Pancreatic neuroendocrine tumours (NETs) are rare tumours arising from embryological neuroendocrine cells of the pancreas, and have been increasing in global incidence in the past few decades.1 The prognosis of pancreatic NETs varies according to numerous factors, including age, disease stage, pathological grade, and treatment.2, 3 NETs of lower grade (1 or 2, based on pathological grading of the proliferation marker protein Ki-67 index and the mitotic rate of tumour cells) are usually less aggressive than those of higher grade. In the metastatic setting, the median overall survival of grade 1 or 2 pancreatic NETs is about 5 years, based on estimates for tumours diagnosed between 2000 and 2012.1
Research in context
Evidence before this study
We searched PubMed for clinical trials of pancreatic neuroendocrine tumours (NETs) with the terms “pancreatic neuroendocrine tumour” and “phase 3 study”. We did not limit our search by date or language. Two randomised, placebo-controlled phase 3 studies in pancreatic NETs were identified. In a phase 3 trial in patients with advanced, well differentiated, progressive pancreatic NETs, sunitinib, a multiple kinase inhibitor targeting vascular endothelial growth factor receptor and other kinases, improved progression-free survival versus placebo. The RADIENT 3 trial reported that everolimus, an oral inhibitor of the serine/threonine-protein kinase mTOR, significantly prolonged progression-free survival compared with placebo in patients with progressive, advanced pancreatic NETs. In both studies, overall survival was improved in the treatment group, but did not reach statistical significance, potentially because of the large proportion of crossover from the placebo group to the treatment group.
Added value of this study
To our knowledge, SANET-p is the first randomised, controlled, phase 3 study showing the efficacy and acceptable safety profile of surufatinib in patients with pancreatic NETs.
Implications of all the available evidence
The results of SANET-p, along with those from previous studies, suggest that surufatinib is a viable therapeutic option for patients with advanced pancreatic NETs.
The currently recommended systemic treatments for unresectable, metastatic, well differentiated, grade 1 or 2 pancreatic NETs include somatostatin analogues (SSAs, eg, octreotide or lanreotide), which are generally used as first-line therapy. Subsequent options following disease progression include sunitinib (a multireceptor tyrosine kinase inhibitor), everolimus (a serine/threonine-protein kinase mTOR inhibitor), peptide receptor radionuclide therapy for somatostatin receptor-positive NETs, and chemotherapy.4, 5, 6, 7, 8, 9
Antiangiogenic targeting is an effective treatment strategy in pancreatic NETs. These tumours are hyper-vascularised because of the overexpression of proangiogenic factors, such as VEGF and VEGF receptors (VEGFRs), especially in liver metastases.10 Positive results from a phase 3 study7 of sunitinib (a drug targeting multiple kinases, including VEGFRs) in pancreatic NETs support the potential benefits of targeting tumour angiogenesis. However, primary and acquired resistance to sunitinib limits its clinical benefit for patients with pancreatic NETs.11
Surufatinib is a novel, small-molecule inhibitor that simultaneously targets tumour angiogenesis (via VEGFR-1, VEGFR-2, VEGFR-3, and fibroblast growth factor receptor 1) and immune evasion (via macrophage colony-stimulating factor 1 [CSF1] receptor). Targeting both the VEGF and fibroblast growth factor (FGF) pathways simultaneously could reduce tumour angiogenesis more effectively than targeting either pathway alone, which might translate into improved clinical outcomes.12, 13 The CSF1 signalling pathway is thought to promote the infiltration of tumour-associated macrophages (TAMs) into the tumour microenvironment, which could antagonise the effects of VEGF pathway blockade by triggering the release of proangiogenic factors.14 Thus, the simultaneous targeting of angiogenesis and TAM depletion might be a uniquely potent strategy to enhance antitumour activity.15
In phase 1 and phase 1b–2 clinical studies, surufatinib showed encouraging antitumour activity and manageable toxicity in patients with advanced NETs.16, 17 Surufatinib showed a significant improvement in progression-free survival in patients with NETs originating outside the pancreas in the phase 3 SANET-ep study.18, 19 In SANET-p, we aimed to assess the safety and efficacy of surufatinib in patients with advanced pancreatic NETs.