Elsevier

The Lancet Oncology

Volume 21, Issue 11, November 2020, Pages 1489-1499
The Lancet Oncology

Articles
Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study

https://doi.org/10.1016/S1470-2045(20)30493-9Get rights and content

Summary

Background

Surufatinib showed superior efficacy in extrapancreatic neuroendocrine tumours (NETs) in the phase 3 SANET-ep study. In SANET-p, we aimed to assess the efficacy and safety of surufatinib in patients with advanced pancreatic NETs.

Methods

SANET-p was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, done in 21 hospitals across China. Eligible patients were adults (aged 18 years or older) with progressive, advanced, well differentiated pancreatic NETs, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and progression on up to two kinds of previous systemic regimens for advanced disease. Patients were randomly assigned (2:1) via an interactive web response system to receive 300 mg of surufatinib or placebo, taken orally once per day in consecutive 4-week treatment cycles until disease progression, intolerable toxicity, withdrawal of consent, poor compliance, use of other antitumour medication, pregnancy, loss to follow-up, or if the investigator deemed discontinuation in the patient's best interest. Randomisation was done centrally using stratified block randomisation (block size three), stratified by pathological grade, previous systemic antitumour treatment, and ECOG performance status score. Patients, investigators, research staff, and the sponsor study team were masked to treatment allocation. Crossover to surufatinib was permitted for patients in the placebo group with disease progression. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, which included all patients in randomisation. A pre-planned interim analysis was done at 70% of the predicted progression-free survival events. This study is registered at ClinicalTrials.gov, NCT02589821.

Findings

Between Feb 18, 2016, and Nov 11, 2019, of 264 patients who were screened, 172 (65%) patients were randomly assigned to receive surufatinib (n=113) or placebo (n=59). The median follow-up was 19·3 months (95% CI 9·3–19·4) in the surufatinib group and 11·1 months (5·7–35·9) in the placebo group. The median investigator-assessed progression-free survival was 10·9 months (7·5–13·8) for surufatinib versus 3·7 months (2·8–5·6) for placebo (hazard ratio 0·49, 95% CI 0·32–0·76; p=0·0011). The trial met the early stopping criteria at the interim analysis and was terminated on recommendation from the independent data monitoring committee. The most common grade 3 or worse treatment-related adverse events were hypertension (43 [38%] of 113 with surufatinib vs four [7%] of 59 with placebo), proteinuria (11 [10%] vs one [2%]), and hypertriglyceridaemia (eight [7%] vs none). Treatment-related serious adverse events were reported in 25 (22%) patients in the surufatinib group and four (7%) patients in the placebo group. There were three on-treatment deaths in the surufatinib group, including two deaths due to adverse events (gastrointestinal haemorrhage [possibly treatment-related] and cerebral haemorrhage [unlikely to be treatment-related]), and one death attributed to disease progression. One on-treatment death in the placebo group was attributed to disease progression.

Interpretation

Surufatinib significantly improves progression-free survival and has an acceptable safety profile in patients with progressive, advanced pancreatic NETs, and could be a potential treatment option in this patient population.

Funding

Hutchison MediPharma.

Introduction

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.

Section snippets

Study design and participants

SANET-p was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, done in 21 hospitals across China. The study was done in accordance with good clinical practice principles and relevant local regulations. The study protocol, amendments, and informed consent forms were approved by the institutional review board or ethics committee of each participating centre. Any protocol deviations were reported and documented. The full study protocol, including summary of all amendments,

Results

From Feb 18, 2016, to Nov 11, 2019, 264 patients were screened, of whom 172 (65%) eligible patients were enrolled (figure 1). A total of 113 patients were randomly assigned to the surufatinib group and 59 to the placebo group. All 172 patients were included in the intention-to-treat population and received at least one dose of their assigned treatment. At the time of data cutoff for the interim analysis (Nov 11, 2019), 65 (58%) of 113 patients in the surufatinib group and 41 (69%) of 59

Discussion

In the interim analysis of this randomised, phase 3 study, patients with progressive, advanced, well differentiated pancreatic NETs who were given surufatinib had significantly longer median progression-free survival (10·9 months) compared with patients given placebo (3·7 months) according to investigator assessment. The improvement in progression-free survival was supported by the BIIRC sensitivity analysis (13·9 months with surufatinib vs 4·6 months with placebo), and was maintained across

Data sharing

The study protocol and statistical analysis plan are available in the appendix. Individual participant data are not available to others.

References (24)

  • PE Sackstein et al.

    Epidemiologic trends in neuroendocrine tumors: an examination of incidence rates and survival of specific patient subgroups over the past 20 years

    Semin Oncol

    (2018)
  • Y Lin et al.

    Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications

    J Hematol Oncol

    (2019)
  • A Dasari et al.

    Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States

    JAMA Oncol

    (2017)
  • Y Gao et al.

    A meta-analysis of prognostic factor of pancreatic neuroendocrine neoplasms

    Sci Rep

    (2018)
  • M Pavel et al.

    ENETS consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site

    Neuroendocrinology

    (2016)
  • A Rinke et al.

    Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group

    J Clin Oncol

    (2009)
  • ME Caplin et al.

    Lanreotide in metastatic enteropancreatic neuroendocrine tumors

    N Engl J Med

    (2014)
  • E Raymond et al.

    Sunitinib malate for the treatment of pancreatic neuroendocrine tumors

    N Engl J Med

    (2011)
  • JC Yao et al.

    Everolimus for advanced pancreatic neuroendocrine tumors

    N Engl J Med

    (2011)
  • J Strosberg et al.

    Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors

    N Engl J Med

    (2017)
  • T Annese et al.

    Angiogenesis in pancreatic cancer: pre-clinical and clinical studies

    Cancers

    (2019)
  • J Pozas et al.

    Targeting angiogenesis in pancreatic neuroendocrine tumors: resistance mechanisms

    Int J Mol Sci

    (2019)
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