Large Clinical Trial For Cachexia Treatment

For decades, cachexia was thought of as an unfortunate and untreatable byproduct of cancer.

But a new understanding of the muscle-wasting syndrome, which is present in about 80 percent of cancer patients, has led to a surge of research. A current cachexia study focuses on the effectiveness of adding an experimental monoclonal antibody drug called ponsegromab to standard-of-care chemotherapy for metastatic pancreatic cancer. Early data regarding the drug looks promising.

“Unfortunately, cachexia is all too common and pancreatic cancer is the poster child for cachexia,” says medical oncologist Jeffrey Crawford, M.D., one of the world’s leading experts in cachexia research. Crawford is the George Barth Geller Distinguished Professor for Research in Cancer at the Duke University School of Medicine and member of the Duke Cancer Institute, in Durham, North Carolina.

He focuses the bulk of his practice on treating lung cancer, another cancer in which cachexia is especially common. “The general thought used to be you get rid of the cancer, you get rid of cachexia,” he says. “But lung cancer patients, especially today, generally have more treatment options than those with pancreatic cancer. So, cachexia is really a terrible burden for pancreatic cancer patients, affecting daily life in innumerable ways. And it’s also tough on caregivers to see their loved ones unable to eat, and if they can eat, unable to gain back the incredible amount of weight they lost.”

Early Data Is Promising

Early ponsegromab data presented at the European Society for Medical Oncology (ESMO) 2024 Congress and simultaneously published in The New England Journal of Medicine showed study participants who received ponsegromab at any dose had improvement in body weight, muscle mass, quality of life, and physical function. The phase II randomized study, called PROACC-1, on which the data is based, included 187 participants with non-small cell lung cancer, pancreatic cancer, or colorectal cancer. Each patient received an injection of ponsegromab or a placebo every four weeks for a total of three different doses. 

Ponsegromab demonstrated significant and robust increases in body weight after 12 weeks across all doses compared to placebo. Participants receiving 400 mg also showed improvements in measures of appetite and cachexia symptoms, physical activity, and skeletal muscle index. No clinically significant undesirable effects were noted with ponsegromab administration.

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At the ESMO Congress 2025, one-year data was presented showing that these benefits were maintained over the initial12 months and then an open-label continuation for a year. One hundred and seventeen patients with either non-small cell lung cancer, pancreatic cancer, or colorectal cancer were placed into the 12-month, open-label extension part of the trial. In these patients, the average weight gain was 2.7 kg (about 6 lbs.) at week 24, 4.4 kg (nearly 10 lbs.) at week 52 and 5.2 kg (11.4 lbs.) at week 64.

Patients who received a placebo in the original 24-week study portion and experienced weight stabilization were also entered into the open-label extension of the study. But their weight gain was less when compared to those who received the monoclonal antibody at the study’s inception.

“These weight gains are significant for someone with cachexia,” says Crawford, lead investigator of the study. “These people got their appetite back. They could eat, which is something we all take so for granted. Plus, their quality of life improved. They were more active and could do something they enjoy. That’s huge for these patients.”

Targeting GDF-15

Growth Differentiation Factor 15 (GDF-15) is a protein often elevated in cancer patients; it drives severe weight loss, muscle wasting, and loss of appetite. Early research showed that GDF-15, which is produced in the liver, kidneys, and intestines, is involved in the desire to eat. And later research showed how it binds to the protein GFRAL, which is involved in appetite control. Further research showed that blocking the GFRAL receptor effectively treated cachexia in mice and even helped them gain weight despite minimal food intake.

This better understanding of the biology of cachexia led to the development of ponsegromab, Crawford explains. Ponsegromab is a monoclonal antibody, a type of immunotherapy. It works by binding to GDF-15 in the blood, preventing it from interacting with receptors in the brain that trigger metabolic changes. 

About the Latest Study

The latest ponsegromab study, known as RIVER-mPDAC, is a double-blind, placebo-controlled, randomized, phase IIb/III study that evaluates ponsegromab combined with first-line chemotherapy in patients with cachexia and metastatic pancreatic cancer. The study hopes to enroll 1,000 patients across the phase IIb and phase III parts of the study. There is no interruption in enrollment between phases IIb and III. The primary endpoint in phase IIb is the percent change from baseline in body weight at week 12. The primary endpoint in the phase III study portion is the percent change from baseline in body weight and the change from baseline in appetite-related symptoms at week 12. Secondary endpoints include changes in physical activity, fatigue, physical function, safety, and tolerability.

This trial is available at many locations in the United States as well as in sites around the world. “This is the largest trial for cachexia,” says Crawford. “That alone is a huge step for cachexia research. We are all hoping for very positive data to come from this trial.”

Since ponsegromab is an experimental drug, it is only available in clinical trials. Currently, there are no FDA-approved drugs to treat cachexia.

But that doesn’t mean you shouldn’t seek help, according to Crawford. “The therapies we currently have for cachexia are not optimal, but they can provide some relief for some patients,” he says. “And that’s an important message to get out both to doctors and to patients. Don’t ignore it thinking nothing can be done.”

To learn more about managing cachexia, visit the Cancer Cachexia Society’s Cancer Cachexia Network, which offers important information about how to talk to your doctor about the syndrome.