CLINICAL QUESTION: Does treatment with ponsegromab, a monoclonal antibody inhibiting growth differentiation factor 15 (GDF-15), improve weight gain in patients with malignancy?
BACKGROUND: Patients with malignancy are at increased risk for cachexia. GDF-15, a stress-induced cytokine, has shown involvement in weight-loss regulation and the cachexia pathway. Ponsegromab tests the hypothesis that GDF-15 is a key driver of cachexia. Its clinical efficacy was evaluated in a phase 2 trial.
STUDY DESIGN: Randomized, double-blinded, placebo-controlled, dose-ranging trial
SETTING: 74 sites in 11 countries
SYNOPSIS: 187 patients with malignancy (40% non-small-cell lung cancer, 32% pancreatic cancer, and 29% colorectal cancer), cachexia (involuntary weight loss of at least 5% within previous six months), and elevated serum GDF-15 (at least 1,500 pg/mL) were randomly assigned doses of Ponsegromab in a 1:1:1:1 ratio of 100 mg, 200 mg, 400 mg, and placebo, respectively. The primary endpoint was the change in body weight after 12 weeks. Across all treatment arms, ponsegromab showed a significant, dose-dependent increase in baseline weight compared to placebo. The median group difference was 1.22 kg (95% credible interval [CrI], 0.37 to 2.25) in the 100-mg group, 1.92 kg (95% CrI, 0.92 to 2.97) in the 200-mg group, and 2.81 kg (95% CrI, 1.55 to 4.08) in the 400-mg group compared to placebo. Adverse events (most commonly diarrhea, nausea, and vomiting) were reported in 70% of the treatment group and 80% of the placebo group. Limitations included underrepresented populations (limited to white and Asian populations) and no clear correlation of ponsegromab-mediated weight gain to the amount of change in GDF-15 levels.
BOTTOM LINE: In patients with specific malignancies (non-small-cell lung cancer, pancreatic cancer, and colorectal cancer), ponsegromab improves cachexia.
CITATION: Groarke JD, et al. Ponsegromab for the treatment of cancer cachexia. N Engl J Med. 2024;391:2291-2303. doi: 10.1056/NEJMoa2409515.
Dr. Mehdi is an assistant clinical professor and a hospitalist at UC San Diego Health in San Diego.