Abstract: Neuroendocrine tumors (NETs) of the lung are well-differentiated neuroendocrine neoplasms (NENs) with a heterogeneous clinical behaviour. Unlike gastroenteropancreatic NENs where therapeutic armamentarium clearly increased over the last decade, everolimus represented the only clinical practical innovation for lung NET patients over the last years. Therefore, for lung NETs, a multidisciplinary discussion within a dedicated team remains critical for an adequate decision-making. Although the main regulatory authorities considered the everolimus-related evidence is enough to approve the drug in advanced lung NETs, several clinical features deserve to be discussed. In this review, we systemically and critically analysed the main clinical studies including patients with advanced lung NETs receiving everolimus. Furthermore, we reported the biological and clinical background of everolimus in lung NET setting. The purpose of this review is to help clinical community to contextualize evidence and experience for a personalised use of this drug in clinical practice in the context of advanced lung NET patients.

Keywords: lung NET, typical carcinoid, atypical carcinoid, everolimus, mammalian target of rapamycin (mTOR) inhibitor, targeted agents


Neuroendocrine neoplasms (NENs) are relatively rare and heterogeneous malignancies originating from cells of the diffuse neuroendocrine system, widely dispersed in the body. They comprise a wide range of grade of malignancy, from very indolent to rapidly proliferative. By extrapolating from the gastroenteropancreatic (GEP) tract terminology more in general the well-differentiated (WD) NENs can be named tumors (NETs) whereas the poorly differentiated (PD) are carcinomas (NECs) also in the lung.

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In accordance with the 2015 WHO lung NEN classification lung NETs represent the low/intermediate grade by comprising typical (T) and atypical carcinoids (AC) whereas large cells and small cells lung NECs are the high-grade forms.1

Depending on symptoms due to the hypersecretion of hormones/amines by the tumor, lung NETs can be distinguished in functioning or non-functioning. The carcinoid syndrome is the most common clinical syndrome associated with a lung NET.2,3

Lung NETs are usually managed similarly to GEP NETs. However while in GEP NETs several new treatments have been approved over the last years, everolimus (EVE) is the only drug ever approved by FDA/EMA specifically for lung NETs. However other drugs can be used in clinical practice despite they were not specifically approved for lung NETs, including somatostatin analogues (SSAs), chemotherapy, liver-directed treatments. Furthermore other therapies can be proposed within clinical trials, such as peptide receptor radionuclide therapy (PRRT).

In this review, we had focussed on clinical and biological features of advanced NETs of the lung treated with EVE.

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