Clinic Conversation of the Week: How to Talk to Patients About Ponsegromab for Cancer Cachexia

Hi everybody, I’m Waqas. I’m a first-year Medical Oncology Fellow at the University of Chicago. In this week’s Clinic Conversation, I’ll be talking about a trial that looked at ponsegromab, a drug that’s been studied for treating cancer cachexia.

What is Cancer Cachexia?

If you go back to Hippocrates, we all learned about the Hippocratic Oath during medical school, but Hippocrates also characterized cancer cachexia, which he described as “flesh being consumed and becoming water.” Cancer cachexia is defined as reduced dietary intake and altered metabolism. There are a lot of different ways that you can break it down, but clinically, it’s defined as a weight loss of 5% over the course of six months.

Despite cancer cachexia being recognized for over two millennia, we don’t actually have any FDA-approved treatments in North America or Europe for treating this condition and treating the weight loss and muscle wasting that we see in cancer patients. Today, I’m going to talk a little bit about this trial, a phase 2 trial published in the New England Journal of Medicine this September, that investigated ponsegromab.

The Pathophysiology Behind Cachexia

Before we go into the trial, I want to talk a little bit about the pathophysiology behind it. The trial centers on growth/differentiation factor 15 (GDF15), which is a cytokine protein that’s frequently overexpressed in cancer. This protein acts on the brainstem, specifically in the area postrema and also the nucleus of the solitary tract, where it basically suppresses appetite and induces nausea.

If you look at different chemotherapies that are emetogenic or contribute to nausea, such as platinum chemotherapies, you have a perfect storm of elevated GDF15 from both the cancer treatment and from the cancer itself. This can really harm patients’ nutrition.

Ponsegromab is a humanized monoclonal antibody, meaning that it’s designed to inhibit the GDF15 cytokine protein and target this pathway while also minimizing immune reactivity. Its development really represents a breakthrough in our understanding of how cancer affects appetite regulation and metabolism.

Investigating Ponsegromab

The trial, which included 187 patients, was randomized and placebo-controlled. It had patients with advanced cancers—either lung, pancreas, or colorectal cancer—who had measured elevated GDF15 levels. Participants received either placebo or ponsegromab at doses of 100, 200, or 400 mg as a subcutaneous dose administered every four weeks.

The nice thing about the trial was how the end points were designed. It had comprehensive end points, with the primary end point looking at how much weight the patients gained or lost over the course of the trial. There were also secondary end points looking at things like measuring appetite, different symptoms of cachexia, and digital markers of physical activity, like how many steps and the amount of physical activity that a patient had in a day.

The results were striking. After 12 weeks, patients on the highest dose of ponsegromab, the 400 mg dose, gained a median of 2.81 kg more than the placebo group. For us Americans who aren’t too good with the metric system, this is about 6 pounds. This weight wasn’t just fluid weight. The trial also measured lumbar skeletal muscle index, and that increased significantly compared with the placebo group as well.

The other important finding was that in the 400 mg group, the quality of life was also increased in terms of physical activity, which increased by 72 minutes compared with the placebo group. The improvements with ponsegromab occurred with minimal treatment-related adverse events, which is important. We also saw the increase in weight among all three doses of the ponsegromab treatment arm.

Future Directions

In terms of future implications, these results are definitely very promising, but there are a lot of questions that remain. The first thing is that this trial was placebo-controlled, so it wasn’t a head-to-head trial with other drugs that we use for weight loss or appetite. In the clinic, patients will be on things like low-dose steroids or mirtazapine, which is an antidepressant that can help with appetite, or even megestrol acetate.

It’d be interesting to see how ponsegromab compares with some of these drugs that are used for cachexia. Also, GDF15 is seen to be elevated in other conditions like heart failure and HIV. It’ll be interesting to see if this drug can be used in non-cancer indications as well.

So, given these results and future directions, what should we tell patients about ponsegromab?

Here’s What I Would Say

“Ponsegromab isn’t FDA-approved yet, but it’s still important to talk about the idea of treating weight loss and appetite loss within the context of comprehensive cancer care. What that means is ponsegromab isn’t going to directly target or cure the cancer itself, but it could improve your ability to tolerate chemotherapy and maintain quality of life. This is going to become increasingly relevant and important as we see increasing survival in cancer and as we see more patients entering cancer survivorship—whether being monitored for recurrence of their cancer or living longer with stage III or stage IV disease that’s incurable, but kind of treated like a chronic condition.

It’s important to keep in mind that maintaining weight during your cancer treatment is not just about comfort; it’s also about putting you in the best position to tolerate and undergo your treatment. I think the really nice thing about this trial was that the measurements of digital activity showed concrete evidence that treating cachexia can also help patients perform activities of daily living (ADLs) or daily routines and help you maintain some your independence as you undergo this very trying time in your life.

Overall, I think that the success in this trial highlights the importance of trying to research how cancer affects the function of the brainstem and also how it regulates our appetite. As we move towards more personalized treatment approaches, understanding these mechanisms is going to become even more optimal for patient care.

As we close, I would say that even though we’ve recognized cachexia for basically 25 centuries, two and a half millennia, it’s been without effective treatments, and this trial of ponsegromab represents a big step forward, especially for patients with advanced lung, pancreatic, and colorectal cancer. It shows that targeting specific molecular pathways is addressing comprehensive cancer care, not just in terms of treating the tumor, but in terms of maintaining the overall wellbeing of the patient.”

About Dr. Haque

Waqas Haque, MD, MPH, is a Hematology/Oncology Fellow at the University of Chicago. He recently completed his Internal Medicine Residency at New York University (NYU) in a Clinical Investigator Track. Dr. Haque has balanced his patient care work with a variety of research projects. During his fellowship training at the University of Chicago, he plans to further his work in innovative clinical trial design, value-based care delivery to cancer patients, and clinical investigation.