underwent randomization, including 40% of patients with non–small cell lung cancer, 32% with pancreatic cancer, and 29% with colorectal cancer.
Patients on trial had a median age of 67 years (IQR, 60-74). Additionally, 37% were female, and 62% were White. Patients had a median weight of 54.8 kg (IQR, 46.0-63.8), and average BMI of 19.8 (IQR, 17.6-22.3).
Furthermore, 47% of patients lost 10% of their body weight or more during the 6 months before screening, most patients had stage IV cancer (73%), and most patients received prior systemic anticancer therapy (90%).
The trial’s primary end point was change in body weight from baseline at 12 weeks. Key secondary end points included change from baseline in the score on the FAACT-ACS, which ranges from 0 to 48; the score on the FAACT-5IASS, which ranges from 0 to 20; and the score on the sponsor-developed Cancer Related Cachexia Symptom Diary, as well as change from baseline in physical activity and safety.
Any-grade adverse events (AEs) occurred in 80% of the placebo arm and 70% of the ponsegromab groups. Furthermore, serious AEs occurred in 24% and 32% of each respective group, with dose discontinuations occurring in 13% and 11%, respectively. Grade 3 AEs related to treatment with placebo or ponsegromab occurred in 0 patients receiving placebo and 3 patients assigned to ponsegromab.
Reference
Groarke JD, Crawford J, Collins SM, et al. Ponsegromab for the treatment of cancer cachexia. N Engl J Med. 2024;391(24):2291-2303. doi:10.1056/NEJMoa2409515
