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Background: 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.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Advanced pancreatic ductal adenocarcinoma (PDAC) is characterized by progressive weight loss and nutritional deterioration. This wasting has been linked to poor survival outcomes, alterations in host defenses, decreased functional ability, and diminished health-related quality of life (HRQOL) in pancreatic cancer patients. There are currently no standardized approaches to the management of pancreatic cancer cachexia. This study explores the feasibility and efficacy of enteral tube feeding of a peptide-based formula to improve weight stability and patient-reported outcomes (PROs) in advanced PDAC patients with cachexia., Methods: This was a single-institution, single-arm prospective trial conducted between April 2015 and March 2019. Eligible patients were adults (>18 years) diagnosed with advanced or locally advanced PDAC and cachexia, defined as greater than 5% unexplained weight loss within 6 months from screening. The study intervention included three 28 day cycles of a semi-elemental peptide-based formula, administered through a jejunal or gastrojejunal feeding tube. The primary outcome was weight stability at 3 months (Cycle 3), defined as weight change less than 0.1 kg/baseline BMI unit from baseline. Secondary outcomes included changes in lean body mass, appendicular lean mass, bone mineral density, fat mass, and percent body fat, as measured with a DEXA scan, HRQOL (EORTC QLQC30) and NIH PROMIS PROs assessed at each cycle. Daily activity (steps, distance, active minutes, heart rate, and sleep) were remotely monitored using a wearable activity monitor (Fitbit) over the 3 month study period., Results: Thirty-six patients were screened for eligibility, 31 patients consented onto study and underwent jejunal tube placement, and 16 patients completed treatment: mean age 67 years (SD 9.3), 43.8% male. Among evaluable patients (n = 16), weight stability was achieved in 10 patients (62.5%), thus completing the trial early. Increases in lean body mass (1273.1, SD: 4078, P = 0.01) and appendicular lean mass (0.45, SD: 0.6, P = 0.02) were observed. Statistically significant improvements at Cycle 3 from baseline were also observed for QLQC30 role function [mean difference (MD): 20.1, P = 0.03], appetite (MD: 27.4, P = 0.02), and global health scores (MD: 13.3, P = 0.05) as well as for NIH PROMIS t-scores for depression (MD: -10.4, P = 0.006) and pain interference (MD: -7.5, P = 0.05). Objectively monitored (Fitbit) activity levels increased, although statistical significance was not reached., Conclusions: Our findings suggest that enteral nutrition support may improve weight stability, lean body mass, appendicular lean mass and PROs in PDAC patients with cachexia who completed treatment, representing a subsample of the study population. The feasibility and role of enteral feeding in routine care remain unclear, and larger and randomized controlled trials are warranted., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Unintentional weight loss in patients with pancreatic cancer is highly prevalent and contributes to low therapeutic tolerance, reduced quality of life, and overall mortality. Weight loss in pancreatic cancer can be due to anorexia, malabsorption, and/or cachexia. Proper supportive care can stabilize or reverse weight loss in patients and improve outcomes. We review the literature on supportive care relevant to pancreatic cancer patients, and offer evidence-based recommendations that include expert nutritional assessment, counseling, supportive measures to ensure adequate caloric intake, pancreatic enzyme supplementation, nutritional supplement replacement, orexigenic agents, and exercise. Pancreatic Cancer Action Network-supported initiatives will spearhead the dissemination and adoption of these best supportive care practices. IMPLICATIONS FOR PRACTICE: Weight loss in pancreatic cancer patients is endemic, as 85% of pancreatic cancer patients meet the classic definition of cancer cachexia. Despite its significant prevalence and associated morbidity, there is no established approach to this disease entity. It is believed that this is due to an important knowledge gap in understanding the underlying biology and lack of optimal treatment approaches. This article reviews the literature regarding pancreas cancer-associated weight loss and establishes a new framework from which to view this complex clinical problem. An improved approach and understanding will help educate clinicians, improve clinical care, and provide more clarity for future clinical investigation., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)