Health-related quality of life in patients with advanced well-differentiated pancreatic and extrapancreatic neuroendocrine tumors treated with surufatinib versus placebo: Results from two randomized, double-blind, phase III trials (SANET-p and SANET-ep)

Highlights

• Surufatinib showed a comparable effect on HRQoL to placebo for patients with NETs.

• Surufatinib increased risk of deterioration in diarrhea versus placebo.

• Surufatinib decreased risk of deterioration in dyspnea versus placebo.

• Surufatinib is a promising treatment option for advanced NETs.

Abstract

Aim

To investigate the health-related quality of life (HRQoL) of patients who had neuroendocrine tumors (NETs) from SANET trials.

Methods

Eligible patients were randomized in a 2:1 ratio to receive surufatinib or placebo. HRQoL questionnaires, including the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-G.I.NET21, were collected. The prespecified HRQoL outcome was the mean change of scores from baseline to the last available visit for each domain. Time until definitive deterioration (TUDD) was defined as the time from randomization to deterioration of ≥10 points from baseline in domain score, disease progression, or death.

Results

370 patients were enrolled and randomly assigned to surufatinib (n = 242) or placebo (n = 128). No significant difference in mean scores change from baseline to the last available visit was observed for QLQ-C30 and QLQ- G.I.NET21 domains, with the exception of diarrhea. The mean score of diarrhea increased 11.7 points from baseline in the surufatinib arm and decreased 1.2 points in the placebo arm, and the between-group difference was 12.9 points. Compared with placebo, surufatinib treated patients had a significantly longer TUDD for dyspnea (hazard ratio [HR] 0.58; 95% confidence interval [CI], 0.39–0.86; P = 0.0058) and a significantly shorter TUDD for diarrhea (HR 2.91; 95% CI, 1.66–5.10; P < 0.0001). There were no significant differences in TUDD for the remaining domains of QLQ-C30 and G.I.NET-21.

Conclusions

HRQoL was similar in patients treated with surufatinib and placebo except for diarrhea. The preservation of HRQoL supports surufatinib as a treatment option for NETs.

Clinical trial information

ClinicalTrials.gov: NCT02589821, NCT02588170.

Introduction

Neuroendocrine tumor (NET) is a relatively rare disease, but incidence rates have been increasing steadily, more than doubling over the two decades to 2012 [1]. About half of patients with NET are diagnosed at an advanced or metastatic stage at the time of diagnosis, and the prognosis of advanced NETs varies substantially by diverse organ origins with highly heterogeneous biological behaviors [1,2]. For advanced or metastatic NETs, the overall survival can range from four months for colon NETs to 5.8 years for small intestine NETs. Although the life expectancy of NET is relatively long, some previous studies have shown that patients with advanced NET often had poor physical, emotional, and social functioning, as well as impaired sleep and fatigue [3,4]. Functional NETs may secrete active peptides that cause carcinoid syndrome and exhibit specific disease-related symptoms such as cutaneous flushing and diarrhea, and NETs can also produce symptoms as a result of primary or metastatic tumor burden [5]. In addition, available therapeutic options for NETs are often administered for longer periods of time that may lead to an increased incidence of exposure-related adverse events. In such cases, health-related quality of life (HRQoL) outcome measure should be a priority in clinical trials from a patient-centered cancer care's perspective. Moreover, several studies have detected a significant relationship between deterioration in HRQoL and worse survival in patients receiving treatment for various types of tumors [[6], [7], [8]]. However, the impact of therapeutic interventions on HRQoL of patients has not been well established in most current clinical trials of NETs [9,10].

Surufatinib is a novel small-molecule tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, fibroblast growth factor receptor 1 (FGFR1), and colony-stimulating factor-1 receptor (CSF-1R) simultaneously [11]. In two randomized, double-blind, and phase III trials named SANET-p and SANET-ep, surufatinib significantly prolonged progression-free survival (PFS) compared with placebo in both pancreatic (10.9 vs. 3.7 months; hazard ratio [HR] 0.49, 95% confidence interval [CI], 0.32–0.76; P = 0.0011) and extrapancreatic (9.2 vs. 3.8 months; HR 0.33; 95% CI, 0.22–0.50; P < 0.0001) NETs [12,13]. The most common treatment-related adverse events were hypertension, proteinuria, and diarrhea, which are known adverse events of small-molecule anti-angiogenic TKIs. Although patients treated with surufatinib had a higher proportion of dose interruption or reduction than placebo (73.1 vs. 40.9%), most surufatinib treatment-related adverse events were generally well tolerated. Based on the encouraging results of the two trials, the China National Medical Products Administration granted regulatory approval to surufatinib for the treatment of progressive, advanced, and well-differentiated pancreatic and extrapancreatic NET. To further support the efficacy and safety findings of surufatinib, we performed a pooled analysis of the SANET-p and SANET-ep trials to assess the HRQoL among these patients.