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Design and Participants: This phase 2, randomized, double-blind trial tested ponsegromab’s effect on body weight in patients with cancer cachexia and an elevated serum GDF-15 level (≥1,500 pg/mL). Patients were assigned (1:1:1:1) to receive 100 mg, 200 mg, or 400 mg ponsegromab or placebo, administered subcutaneously every 4 weeks for three doses. The primary endpoint was weight change from baseline at 12 weeks. Secondary endpoints were change on the Functional Assessment of Anorexia Cachexia Treatment-Anorexia Cachexia Subscale (FAACT-ACS), the FAACT 5-Item Anorexia Symptom Scale (FAACT-5IASS), the sponsor-developed Cancer Related Cachexia Symptom Diary, digital wearable–measured physical activity and gait, and safety. Post hoc Bayesian analysis and ANCOVA were used.
Results: Patients (N=187) were aged median 67 years (IQR=60-74); 37% women; and 62% White and 37% Asian. Forty percent had non–small cell lung cancer, 32% pancreatic, and 29% colorectal. At 12 weeks, patients in the ponsegromab groups had greater weight gain than those in placebo, with a median between-group difference of 1.2 kg (95% credible interval=0.37-2.3) in 100 mg, 1.9 (0.92-3.0) in 200 mg, and 2.8 (1.6-4.1) in 400 mg. Additionally, 100 mg and 400 mg had improvements from baseline vs placebo at 12 weeks regarding scores on the FAACT-ACS (4.1 [0.86-7.3] and 4.5 [1.3-7.8], respectively) and the FAACT-5IASS (2.2 [0.36-4.0] and 2.4 [0.61-4.2], respectively). Any-cause adverse events were reported in 70% of the ponsegromab group and in 80% of placebo, most commonly diarrhea, cancer progression, anemia, hypokalemia, nausea, vomiting, and pyrexia.
Commentary: Observing a loved one lose weight and experience lack of appetite can be emotionally difficult. Patients with cancer and their families often want to know how to increase appetite, gain weight, and improve strength so they can perform valuable daily activities. With an adverse event profile equivalent to the placebo arm, and clinically meaningful improvements in weight, quality of life, and physical activity, ponsegromab may be favored over other medications for cancer cachexia with less favorable outcomes such as progesterone analogues, ghrelin-receptor agonists, and glucocorticoids. Ponsegromab inhibits GDF-15, which is elevated due to tissue injury, oxidative stress, and systemic inflammation,3 and may potentially improve appetite and prevent weight loss in a host of other chronic illnesses in addition to cancer, though further study is warranted for non-cancer cachexia syndromes.
Bottom Line: Ponsegromab is a promising drug that demonstrated reduced cancer cachexia symptoms and improved weight gain, quality of life, and physical function for patients with cancer and elevated circulating levels of GDF-15.
Reviewer: Briana Ketterer, MD MS FACP, Oregon Health & Science University, Portland, OR
References:
1. Emmerson PJ, Wang F, Du Y, et al. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat Med. 2017;23:1215-1219.
2. Breit SN, Brown DA, Tsai VW-W. The GDF15-GFRAL pathway in health and metabolic disease: friend or foe? Annu Rev Physiol. 2021;83:127-51.
3. Ling T, Zhang J, Ding F, Ma L. Role of growth differentiation factor 15 in cancer cachexia (Review). Oncol Lett. 2023;26(5):462.
Source: Groarke JD, Crawford J, Collins SM, et al. Ponsegromab for the treatment of cancer cachexia [online ahead of print September 14, 2024]. N Engl J Med. doi:10.1056/NEJMoa2409515.
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