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Ponsegromab for Treating Cancer Cachexia
TAKE-HOME MESSAGE
- This phase II trial assessing the safety and efficacy of ponsegromab in patients with pancreatic, colorectal, and non–small cell lung cancer who had cachexia showed that patients had a significant and robust weight gain at 12 weeks with ponsegromab than with placebo. Ponsegromab resulted in reduced cachexia symptoms and improved appetite, overall physical activity, and skeletal muscle mass. All ponsegromab doses were considered to be safe, and the adverse effect profile was similar to that of placebo.
- 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.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
Cachexia is a common complication of cancer and is associated with an increased risk of death. The level of growth differentiation factor 15 (GDF-15), a circulating cytokine, is elevated in cancer cachexia. In a small, open-label, phase 1b study involving patients with cancer cachexia, ponsegromab, a humanized monoclonal antibody inhibiting GDF-15, was associated with improved weight, appetite, and physical activity, along with suppressed serum GDF-15 levels.
METHODS
In this phase 2, randomized, double-blind, 12-week trial, we 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 end point was the change from baseline in body weight at 12 weeks. Key secondary end points were appetite and cachexia symptoms, digital measures of physical activity, and safety.
RESULTS
A total of 187 patients underwent randomization. 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. Improvements were observed across measures of appetite and cachexia symptoms, along with physical activity, in the 400-mg ponsegromab group relative to placebo. 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.
CONCLUSIONS
Among patients with cancer cachexia and elevated GDF-15 levels, the inhibition of GDF-15 with ponsegromab resulted in increased weight gain and overall activity level and reduced cachexia symptoms, findings that confirmed the role of GDF-15 as a driver of cachexia. (Funded by Pfizer; ClinicalTrials.gov number, NCT05546476.)
Additional Info
Disclosure statements are available on the authors' profiles:
Ponsegromab for the Treatment of Cancer Cachexia
N. Engl. J. Med 2024 Sep 14;[EPub Ahead of Print], JD Groarke, J Crawford, SM Collins, S Lubaczewski, EJ Roeland, T Naito, AE Hendifar, M Fallon, K Takayama, T Asmis, RF Dunne, I Karahanoglu, CA Northcott, MA Harrington, M Rossulek, R Qiu, AR SaxenaFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Cancer cachexia is a complex syndrome characterized by weight loss, loss of muscle mass, inflammation, and poor survival outcomes. To date, there are no approved medications for the treatment of cancer cachexia in the US or Europe.
The results of a phase II trial using ponsegromab, a monoclonal antibody inhibiting growth differentiation factor-15 (GDF-15), for the treatment of cancer cachexia have been published in The New England Journal of Medicine. GDF-15 is a stress-induced cytokine that binds to receptors in the hindbrain and is thought to mediate the appetite/weight loss observed in these patients. This trial was a randomized, double-blind, placebo-controlled trial conducted in 11 countries. The primary endpoint was the change from baseline in body weight at 12 weeks. A total of 187 patients were enrolled and randomized 1:1:1:1 to receive placebo or ponsegromab at 100 mg, 200 mg, or 400 mg subcutaneously every 4 weeks for three doses. To enroll, participants had to be diagnosed with lung, pancreas, or colon cancer; meet the definition of cancer cachexia; and have elevated GDF-15, among other inclusion criteria.
The trial met its primary endpoint: the use of ponsegromab was associated with weight gain in a dose-dependent manner. Patients in the 400 mg group gained 2.81 kg more than those in the placebo group. Additionally, patients on the medication reported improvements in appetite, nausea, vomiting, and skeletal muscle mass. In a subgroup analysis of 59 patients with wearable device data, there was an increase in physical activity.
This trial is an exciting development as it offers an option to address cancer cachexia without any concerning safety signals. However, the study does not address survival outcomes and whether patients would need longer-term repeated dosing beyond 12 weeks. Future studies should focus on other important outcomes, such as overall survival (possibly through allowing more robust anticancer therapies) and quality of life. As the medication was well-tolerated, one might ask whether patients with cancer with earlier stages of cachexia, such as pre-cachexia or lower levels of GDF-15 elevation, might also benefit from using it.