Ponsegromab a targeted therapy for cancer cachexia

In patients with cancer cachexia and elevated levels of growth differentiation factor-15 (GDF-15), GDF-15 inhibition with ponsegromab led to a significant increase in body weight and overall activity level and reduction in cachexia symptoms, a phase II study suggests.

“GDF-15, a circulating cytokine, is elevated in cancer cachexia … [Our] findings confirm the role of GDF-15 as a driver of cachexia,” said the researchers.

At 12 weeks, patients on ponsegromab had significantly greater weight gain than placebo recipients. The median between-group differences in the 100-, 200-, and 400-mg groups were 1.22, 1.92, and 2.81 kg, respectively (posterior probability <0.05 for all). [N Engl J Med 2024;doi:10.1056/NEJMoa2409515]

While the minimum change in body weight deemed clinically important has not been clearly established in patients with cancer cachexia, the Cancer Cachexia Endpoints Working Group has recently suggested a weight gain of >5 percent. [J Cachexia Sarcopenia Muscle 2024;15:816-852] “In our trial, patients on ponsegromab 400 mg exceeded 5 percent weight gain by 12 weeks vs placebo,” the researchers said.

Of note, half of the participants had a BMI-adjusted weight loss of grade 4, which signifies more refractory cachexia and shortest survival. [J Clin Oncol 2015;33:90-99] Yet, ponsegromab recipients experienced robust weight gain. “[This implies that] ponsegromab is associated with weight gain in patients with even the most severe weight loss … The results challenge the concept of refractory cachexia and suggest that even patients with advanced cachexia may benefit from ponsegromab,” the researchers said.

Seventy percent of ponsegromab recipients had adverse events (AEs) of any cause; in the placebo arm, the corresponding rate was 80 percent. The most common AEs were diarrhoea, cancer progression, and anaemia. Most AEs were mild to moderate. Serious AEs from any cause occurred in 22–40 percent of ponsegromab recipients and 24 percent of those on placebo.

Other treatment goals achieved

More patients on ponsegromab 200 mg reported no appetite loss at baseline vs the other groups (39 percent vs 21–28 percent). At week 12, ponsegromab 100 mg led to improved FAACT-ACS* and FAACT-5IASS** scores (4.12 and 2.20, respectively), as did the 400-mg dose (4.50 and 2.39).

In the subgroup of patients with data on physical activity and gait, those on ponsegromab 400 mg had increased overall activity at week 12 vs those on placebo, with a difference of 72 min/day with regard to non-sedentary physical activity.

“Weight gain alone is not considered a sufficient treatment goal for the multidimensional cachexia phenotype,” the researchers noted. The improvement in physical activity may represent clinically meaningful functional improvement by allowing patients to accomplish important daily activities. [Intern Med J 2015;45:474-482]

The appetite improvement may lead to improved quality of life (QoL) and reduced emotional stress. [J Cachexia Sarcopenia Muscle 2024;15:513-535] “The ponsegromab-mediated improvements in appetite and reductions in cachexia symptoms, as assessed by FAACT-ACS and FAACT-5IASS, are considered moderate-sized improvements based on standardized effect sizes,” they said.

Targeted therapies needed

Cachexia is prevalent in patients with multiple types of cancer and can lead to weight loss, muscle wasting, QoL and functional impairment, and reduced survival. [J Cachexia Sarcopenia Muscle 2016;7:507-509; Lancet Oncol 2011;12:489-495] “With no [approved] medications for the treatment of cancer cachexia in the US or Europe, pharmacologic options are limited,” the researchers noted.

Although low-dose olanzapine is recommended for advanced cancer patients, this is only based on a single-centre study. [J Clin Oncol 2023;41:2617-2627] Moreover, the benefits of a progesterone analogue or glucocorticoids are confounded by adverse effects (eg, thromboembolic events with progestins). [J Clin Oncol 2023;41:4178-4179; J Clin Oncol 2020;38:2438-2453]

The ghrelin receptor agonist anamorelin, approved in Japan, fell short of FDA approval due to modest improvements in body composition and none in terms of hand-grip strength. [ESMO Open 2021;6:100092] “Safe, effective, and targeted therapies for cancer cachexia are needed,” they stressed.

In this study, 187 patients with cancer cachexia (median age 67 years, 37 percent women, 37 percent Asian, median weight 54.8 kg) and an elevated serum GDF-15 level (median 3,903 pg/mL) were randomized 1:1:1:1 to receive SC ponsegromab 100, 200, or 400 mg or placebo Q4W for three doses. Of these, 40 percent had non-small cell lung cancer, 32 percent had pancreatic cancer, and 29 percent had colorectal cancer.

Eighty-six percent of patients on ponsegromab 400 mg had stage IV disease (65–74 percent in the other three groups). Ninety percent were on systemic anticancer therapies at randomization. A third were receiving platinum-based chemotherapy.

“Collectively, the results highlight the potential for ponsegromab as a targeted therapy for cancer cachexia,” said the researchers. “The benefit seen across three cancer types provides the first conclusive demonstration that GDF-15 is a primary driver of cachexia across different malignant solid tumours, thereby establishing this cytokine as a potential therapeutic target for further evaluation in clinical trials.”