Ponsegromab for the Treatment of Cancer Cachexia
1. Ponsegromab at increasing doses resulted in a mean increase in body weight compared to placebo; 1.22 kg (2.21%) in the 100-mg group, 1.92 kg (2.99%) in the 200-mg group, and 2.81 kg (5.46) in the 400-mg group.
2. Adverse events of any cause were reported in 67%-74% in the ponsegromab group vs 80% in the placebo group, with most (88%) being mild to moderate.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Cachexia is a multifactorial syndrome seen in cancer patients with limited pharmacologic treatment options available. It was found that the GDF-15 pathway is a key modulator of anorexia and body-weight regulation, and elevated GDF-15 levels are linked to weight loss, muscle wasting, and reduced survival in cancer patients. A promising treatment, ponsegromab, targets the GDF-15 pathway and has shown improvements in weight, appetite, and physical activity in early trials. This is a phase 2 trial that assessed the safety and efficacy of ponsegromab, as compared with placebo in patients with cancer cachexia who had elevated circulating GDF-15 levels. The primary endpoint was the change in body weight and secondary endpoints included patient-reported outcomes such as change in cachexia scales, physical activity and gait. At 12 weeks, the increase in weight compared to placebo was higher in the experimental arm with greater increases with the higher dosage. Weight changes were consistent with GDF-15 suppression at 12 weeks. Patient-reported outcomes on cachexia scales showed improvements in the 100-mg and 400-mg ponsegromab groups vs the placebo group at 12 weeks however no differences in the score were seen in the 200-mg ponsegromab group relative to the placebo group. Regarding physical activity, it was found that patients in the 400-mg ponsegromab group had increased overall activity compared with the placebo group. The most common adverse events are diarrhea, cancer progression, anemia, hypokalemia, nausea, vomiting, and pyrexia. Most of the adverse events (88%) were mild to moderate. The strengths of this study included its methodology and the limitations included the small sample size, the follow-up period, and only including patients with elevated CDF-15 levels. Overall, this study found that ponsegromab at increasing doses resulted in a reduction in cachexia symptoms and increases in body weight as compared with placebo in patients with cancer cachexia and an elevated circulating GDF-15 level.
Click to read the study in NEJM
Click to read an accompanying editorial in NEJM
Relevant Reading: The GDF15-GFRAL Pathway in Health and Metabolic Disease: Friend or Foe?
In-Depth [randomized controlled trial]: This international, double-blind study enrolled patients with NSCLC, pancreatic cancer, or colorectal cancer with defined cachexia and an elevated serum GDF-15 level, and randomized them (1:1:1:1) to ponsegromab at a dose of 100 mg (n=46), 200 mg (n=46), or 400 mg (n=50) or to receive placebo (n=45), respectively. The median interval from cancer diagnosis to randomization was 11.7 months (4.0-26.4). The ponsegromab 400-mg group had the highest proportion of patients with stage IV disease (86% vs 65-74% in the other three groups). At 12 weeks, the increase in weight compared to placebo was 1.22 kg (95%CI, 0.37-2.25, p<0.05) in the 100-mg group, 1.92 kg (95%CI, 0.92-2.97, p<0.05) in the 200-mg group, and 2.81 kg (95%CI, 1.55-4.08, p<0.05) in the 400-mg group. This correlated to a mean percent change from baseline in body weight of 2.21% (95%CI, –0.20-4.46) in the 100-mg group, 2.99% (95%CI, 0.64-5.35) in the 200-mg group, and 5.46% (95%CI, 3.05-7.87) in the 400-mg group. Changes in weight were consistent with GDF-15 suppression at 12 weeks, with a median factor change from baseline in the unbound GDF-15 level of 0.15 (interquartile range, 0.03-1.02) in the 100-mg group, 0.07 (0.02-0.75) in the 200-mg group, and 0.02 (0.02-0.04) in the 400-mg group, as compared with 1.02 (0.74 to 1.40) in the placebo group. Patient-reported outcomes on cachexia scales showed improvements in the 100-mg and 400-mg ponsegromab groups vs the placebo group at 12 weeks however no differences in the score were seen in the 200-mg ponsegromab group relative to the placebo group. Regarding physical activity, it was found that patients in the 400-mg ponsegromab group had increased overall activity compared with the placebo group, with a difference of 72 minutes (95%CI, 37-107) per day. An exploratory endpoint that was investigated was a change in lumbar skeletal muscle index which found a difference of 2.04 cm2 per square meter (95%CI, 0.27-3.83) in the 400-mg ponsegromab group compared to the placebo group. With regards to safety, adverse events of any cause were reported in 67%-74% of the ponsegromab group compared to 80% in the placebo group, with the most common adverse events being diarrhea, cancer progression, anemia, hypokalemia, nausea, vomiting, and pyrexia. Most of the adverse events (88%) were mild to moderate. Overall, this study found that ponsegromab at increasing doses resulted in a reduction in cachexia symptoms and increases in body weight as compared with placebo in patients with cancer cachexia and an elevated circulating GDF-15 level.
Image: PD
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