Open-Label Extension of Ponsegromab Shows Efficacy in Cancer-Associated Cachexia

Ponsegromab treatment over 64 weeks resulted in sustained improvements in body weight and suppression of growth differentiation factor 15 (GDF-15), a stress-induced cytokine, irrespective of prior treatment assignment, with a consistent tolerable safety profile, according to information shared in a presentation at the 2025 ESMO Congress.

Patients initially randomized to placebo benefited from weight gain upon transitioning to ponsegromab, although absolute gains were lower than those continuously treated, presenter Dr. Jeffrey Crawford emphasized during the presentation.

Crawford, a medical oncologist at Duke Cancer Center and Duke Cancer Center Thoracic Clinic in Durham, North Carolina, presented the one-year open-label extension results from the randomized phase 2 study evaluating ponsegromab in patients with cancer-associated cachexia, building on previously reported 12-week double-blind data.

“Improvements in body weight at week 12 … continued with ponsegromab through week 64 in the open-label extension,” explained Crawford to the audience in Berlin. “Patients assigned to placebo in Part A showed an improvement in body weight during the open label extension, but overall, their body weight gain was less than what we observed for patients who received ponsegromab throughout the study.”

What Is Cancer-Associated Cachexia and GDF-15’s Role

Cachexia remains a common complication in oncology with no currently approved pharmacologic therapies in the United States or Europe. GDF-15 has been implicated in cachexia pathogenesis through its interaction with the GFRAL receptor in the hindbrain. Crawford explained that ponsegromab is a potent, highly selective humanized monoclonal antibody that binds GDF-15, preventing its signaling through GFRAL.

In the preceding 12-week double-blind study, ponsegromab demonstrated improvements in body weight, appetite, cachexia-related symptoms, overall physical activity and skeletal muscle mass versus placebo, with a favorable safety profile. The current analysis aimed to evaluate longitudinal changes in body weight, GDF-15 levels, and safety over a 64-week treatment period.

Randomized Phase 2 Ponsegromab Study Design: Part A and Part B

The trial comprised two parts. Part A was a 12-week double-blind, randomized, placebo-controlled study. Eligible patients included those with non-small cell lung cancer, pancreatic cancer, or colorectal cancer meeting Fearon criteria for cachexia, with elevated circulating GDF-15, ECOG performance status 3 or less, and life expectancy 4 months or more.

Patients were randomly assigned to receive placebo or ponsegromab at 100 milligrams (mg), 200 mg, or 400 mg subcutaneously (by injection) every four weeks for three doses. The primary endpoint of Part A was change in body weight at week 12, with secondary endpoints including patient-reported outcomes, physical activity, gait, safety, and lumbar skeletal muscle index.

Part B consisted of a 52-week open-label extension in which all eligible patients received ponsegromab 400 mg subcutaneously every four weeks through week 64. Exploratory endpoints included changes from baseline in body weight, pharmacokinetics, circulating GDF-15 concentrations, immunogenicity, and safety.

A total of 281 patients were screened, with 187 randomized to Part A, and 117 patients entered Part B.

Sustained Weight Gain Observed Across 64-Week Study of Ponsegromab

Observed mean changes from baseline in body weight for Part B patients demonstrated progressive gains over the 52-week open-label extension. At week 12, reflecting Part A treatment assignment, the overall mean increase was 1.26 kilograms (kg), rising to 5.18 kg at week 64, corresponding to a mean 9.35% increase from baseline.

When stratified by Part A assignment, patients initially randomized to placebo experienced weight loss at week 12 but gained weight following initiation of open-label ponsegromab 400 mg, albeit achieving less overall gain than patients continuously treated with ponsegromab from Part A. Mixed-model analyses corroborated these outcomes, demonstrating consistent weight increases across all Part B participants.

“We note that the placebo group, across all those time points, tends to gain less weight than the group initially assigned ponsegromab,” said Crawford. “… We see an increase across all groups in weight with open-label ponsegromab 400 mg, but the initial placebo group lags behind.”

GDF-15 suppression was robust and sustained. At week 12, placebo patients demonstrated rising GDF-15 levels, whereas ponsegromab-treated groups (100 mg-400 mg) exhibited 55% to 97% reductions. After transitioning to open-label ponsegromab 400 mg, all patients achieved a median 97% decrease in GDF-15, maintained through week 64, regardless of initial treatment.

Safety Profile: Ponsegromab Well-Tolerated With Minimal Treatment-Related Side Effects

Side effects were common (84.2%), largely driven by underlying malignancy, concomitant therapies, and comorbidities, according to Crawford. Grade 1 to 2 side effects occurred in 34.2%, grade 3 to 4 in 29.8%, and grade 5 (death) in 20.2% of patients.

Serious side effects affected 43.9%, with 24.6% permanently discontinuing study interventions. Importantly, treatment-related side effects were rare (less than 5%) and limited to grade 1-2; no deaths were considered related to ponsegromab.

Next Steps: Phase 2b Study in Metastatic Pancreatic Cancer

These results support ongoing evaluation in the phase 2b study of ponsegromab in patients with metastatic pancreatic cancer receiving first-line chemotherapy, designed to define optimal dosing for a subsequent pivotal phase 3 trial, incorporating both cachexia-specific and treatment-related outcomes.

Reference

1. “Efficacy and safety of ponsegromab in patients with cancer-associated cachexia: Results from the open-label extension of a randomized, placebo-controlled,” by Dr. Jeffrey Crawford. Presented at: ESMO 2025 Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA102.

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