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Novel Agent Effective for Cancer Wasting Disorder

— Cancer patients with cachexia added needed pounds with GDF-15 antibody

MedpageToday

Patients with cancer cachexia and an elevated level of growth differentiation factor 15 (GDF-15) achieved significant increases in body weight with investigational ponsegromab, as well as other improvements, a randomized dose-ranging phase II study found.

At 12 weeks, the placebo-adjusted median weight increase with the highest dose of the GDF-15 inhibitor reached 3.00 kg (95% credible interval [CrI] 1.43-4.60), a 6.6 lb difference, reported Jeffrey Crawford, MD, of Duke University Medical Center in Durham, North Carolina.

Furthermore, the mean increase in body weight with the highest dose of the monoclonal antibody exceeded 5 percentage points compared with placebo, "which is not only statistically significant, but I think clinically significant for our patients," he said at the European Society for Medical Oncology (ESMO) annual congress in Barcelona.

Other improvements with the highest ponsegromab dose included measures of appetite and cachexia symptoms, physical activity, and skeletal muscle mass.

"This study supports GDF-15 as a primary driver of cachexia and an important therapeutic target in this area of unmet medical need for our patients," Crawford concluded. Findings from the study were published simultaneously in the .

Cachexia is a wasting syndrome prevalent in cancer patients (as well as patients with other conditions) that is marked by weight loss, loss of muscle mass, fatigue, and lack of appetite, and is associated with an increased risk of death. There are no currently approved medications for the condition in the U.S. or Europe.

GDF-15 is a stress-induced cytokine implicated in the pathogenesis of cachexia, Crawford explained. In a involving fewer than a dozen patients with cancer cachexia, ponsegromab -- a first-in-class inhibitor of GDF-15 -- was associated with increases in weight, appetite, and physical activity, along with suppressed serum GDF-15 levels.

During a discussion period, Crawford was asked whether ponsegromab would advance to phase III study and evaluate survival outcomes.

"That's a subject for discussion at this point," said Crawford. "We've identified GDF-15 as a very important target in cachexia and I think perhaps it is the first one defined that shows a response to treatment and correlates not only with weight, but the endpoints of [patient-reported outcomes], physical activity, and muscle mass."

"The question is how to develop this further," he added. "Cachexia runs from very early-stage disease to very advanced, end-of-life [disease]. Ideally, we'll have a combination of studies, some that will confirm in a phase III setting what we've shown in phase II ... and in another setting there will hopefully be another option to show whether or not there is a survival benefit."

Crawford presented data at ESMO from the , which enrolled patients with cancer cachexia and an elevated serum GDF-15 level (≥1,500 pg/mL). Participants were assigned 1:1:1:1 to receive ponsegromab at a dose of 100 mg, 200 mg, or 400 mg, or placebo, administered subcutaneously every 4 weeks for three doses.

A total of 187 patients (median 67 years, 63% men) underwent randomization at 74 sites in 11 countries. Of these, 40% had non-small cell lung cancer, 32% pancreatic cancer, and 29% colorectal cancer, with the vast majority having stage III or IV disease.

Participants had a mean weight of 54.8 kg (120.8 lb) at baseline, with nearly half dropping 10% or more of their body weight in the 6 months prior to screening. Median time from cancer diagnosis to randomization was about a year. About 90% were receiving systemic anticancer therapies at the time they were randomized, with 36% receiving platinum-based chemotherapy. The percentage of patients who were receiving palliative care was similar across trial groups.

The study's primary endpoint was weight gain at week 12, analyzed with a Bayesian hierarchical Emax model. Each dose level of ponsegromab resulted in significant improvements, with the following placebo-adjusted median increases: 1.33 kg (95% CrI 0.36-2.56) at the 100-mg dose, 2.08 kg (95% CrI 0.87-3.39) at the 200-mg dose, and 3.00 kg (95% CrI 1.43-4.60) with the 400-mg dose.

In addition to weight gain, other benefits at the 400-mg dose (shown as significant placebo-adjusted differences) included the following:

  • Least square (LS) mean change of 4.11 (95% CI 0.46-7.76) from baseline on the Functional Assessment of Anorexia Cachexia Treatment (FAACT)-Anorexia Cachexia Subscale (a 0-48 scale where higher scores indicate a better outcome and where 4 points represents a response)
  • LS mean change of 2.30 (95% CI 0.37-4.23) on the FAACT 5-Item Anorexia Symptom Scale (a 0-20 scale where 2 points represents a response)
  • Increase in the lumbar skeletal muscle index of 2.15 cm2 per square meter (95% CI 0.34-3.96)
  • Mean daily increase in non-sedentary physical activity of 50 minutes (95% CI 3-97) in the subgroup able to use wearable technology

Adverse events (AEs) of any cause ranged from 67% to 74% with ponsegromab versus 80% with placebo. The most common AEs included diarrhea, cancer progression, anemia, hypokalemia, nausea, vomiting, and pyrexia, with placebo-treated patients reporting higher rates of diarrhea, nausea, and vomiting.

Treatment-related AEs occurred in 4.3% to 10.9% of patients on ponsegromab versus 8.9% with placebo, most of which were mild to moderate.

  • author['full_name']

    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

The study was sponsored by Pfizer.

Crawford reported relationships (including institutional funding) with Pfizer, Actimed, AstraZeneca, BioAtla, Enzychem, Faraday, G1 Therapeutics, Helsinn Healthcare, and Tensegrity.

Primary Source

New England Journal of Medicine

Groarke JD, et al "Ponsegromab for the treatment of cancer cachexia" N Engl J Med 2024; DOI: 10.1056/NEJMoa2409515.