Potential new treatment for cancer-related cachexia

Abstract

An investigational drug that inhibits a critical driver of cachexia shows promise in improving body weight, muscle mass, quality of life, and physical function in patients with cancer-related cachexia.

After 12 weeks of treatment, patients with cancer-related cachexia who were treated with ponsegromab, a humanized monoclonal antibody that inhibits GDF-15, had a significant increase in weight gain from the baseline in comparison with patients treated with a placebo.

When patients were treated with the highest dose of ponsegromab (400 mg), improvements were seen in appetite and cachexia symptoms, physical activity, and muscle mass in comparison with those treated with the placebo. At this dosage, weight increased by a mean of 5.6%. This suggests a clinically important result according to the Cancer Cachexia Endpoints Working Group, which has suggested that a weight gain of more than 5% is clinically important.¹

“Collectively, these results point to the potential for ponsegromab as a novel, targeted therapy to address an unmet medical need of patients with cancer and cachexia,” says the lead author of the study, John D. Groarke, MBBCh, MSc, MPH, senior director of Cardiometabolic Clinical Research in the Internal Medicine Research Unit at Pfizer. The “findings offer hope that a breakthrough targeted treatment is potentially on the horizon for our patients.”

He also underscores that the findings provide “strong evidence that we have unlocked a mechanism to interrupt a critical driver of cachexia, GDF-15, which has the potential to impact patients with cancer cachexia and other diseases.”

In the phase 2 study, investigators assessed the safety and efficacy of ponsegromab at three different doses versus a placebo. The study included 187 patients with cancer cachexia who were randomized to 12 weeks of ponsegromab at a dose of 100 (n = 46), 200 (n = 46), or 400 mg (n = 50) or the placebo (n = 45). All patients had experienced involuntary weight loss of >5% within the previous 6 months or >2% with a body mass index of <20 kg/m² (the definition of cachexia used in the study) and had a serum GDF-15 level of at least 1500 pg/mL. Most patients had non–small cell lung cancer (40%), which was followed by pancreatic cancer (32%) and colorectal cancer (29%), and most patients (90%) were receiving systemic treatment for their cancer at the time of randomization.

The primary endpoint of the study was body weight change from the baseline after 12 weeks of treatment. The study also assessed functional outcomes, appetite, and physical activity along with safety.

At 12 weeks, patients treated with ponsegromab had significantly greater weight gain than those treated with the placebo according to Bayesian statistical analyses that included adjustments for the competing risk of death and other events such as treatment discontinuation. In comparison with the placebo, the between-group difference in weight gain was 1.22 kg (100-mg dose), 1.92 kg (200-mg dose), and 2.81 kg (400-mg dose); all these values were statistically significant (<0.05).

An additional prespecified analysis showed that compared to placebo, the mean percentage change in body weight from the baseline to week 12 was 2.02% (100-mg dose), 3.48% (200-mg dose), and 5.61% (400-mg dose).

Secondary outcomes showed that patients treated with the highest dose (400 mg) of ponsegromab had improvements in measures of appetite and cachexia symptoms compared to patients treated with the placebo. Improvements in skeletal muscle mass also were found compared to the placebo group via an exploratory analysis that showed an increase in the lumbar skeletal muscle index of 2.04 cm²/m² in patients treated with a 400-mg dose.

Adverse events were similar between the treatment and placebo groups and were reported in 70% and 80% of the patients, respectively. The most common adverse events in the treatment groups were diarrhea, cancer progression, anemia, hypokalemia, nausea, vomiting, and pyrexia. Serious adverse events occurred in 22%–40% of the patients treated with ponsegromab and in 24% of the patients in the placebo group. In the ponsegromab groups, two of these serious adverse events were considered by the investigators to be trial-related. One occurred in a patient on a 100-mg dose (abdominal pain), and the other occurred in a patient on a 200-mg dose (dyspnea).

David Hui, MD, a professor of palliative, rehabilitation, and integrative medicine and a professor of oncology at The University of Texas MD Anderson Cancer Center, calls the findings promising and says that ponsegromab is the first-in-class agent to show clinical activity in improving body weight, function, and quality of life in patients with cancer cachexia.

He notes that although several GDF-15 inhibitors have been tested in cancer cachexia, the current study is the largest to date demonstrating positive clinical outcomes. However, he emphasizes that the current trial is only one trial and that patients were followed for only 12 weeks.

Confirmation of the study’s findings also could open novel drug development to target GDF-15, says Dr Hui. “Confirmation that inhibition of GDF-15 could effectively improve cachexia-related outcomes could lead to the development of other novel agents targeting this pathway,” he says.

Given the complexity of cachexia and its wide-ranging implications for patients with cancer, Dr Hui says that although specific agents targeting cachexia are important, he encourages oncologists to consider referring their patients with advanced cancer and cachexia to a specialist palliative care team to optimize management of the multiple issues facing these patients, including nutrition and psychosocial challenges.