CACHEXIA IS A COMMON AND CONCERNING PROBLEM facing people with advanced cancer. This poorly understood condition—marked by substantial and unintentional loss of body mass—causes people to lose fat, muscle and bone and can be severely debilitating.

According to Thomas J. Smith, an oncologist and palliative care specialist at Johns Hopkins Medicine in Baltimore, it’s impossible to overestimate the emotional challenges cachexia can pose for patients, who can become severely fatigued and frail. “Patients who have cachexia often ask me how they can continue to fight their cancer when they are so weak,” he says. “And cachexia can have a devastating effect on family dynamics if the patient will no longer come to the dinner table or eat a favorite meal.”

The effects of cachexia can go beyond quality of life too: The National Cancer Institute estimates that cachexia can cause as many as 30% of deaths in some cancer types.

Cachexia occurs most often in advanced cancers of the lung, pancreas, colon and skin. But it may also happen with other cancer types, including head and neck, ovarian, and liver cancers. Although cachexia is commonly associated with cancer, it also occurs in people with other advanced chronic diseases, including heart failure and chronic obstructive pulmonary disease (COPD).

The Food and Drug Administration has not approved any medications to treat cachexia. But in 2023, the American Society of Clinical Oncology (ASCO) issued an update to its cachexia management guideline that suggested low doses of the antipsychotic drug Zyprexa (olanzapine) to increase appetite in adults with advanced cancer. For those who can’t tolerate Zyprexa, the ASCO report says that it is safe to try a short course of certain steroids.

The outlook for cachexia treatment improved more with the publication of a randomized phase II clinical trial that found patients who received the experimental drug ponsegromab at any dose gained weight. The study, which appeared Sept. 14, 2024, in the New England Journal of Medicine, tested the drug at three different doses and against a placebo.

The double-blind study included 187 people with pancreatic, colorectal or non-small cell lung cancer who had cachexia, as well as elevated blood levels of the hormone growth differentiation factor 15 (GDF-15), which has been linked to the condition. Each patient received an injection of ponsegromab or a placebo every four weeks for a total of three doses. At the end of 12 weeks, investigators compared participants’ current and baseline weights. They also measured participants’ changes in appetite, cachexia symptoms and physical activity.

Patients who received 400 mg of ponsegromab gained the most weight: 6.2 pounds. People who received 200 mg gained 4.2 pounds, while those in the 100-mg ponsegromab group gained 2.7 pounds.

“At 400 mg, the highest dose evaluated, we saw improvements from baseline in appetite and cachexia symptoms, physical activity and muscle mass, compared to patients in the placebo group,” says John Groarke, the study’s lead author and a researcher in the Pfizer Internal Medicine Research Unit. (The study was supported by Pfizer, which manufactures ponsegromab.) “These results point to the potential for ponsegromab as a novel targeted therapy to address unmet medical need of patients with cancer and cachexia.”

Ponsegromab was generally considered safe and well tolerated at all dose levels, according to Groarke. The most common adverse events in all groups were diarrhea, cancer progression, anemia and low potassium.

Smith, who was not involved with the study, called the results “striking,” adding that 6 pounds is a significant gain for patients with cachexia. “Appetite and quality of life increased during the study, and patients’ activity increased by 72 minutes per day,” he says. “That’s time the person could be sitting at the dinner table with their family, getting some light exercise or doing something else meaningful they enjoy.”

Every trial participant was tested for elevated levels of GDF-15, allowing researchers to study how well the drug worked at inhibiting this hormone. The results showed the drug blocked GDF-15 throughout the body. “These results provide the first demonstration that GDF-15 is a common driver of cachexia across different malignant solid tumors, thereby establishing GDF-15 as a therapeutic target,” says Groarke.

Smith calls this finding a breakthrough in scientific knowledge and patient care. “We have suspected for years that GDF-15 causes cachexia, and now we can finally identify it as one of the primary mediators of weight loss and loss of appetite,” Smith says. “By showing that GDF-15 is intimately involved in anorexia and cachexia, it opens the door to a wide variety of potential targets for new drugs.”

As a co-author of the ASCO cachexia guideline, Smith has studied the data closely. “I’ve been a big fan of Zyprexa as an appetite stimulant, but it doesn’t increase muscle mass,” he says. “Ponsegromab now shows it does both. That is a significant benefit in a serious condition.”