In a randomised phase II study involving patients with cancer cachexia and an elevated growth differentiation factor 15 (GDF-15) level, the inhibition of GDF-15 with ponsegromab resulted in a significant, robust increase in body weight at 12 weeks, as compared with placebo. In addition, patients in the ponsegromab groups had reduced cachexia symptoms and improved appetite, overall physical activity, and skeletal muscle mass.
Differences in body weight relative to placebo were evident at 8 weeks after two doses of ponsegromab. In addition, all ponsegromab doses were considered to be safe and had a side-effect profile similar to that of placebo. The findings are presented at the ESMO 2024 Congress along with a simultaneous publication in the NEJM.
The authors wrote in the background that GDF-15 is a stress-induced cytokine that binds to the glial cell–derived neurotrophic factor family receptor alpha-like protein (GFRAL) in the hindbrain. The GDF-15–GFRAL pathway has emerged as a main modulator of anorexia and body-weight regulation and is implicated in the pathogenesis of cachexia.
Ponsegromab is a potent, highly selective, humanised monoclonal antibody that binds to circulating GDF-15 inhibiting the interaction with its GFRAL receptor. In a small, open-label, phase Ib study, ponsegromab was associated with improved weight, appetite, and physical activity, along with suppressed serum GDF-15 levels, with a low frequency of adverse events. The researchers conducted this phase II study to assess the safety and efficacy of ponsegromab, as compared with placebo, in patients with cancer cachexia who had elevated circulating GDF-15 levels to test the hypothesis that GDF-15 is a main mechanistic driver of this condition.
In this phase II, randomised, double-blind, 12-week study, the researchers assigned patients with cancer cachexia and an elevated serum GDF-15 level (≥1500 pg per milliliter) in a 1:1:1:1 ratio to receive ponsegromab at a dose of 100 mg, 200 mg, or 400 mg or to receive placebo, administered subcutaneously every 4 weeks for three doses. The primary endpoint was the change from baseline in body weight at 12 weeks. Key secondary endpoints were appetite and cachexia symptoms, digital measures of physical activity, and safety.
A total of 187 patients underwent randomisation. Of these patients, 40% had non–small cell lung cancer, 32% had pancreatic cancer, and 29% had colorectal cancer. At 12 weeks, patients in the ponsegromab groups had significantly greater weight gain than those in the placebo group, with a median between-group difference of 1.22 kg (95% credible interval 0.37 to 2.25) in the 100 mg group, 1.92 (95% credible interval 0.92 to 2.97) in the 200 mg group, and 2.81 (95% credible interval 1.55 to 4.08) in the 400 mg group.
The authors commented that ponsegromab was associated with weight gain in patients with even the most severe weight loss. Half the patients in this study had a body mass index-adjusted weight loss of grade 4; nevertheless, these patients had robust weight gain as compared with placebo in response to ponsegromab. These results challenge the concept of refractory cachexia and suggest that even patients with advanced cachexia may benefit from ponsegromab. Additional studies are needed to determine the appropriate timing for ponsegromab initiation along the cancer cachexia continuum.
Improvements were observed across measures of appetite and cachexia symptoms, along with physical activity, in the 400 mg ponsegromab group relative to placebo. Among all the patients in the study, a higher percentage of those in the 200 mg ponsegromab group (39%) reported no appetite loss at baseline than in the other groups (26% in the 100 mg group, 28% in the 400 mg group, and 21% in the placebo group). Patients in the 100 mg and 400 mg ponsegromab groups had improvements from baseline as compared with the placebo group at 12 weeks regarding scores on the FAACT-ACS and the FAACT-5IASS.
Patients in the 400 mg ponsegromab group had increased overall activity at 12 weeks as compared with the placebo group, with a difference of 72 minutes (95% credible interval 37 to 107) per day with respect to nonsedentary physical activity. The ponsegromab-mediated increase in nonsedentary physical activity may represent clinically meaningful functional improvement by enabling patients to complete important daily activities.
Adverse events of any cause were reported in 70% of the patients in the ponsegromab group and in 80% of those in the placebo group. In this population with advanced cancer, overall rates of adverse events were similar across groups and occurred in patients who were receiving a high rate (90%) of concurrent systemic anticancer therapies. Nausea and vomiting were reported less frequently in the ponsegromab group than in the placebo group (4% versus 16% for nausea and 5% versus 13% for vomiting). The early discontinuation rate (27%) and percentage of deaths (12%) before 12 weeks reflect rates that have been reported in previous clinical trials involving patients with cancer cachexia. The authors commented that placebo-like safety profile may differentiate ponsegromab from other agents used in cancer cachexia.
The authors concluded that their 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.
The study was funded by Pfizer.
Reference
Groarke JD, Crawford J, Collins SM, et al. Ponsegromab for the Treatment of Cancer Cachexia. NEJM; Published online 14 September 2024.