make cancer patients "fat"! nejm: innovative targeted therapy solves the important "cause of death" of cancer
2024-09-22
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▎edited by wuxi apptec content teamcachexia is common in cancer patients and is a clinical syndrome characterized by nutrient wasting that leads to decreased appetite, weight loss, muscle atrophy, decreased quality of life, functional impairment, and reduced survival.international consensus generally defines cachexia as weight loss ≥5% within 6 months;kg/m2orin patients with sarcopenia, a weight loss of more than 2% is considereddefinition.many studies have shown thatup to 60%-80% of cancer patients are affected by cachexia, and up to 20%-30% of cancer deaths are caused by cachexia. in some cases, cachexia can also reduce the effectiveness of cancer treatment.however, there is currently a lack of effective therapies to specifically improve cachexia.recently released at the 2024 european society for medical oncology (esmo) congress and published simultaneously in the new england journal of medicine (The New England Journal of Medicinean important study bycreationnew therapy ponsegromab is used in higherdosethe results showed that patients with cancer cachexia could recover about 5.6% of their body weight within 12 weeks.appetite, physical activity, and skeletal muscle mass all improved.screenshot source:The New England Journal of Medicineponsegromab is a monoclonal antibody targeting growth differentiation factor 15 (gdf-15) that blocks its binding to the gfral receptor.cytokines, which is elevated in cachexia patients. gdf-15 can bind to the gfral receptor in the brain, and the combination of the two is closely related to anorexia and weight loss. early studies have shown that gdf-15 is a potential therapeutic target for cachexia.the study was a 12-week phase 2 randomized double-blind trial in which 187 patients with common cancers who had cachexia and elevated serum gdf-15 levels (≥1500 pg/ml) were randomized to receive three different doses of ponsegromab (100 mg, 200 mg, 400 mg) or placebo in a 1:1:1:1 ratio, subcutaneously injected once every 4 weeks for a total of 3 doses.of these patients, 39.6% hadnon-small cell lung cancer, 31.5% suffer frompancreatic cancer, 28.9% had colorectal cancer. before treatment, the median interval from cancer diagnosis in these patients was 11.7 months, and the median weight was 54.8 kg.the primary endpoint of the study was the change in body weight from baseline at week 12. the average weight loss in the placebo group was 0.45 kg, while in theall three groups of patients receiving ponsegromab had significant weight gain.patients in the 100 mg, 200 mg, and 400 mg groupscompared with the placebo groupweightthe average increases were 1.22 kg, 1.92 kg, and 2.81 kg, respectively, equivalent to a 2.21%, 2.99%, and 5.46% increase in body weight compared to the placebo group.the highest dose of ponsegromab, 400 mg, significantly promoted weight restoration. of note, the ponsegromab 400 mg group had a significant effect on weight restoration in patients with advanced cancer.patientmore (86% of patients in stage iv and 65%-74% in the other three groups).the results of gdf-15 level detection indicate that the patient's weight change is consistent with the degree of gdf-15 inhibition. as the dose increases, the amount of unantagonized gdf-15 factor in the patient's body decreases.key secondary endpoints of the study were improvements in appetite and cachexia symptoms, and physical activity.patients in the ponsegromab 100 mg and 400 mg groups showed improvement in anorexia compared with the placebo group(assessed by faact-acs score and faact-5iass score scale). given that a high proportion (90%) of these patients are also receiving systemic anticancer therapy, nausea and vomiting are theoretically common treatment reactions they face, but in realitypatient-reported nausea and vomiting rates were significantly lower in the ponsegromab group than in the placebo group(nausea 4% vs. 16%, vomiting 5% vs. 13%)in addition, patients in the ponsegromab 400 mg group had improved lumbar spine skeletal muscle index (which reflects systemic skeletal muscle condition) at week 12; wearable device measurements showed thatpatients in the ponsegromab 400 mg group also experienced an increase in overall activity, with non-sedentary physical activity increasing by 72 minutes per day, a number that potentially reflects clinically meaningful improvements in function.this means that the patient may be able to complete important daily activities such as showering, dressing, and light housework.in terms of safety, 70% of patients in the ponsegromab group reported adverse events of any cause, while 80% of patients in the placebo group reported adverse events of any cause. most adverse events (88%) were mild to moderate.although it is not clear what weight gain is considered clinically significant for patients with cancer cachexia, a relevant expert group recently recommended a weight gain of more than 5% as an intervention goal. in this trial, high-dose ponsegromab treatment resulted in a combined improvement in weight as well as appetite, total activity, and skeletal muscle mass, data that support the potential of ponsegromab as a targeted therapy for cancer cachexia.
