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Background: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data., Methods: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs)., Results: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9-16.7): 13.2 (7.4-16.8) and 13.0 (9.2-20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7-33.8) in the total population: 21.3% (11.9-33.7) in treatment-naive and 28.9% (16.4-44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0-not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%)., Conclusions: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib., (© 2018 S. Karger AG, Basel.)

Neuroendocrine tumors (NETs) describe a heterogeneous group of tumors with a wide range of morphologic, functional, and behavioral characteristics. These tumors are generally slow growing and behave in an indolent fashion. However, they have the potential to spread, primarily to the liver and when they do, they can be life threatening and difficult to treat with current modalities. A subset of NETs, the pancreatic neuroendocrine tumors (pNET) represent a small percentage of all pancreatic tumors (1.3%) but their incidence is rising. Prior to 2011, the only approved agent for unresectable pNETs was streptozocin (often used in combination with doxorubicin) but the efficacy of this drug was questionable. In 2011, the landscape of treatment for pNET was changed with the approval of the first new agents in 20 years, sunitinib and everolimus, that demonstrated improvement in time to progression in patients with progressive pNET. Sunitinib is a multikinase inhibitor and everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) pathway. These drugs were approved by the Food and Drug Administration (FDA) on the basis of separate large randomized placebo-controlled trials. Data from these two trials and an additional phase III trial looking at everolimus in other neuroendocrine tumors has generated intense interest in this challenging disease. At the 2012 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, several researchers presented updated data regarding the risk stratification, treatment, and outcome for patients with pNET in the new era of targeted therapy. Choti et al. (Abstract #187) reviewed demographic data from a large set of patients who presented to National Comprehensive Cancer Network (NCCN) sites with neuroendocrine tumors. Casciano et al. (Abstract #226) and Signorovitch et al. (Abstract #237) presented post-approval analysis of the relative role of everolimus and sunitinib in the treatment of pNET. Alistar et al. (Abstract #166) explored predictive biomarkers in pNET, and Yao et al. (Abstract #157) conducted multivariate analysis of patients treated with everolimus in the phase III, RADIANT-2 trial which included the identification of relevant biomarkers. Hobday et al. (Abstract #260) and Bergsland et al. (Abstract #285) reported phase II data from two clinical trials looking at novel targeted combinations for the treatment of pNET. Finally the role of treatment for poorly differentiated NETs (including pNETs) remains ill-defined and Yamaguchi et al. (Abstract #274) presented a report reviewing the experience at 23 centers in Japan in treating this population. The authors review and summarize these abstracts in this article.

Neuroendocrine tumors (NETs) consist of a diverse family of tumors which are derived from the neuroendocrine system. Most NETs are well or moderately differentiated tumors with a relatively indolent growth pattern. However, these tumors can cause significant clinical disease due to release of functional products that mediate the carcinoid syndrome and other diverse sequela. They also can grow progressively and cause symptoms from local invasion or distant metastasis. NETs are optimally treated with surgery and somatosatin analogs (SSA's) to control symptoms but are relatively insensitive to systemic chemotherapy. As a result, patients with advanced unresectable NETs have a poor prognosis. In 2011, two targeted therapies, sunitinib and everolimus were approved in the subset of progressive pancreatic NETs (pNETs). Everolimus is an oral inhibitor of the growth stimulatory mTOR pathway. In Phase 2 trials in NETs and pNETs, everolimus was well tolerated and associated with some response and widespread disease stabilization. In follow-up, randomized Phase 3 trials, everolimus was compared to placebo. In the RADIANT-2 trial, everolimus and a somatostatin analog were used in patients with functional NETs and treatment was associated with an improvement in progression-free survival (PFS). In the RADIANT-3 trial, patients with pNET were randomized to receive everolimus or placebo along with best supportive care. Everolimus was again associated with improvement in PFS compared to placebo and it has been approved by the FDA for patients with progressive pNET. Everolimus is associated with frequent low grade toxicity but is also notable for increased rates of infection as well as non-infectious pneumonitis. mTOR inhibition with everolimus represents a significant advance in the treatment of advanced neuroendocrine tumors. [ABSTRACT FROM AUTHOR]