Ponsegromab for the Treatment of Cancer Cachexia.
Level 2 - randomized trial
Individual randomized, double-blind, placebo-controlled phase 2 trial.
PubMed 39282907 · doi:10.1056/NEJMoa2409515
What was done
In a multicenter, phase 2, randomized, double-blind trial, 187 patients with cancer cachexia (non-small-cell lung cancer [40%], pancreatic cancer [32%], or colorectal cancer [29%]) and elevated serum GDF-15 levels (≥1500 pg/mL) were randomized 1:1:1:1 to receive subcutaneous ponsegromab at doses of 100 mg, 200 mg, 400 mg, or placebo every 4 weeks for three doses over 12 weeks. The primary endpoint was change in body weight from baseline at week 12. Key secondary endpoints included appetite, cachexia symptoms, digital physical activity measures, and adverse events.
What was found
At 12 weeks, ponsegromab produced dose-dependent increases in body weight compared with placebo, with median between-group differences of 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. The 400-mg dose also demonstrated improvements in appetite, cachexia symptoms, and physical activity relative to placebo. Adverse events of any cause were reported in 70% of patients receiving ponsegromab versus 80% receiving placebo.
Why it matters
GDF-15 inhibition with ponsegromab demonstrates clinically meaningful reversal of weight loss and symptom burden in patients with cancer cachexia and elevated GDF-15, targeting a major driver of cachexia where effective therapies are currently lacking.
Limits
The study was a 12-week phase 2 trial with a modest sample size (n = 187). Eligibility was restricted to patients with elevated GDF-15 and three specific cancer types, limiting generalizability to all cancer cachexia. The abstract does not report body composition changes (lean vs. fat mass) or overall survival outcomes.
Cited by
- supports Cancer patients who develop cachexia exhibit elevated circulating levels of GDF15.
- contradicts A clinical trial published in the New England Journal of Medicine showed that a GDF15-blocking monoclonal antibody attenuated weight loss in cancer patients but doubled mortality.