Telotristat ethyl with PRRT in the treatment of well differentiated neuroendocrine tumors.
Authors: Zhuang Tony Z. , Muzahir Saima , Murphy Kristina D. , Akce Mehmet , Alese Olatunji B. , Diab Maria , Gbolahan Olumide B. , Shaib Walid Labib 
Published: June 2022

e16205

Background: Feasibility of telotristat ethyl, a tryptophan hydroxylase inhibitor in serotonin synthesis, in combination with PRRT/lutetium Lu 177 DOTATATE is unclear in well differentiated neuroendocrine tumors (WDNET). We explore real world treatment patterns in patients receiving telotristat and PRRT. Methods: A retrospective study was conducted on 67 patients with a histopathologic diagnosis of WDNET, treated with telotristat and/or PRRT at the Winship Cancer Institute in Emory University from 2018 to 2022. OS and PFS were assessed by Kaplan Meier curves. Descriptive analysis was performed with associations characterized by multi- (MVA) and univariate (UVA) Cox proportional hazards model, t-test, and ANOVA. Results: Of the 67 patients, 44 received PRRT alone and 23 received PRRT with telotristat for carcinoid symptoms. Median age was 69 (range 18-80) with male 57% and white race 65%. 16 (26%), 41 (67%), 4 (7%) had grades 1 (Ki67 < 3%), 2 (3-20%), and 3 (> 20%) disease respectively. The plurality (n = 31, 46%) had primary small bowel (SB) NETs and 40 (65%) underwent primary NET resection. 2 had gastrinomas, 1 VIPoma, and 1 insulinoma. All had liver and 23 (40%) had bone metastases. Most patients received PRRT as 3rd line therapy. 59 (88%) in the entire cohort and 17 (74%) in the telotristat group received 4 doses of PRRT. 15 (17%) in the entire cohort had delayed/dose reduced PRRT. Telotristat was associated with improved diarrhea and decreased serotonin (all p < 0.003). 16 (70%) on telotristat reported improvement in diarrhea and flushing. 5 (17%) had grade 3/4 adverse events while receiving telotristat. Of those, 1 developed hypotension, 1 hypokalemia, 1 myelodysplastic syndrome, 1 febrile neutropenia, and 1 anemia and pursued hospice care after a cerebrovascular event. Median(m) OS, PFS, and follow up were 216, 33, 67 months (mo) for the entire cohort respectively. 6 (26%) died in the telotristat/PRRT group vs 17 (39%) PRRT only. 10 (43%) in the telotristat group progressed vs 18 (41%) in PRRT only. mPFS was 33 mo in telotristat/PRRT and not reached (NR) in PRRT only (p = 0.684). mOS was NR in the telotristat/PRRT group vs 216 mo in PRRT only (p = 0.717). In MVA, OS was associated with primary NET resection (HR 0.232), age > 60 (HR 7.88), SB primary NET (HR 0.097), and PRRT completion (HR 0.062, all p < 0.05). In MVA, PFS was associated with diarrhea (HR 3.7) and small bowel primary NET (HR 0.264, all p < 0.05). In UVA, lower OS and PFS were associated with elevated chromogranin A (CGA) (upper limit 225, HR 3.34, p < 0.02). Initial neutrophil-eosinophil ratio (NER) was associated with OS (HR 21.2) and PFS (HR 10.8) in MVA with optimal cutoff of 35.28 ( both p < 0.02). Conclusions: Patients with primary SB WDNETs and carcinoid symptoms benefited from receiving telotristat/PRRT in our study. CGA, serotonin, and NER are potential biomarkers to assess disease patterns. Multi-institutional studies and further follow up are needed to confirm these findings.