Telotristat Ethyl Plus Chemo May Stabilize Weight in Metastatic PDAC

Telotristat ethyl may stabilize weight in patients with PDAC experiencing cachexia who receive chemotherapy, a phase 2 study reported.

Adding telotristat ethyl to chemotherapy may result in weight stabilization in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and cachexia, according to findings from a phase 2 study (NCT03910387) presented at the 2025 ASCO Gastrointestinal Cancers Symposium.

“Telotristat ethyl may be an option for the management of weight loss in patients with pancreatic cancer,” the study authors wrote in the poster. “…Telotristat [ethyl] is tolerable and may improve survival in patients with advanced pancreatic cancer when combined with chemotherapy,” the study authors wrote in the poster.

Researchers enrolled 22 patients into this study, who were then split into 2 groups. Group 1 (n = 14) included patients who had lost at least 10% of their body weight from baseline, and they received gemcitabine and nab-paclitaxel on days 1, 8, and 15, plus telotristat ethyl. In particular, telotristat ethyl was administered orally as a 250-mg dose 3 times per day. Group 2 (n = 8) consisted of patients with less than 10% loss of their body weight, and they received chemotherapy without telotristat ethyl.

According to the poster, over 3 months, the mean percent weight change in group 1 was -1.6% (90% CI, -6.7 to 3.4; P = .0595) and -4.4% for group 2 (90% CI, -9.4 to -1.7; P = .5274).

Researchers also assessed serum serotonin on a monthly basis during the study. As noted in the poster, at 3 months, the median change in serotonin levels was -37.8% in group 1 (IQR: -59.1 to -13; P = .064) and -42.6% in group 2 (IQR: -57.8 to -29.9; P = .016).

According to Kaplan-Meier overall survival (OS) estimates, the median OS was 10.7 months for group 1 (95% CI, 5.4-16.9) and 12.2 months for group 2 (95% CI, 6.1-21.4; HR = 1.41; 95% CI, 0.57-3.52; P = .46).

The adverse events (AEs) observed in this study were consistent with the known profiles of gemcitabine and nab-paclitaxel and with telotristat ethyl. AEs were reported in 13 patients (93%) in group 1, according to the poster. Sixty-four percent of patients in group 1 and 57% of those in group 2 experienced general disorders and administration site conditions, in addition to gastrointestinal disorders. Additionally, 2 patients (14%) reported grade 3 AEs, 1 of whom had abdominal disorders and 1 had respiratory disorders.

Study Background and Design

According to the abstract, a key feature of PDAC is cachexia, which affects approximately 80% of patients and may be linked with worse outcomes. Serotonin may contribute to this weight loss, as it has tumorigenic potential and can affect the gut’s function.

Researchers aimed to develop this phase 2 study to assess telotristat ethyl, a drug that inhibits serotonin production, and its potential impact on the weight of patients with metastatic PDAC treated with first-line chemotherapy.

The primary end point of this study was weight stability, which was evaluated as a percentage of weight change at 3 months vs. baseline. The goal of this study was to achieve a less than 5% decrease in weight. A key secondary end point was the change in serotonin levels at 3 months vs baseline. Researchers noted that the groups were analyzed independently.

Patients in this study had a median age of 70 years (IQR, 62-75), most were male (68%), and 50% of patients were Black. At the start of treatment, patients in group 1 had a mean weight of 77.9 kg (SD, 19.16), and those in group 2 had a mean weight of 90.6 kg (SD, 24.71). At baseline, group 1 had a mean serotonin level of 165.07 ng/ml (SD, 60.49) and 296.9 ng/ml (SD, 166.65) in group 2.

Future Research

Researchers noted that an ongoing analysis to evaluate the impact of telotristat ethyl and/or chemotherapy on muscle changes is warranted, as noted in the poster. They also indicated the potential to evaluate biomarkers in a large prospective group of patients to determine the potential link between serotonin and pancreatic cancer prognosis as an area for future research.

“A large, randomized study is required to confirm the effect of telotristat [ethyl] in promoting weight stability and ultimately improving overall survival in pancreatic cancer,” the study authors wrote.

Reference

Gbolahan O, Babadi E, McPherson T, et al. Telotristat ethyl to promote weight stability in patients with advanced pancreatic cancer. J Clin Oncol. 2025;43(suppl 4):747. doi:10.1200/JCO.2025.43.4_suppl.747