Phase-II Trials of Pazopanib in Metastatic Neuroendocrine Neoplasia (mNEN): A Systematic Review and Meta-Analysis

Abstract

Background: Several phase-II trials have been designed to evaluate tyrosine kinase inhibitors (TKIs), in particular, pazopanib in neuroendocrine neoplasia (NEN), but its efficacy has not yet been demonstrated in a randomised-controlled Phase III trial. A systematic review of the published clinical trials of metastatic NEN patients could reduce the possible bias of single phase II studies. The present systematic review focuses on the efficacy and safety of pazopanib in patients with metastatic and locally advanced NEN. Methods: A systematic search in the major databases Medline/PubMed, Cochrane and Embase and in supplementary material from important international Meetings was performed to identify publications on pazopanib for the treatment of neuroendocrine neoplasia. English language was defined as a restriction. Four authors of the present review independently performed the study selection, assessed the risk of bias and extracted study data. Four published clinical trials and 2 abstracts were identified. One trial was excluded because the topic was Von-Hippel Landau disease and one abstract was eliminated because of the lack of information on meeting proceedings. Results: In all of the trials pazopanib was orally administered at a dose of 800 mg daily continuously with a 28-day cycle. The intention-to-treat population for efficacy was composed of 230 patients with a median age of 62 years. The partial response rate was 10.7% (95% confidence interval 2.6-20.5). The rate for stable disease was 79.6% (range: 61.7-92.1%) with a disease control rate (DCR) of 90.3%. Progressive disease was reported in 9.7% (range 5.2-17.6) of patients. No complete responses were observed. Median progression-free survival was 11.6 months (95% CI: 9.2-13.9). Overall survival from all the trials was 24.6 (95% CI: 18.7-40.8) months. Severe adverse events (grade III-IV) included hypertension 31%, 16% increase in AST/ALT, diarrhoea 10% and fatigue 10%. Bongiovanni et al. Systematic Review on Pazopanib in mNEN Conclusions: Pazopanib monotherapy achieved a DCR of 90.3% in patients with locally advanced and/or metastatic neuroendocrine neoplasia, with an overall response rate comparable to other TKIs and mTOR inhibitors and a safety profile similar to that of drugs of the same class.

Identification of m6A/m5C/m1A-associated LncRNAs for prognostic assessment and immunotherapy in pancreatic cancer

“…However, the former has a broader range of targets, including vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3; platelet-derived growth factor receptors (PDGFR) α and β, etc. 61 . Given its ability to inhibit numerous targets, pazopanib can potentially be used to treat pancreatic cancer 62 .…”

A Phase II Study of Ziv-Aflibercept in Patients With Advanced Extrapancreatic Neuroendocrine Tumors

“…In one metaanalysis evaluating pazopanib therapy in the treatment of advanced neuroendocrine neoplasms, the incidence of grade 3 or higher HTN was 31.3%. 16 In contrast, in a meta-analysis of patients with a variety of cancers not including NET, the incidence of high-grade HTN was 6.5%. 17 The mechanism for this difference in incidence of HTN is not clear but likely involves the vascular nature of NETs when compared with other tumor types, vasoactive peptides secreted by NETs, and potentially the concurrent use of somatostatin analogs, which can also be associated with HTN.…”

Primary Neuroendocrine Tumor of the Breast: Current Understanding and Future Perspectives

“…Pazopanib, an oral multitargeted tyrosine kinase inhibitor, acts through VEGFR types 1–3. A systematic review has elucidated the efficacy and safety of pazopanib in patients with locally advanced and metastatic NEN, indicating that pazopanib may be an option for NECB patients ( 67 ). Immunotherapy using checkpoint inhibitors that block PD-1/PD-L1 has emerged as a highly effective therapy in numerous patients across a range of malignancies.…”