Inhibiting monoclonal antibody GDF-15 improves cancer cachexia symptoms

A new phase 2 study found that ponsegromab (Pfizer) helped with issues typically associated with cancer cachexia by suppressing weight loss and improving appetite and physical activity. Researchers found that the monoclonal antibody inhibited the serum level of growth differentiation factor 15 (GDF-15), which is associated with cachexia’s multifaceted syndrome. Currently, there are no medicines approved for treating cancer cachexia.

“We believe this study is a unique development elevating symptom science because it is a biomarker-driven symptom intervention,” says study author Eric Roeland, MD, an associate professor of medicine in the Division of Hematology/Medical Oncology at the Oregon Health and Science University’s Knight Cancer Institute Clinic in Portland, Oregon.

The study appears in The New England Journal of Medicine (doi:10.1056/NEJMoa2409515).

This first in-patient, open-label, phase 1b study assessed the use of ponsegromab in 10 patients with cancer cachexia and elevated GDF-15 serum concentrations. Researchers found that ponsegromab improved the patients’ body weight and appetite, with lower serum GDF-15 levels and few adverse events (doi:10.1158/1078-0432.CCR-23-1631).

Dr Roeland says that a key reason for this latest study was the recognition that the GDF-15 cytokine binds to the glial cell–derived neurotrophic factor family receptor alpha-like protein (GFRAL) in the hindbrain. The GDF–GFRAL pathway is recognized as a main modulator of anorexia and body-weight regulation that potentially results in cachexia. These reported results are included in Part A of the study; Part B, an optional open-label extension, is ongoing.

The study was conducted from February through December 2023 with 187 patients: 40% had non–small cell lung cancer (74 patients), 32% had pancreatic cancer (59 patients), and 29% had colorectal cancer (54 patients). Patients were at least 18 years old with a median age of 67 years. Approximately two thirds of the participants were male; 37% of the participants were female.

The potential cachexia symptoms that the researchers investigated included a non–diet-related weight loss of 5% or more in the prior 6 months and an elevated serum GDF-15 level (≥1500 pg/mL). Patients with cachexia due to a nonmalignant illness, planned surgery, or weight-gaining prescribed drugs were excluded.

Ponsegromab was administered to patients at 74 sites in 11 countries. Four similarly sized groups underwent randomization. Every 4 weeks, one group (46 patients) received 100 mg subcutaneously, the second group (46 patients) received 200 mg subcutaneously, the third group (50 patients) received 400 mg subcutaneously, and 45 patients received a placebo, for a total of three doses each.

All 187 patients were treated, with 137 patients (73%) completing the 12-week trial. A similar number of patients in each group did not complete the study.

The primary end point was weight variations from the baseline after 12 weeks. Key secondary end points included changes in appetite, nausea, and cachexia symptoms along with measures (wearable digital health devices) of physical activity, including fatigue and safety. The researchers also investigated changes in the lumbar skeletal muscle index.

“This study is important because it provides early evidence that elevated GDF-15 is associated with cancer cachexia,” says Elizabeth Isenring, PhD, a professor of nutrition and dietetics at Bond University in Robina, Queensland, Australia, and chief executive officer of Linc Nutrition in Hope Island, Queensland, Australia. “Also, because it shows that ponsegromab improves weight, appetite, physical function, and symptoms.”

Dr Isenring notes that because no drug has been proven effective across the globe, the current paradigm is that there is not much one can do when a patient is experiencing refractory cachexia. “This RCT [randomized controlled trial] provides emerging evidence that a monoclonal antibody inhibiting GDF-15 may offer symptom relief even in cases of advanced disease and severe weight loss.”

Dr Isenring believes that future RCTs powered to detect changes in skeletal muscle mass and function, physical activity, quality of life, and survival as well as further investigations into the timing of the initiation of ponsegromab and the length of its treatment are required. “Even in advanced cases—large weight loss or refractory cachexia—ponsegromab appears to be of benefit without significant side effects.”

She adds, “If confirmed in a well powered study, this would be a breakthrough, as increased muscle mass and strength are closely associated with activities of daily living and quality of life.” She says that is important because muscle wasting is a hallmark of cancer.

Dr Roeland adds, “I was taught as an oncology fellow that the way to treat cancer cachexia was to control the cancer, and I agree with that. However, I also recognize that improving symptoms and focusing on the patient as a person is essential, and when we think about things like evidence-based strategies for nausea and pain, for example, we’re not going to just treat the underlying cancer and not also treat those symptoms.”

He believes that non-sensory physical activity is very patient centered, and as a practicing oncologist and palliative care specialist, he thinks that is meaningful in successfully treating patients. “How we measure that broadly in a larger sense is part of the next steps.”

Dr Roeland sees the major hurdle facing drug approval by the US Food and Drug Administration as defining the functional end point in cancer cachexia, “and I don’t think that has been well-defined. This is all very exciting, but we still have a lot of work to do.”