Everolimus in the treatment of neuroendocrine tumors of the

respiratory and gastroenteropancreatic systems

Nicola Flaum 1, Juan W Valle 1,2, Wasat Mansoor 1, Mairéad G McNamara 1,2

1 – Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK

2 – University of Manchester, Institute of Cancer Sciences, Manchester, UK

Corresponding author

Dr Mairéad G McNamara

Department of Medical Oncology

The Christie NHS Foundation Trust/University of Manchester, Institute of Cancer Sciences

Manchester

M20 4BX

UK

Tel: 0161 446 8106

Fax: 0161 446 3468

Email: Mairead.McNamara@christie.nhs.uk

Keywords:

Neuroendocrine tumor, pancreatic, carcinoid, metastatic, targeted therapy, everolimus, mTOR

inhibitor

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Word count: 5743

Summary (144 words)

Neuroendocrine tumors (NETs) are a rare diverse group of malignancies occurring most commonly in

the gastroenteropancreatic system and the lungs. The incidence of NETs is increasing worldwide,

and life expectancy for patients with metastatic NETs is currently 24-37 months. A growing body of

evidence is being amassed showing survival benefit in patients with advanced NETs

(gastroenteropancreatic and lung) treated with the mammalian target of rapamycin inhibitor

everolimus, with improvement in progression free and overall survival being demonstrated in the

clinical trial and real-world setting. Everolimus has also been shown to have a good toxicity profile,

with the commonest adverse events being stomatitis, rash, diarrhea, fatigue and infections. Due to

the rarity of the condition, there are ongoing challenges in conducting clinical trials in these patients.

Further research is required to clarify the role of adjuvant therapy, treatment sequencing and the

use of multimodality treatments.

Executive Summary

Mechanism of action

Everolimus is an oral highly selective mammalian target of rapamycin (mTOR) inhibitor.

mTOR mediates the inhibitory effects of rapamycin in mammalian cells and integrates

signals from multiple pathways, including the phosphatidylinositol 3 kinase (PI3K)-Akt-mTOR

pathway, which is implicated in the development and progression of neuroendocrine

tumors.

Pharmacokinetic properties

Everolimus has a narrow therapeutic index with an oral bioavailability of 16%.

Oral everolimus is absorbed rapidly, and reaches peak concentration after 1.3 -1.8 hours.

Steady state is reached within 7 days.

Everolimus is metabolized mainly by cytochrome P450 (CYP 3A4), 3A5, and 2C8 in the gut

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and liver.

Approximately 98% of everolimus is excreted in the bile in the form of metabolites and 2%

excreted in the urine.

Clinical efficacy

RADIANT II, a phase III study reported an increase in PFS from 11.3 to 16.4 months in

patients with low-grade or intermediate-grade advanced gastroenteropancreatic and lung

neuroendocrine tumors receiving everolimus.

RADIANT III, a phase III study reported an increase in PFS from 4.6 to 11.0 months in patients

with pancreatic neuroendocrine tumors receiving everolimus, and a 6.3 month prolongation

in median OS from 37.68 to 44.02 months.

A real-world retrospective study of everolimus used in patients with pancreatic and non-

pancreatic NETs through a compassionate-use program reported a median PFS of 12

months.

Safety & tolerability

The most common adverse events reported in patients treated with everolimus in phase III

studies were stomatitis, rash, diarrhea, fatigue and infections.

Pneumonitis is a serious reaction reported in 6-35% of studies.

Dosage & administration

Available as a 10mg tablet, administered once daily orally.

Introduction

Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies that arise from

neuroendocrine cells, the majority of which originate from the gastroenteropancreatic (GEP) or

bronchopulmonary systems (1).

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The incidence of NETs has increased over the last 30 years from 1.09 per 100,000 in 1973 to 5.25 per

100,000 in 2004 in the United States (2). An increase in incidence over time has also been observed

in the Netherlands and Sweden (3). This may reflect improvement in awareness and diagnosis of the

condition, as opposed to a true rise in incidence. The 29-year limited-duration prevalence of NETs in

2004 was 103,312 in the United States or 35 per 100,000 (2). The incidence of NETs in Europe ranges

from 0.6 to 2.4 per 100,000, across different studies (3).

A study of 35,618 patients with a diagnosis of NET identified in the Surveillance, Epidemiology and

End Results (SEER) database, found that the most common primary site varied considerably by

gender and ethnic origin. By organ, the most common primary site was lung at 1.35 per 100,000, but

collectively gastroenteropancreatic tumors had an age-adjusted incidence of 2.85 cases per 100,000.

Of these patients, 52% were women and 48% men, the median age at diagnosis was 63 years, and

the mean age was 62 (2). The primary site in European studies was most often the gastrointestinal

tract (62%), especially in the appendix (27%) and small bowel (15%), and the lung was the second

most common site (23%) (3). The majority presented with locoregional disease, and 22% with distant

metastases, whereas 13% presented with metastatic disease in an American series (4,5). Pulmonary

carcinoids account for 1-2% of all invasive lung malignancies, and a quarter to a third of all well-

differentiated NETs throughout the body. The majority occur in never or light smokers, although

atypical carcinoid patients are more likely to be current or former smokers than typical carcinoid

patients. Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are

associated with heavy smokers. The ratio of typical to atypical carcinoids is approximately 8-10:1 (6).

The classification of GEP and lung NETs have changed considerably since first identified, and current

World Health Organization (WHO) classifications incorporate histopathological and prognostic

factors. Gastroenteropancreatic NETs are categorized as well-differentiated low grade (G1) and

intermediate grade (G2), and poorly-differentiated high grade (G3) (7)(Appendix 1). The 2015 WHO

classification differentiates high grade SCLC and LCNEC from intermediate grade atypical carcinoids

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and low grade typical carcinoids, as well as from pre-invasive lesions diffuse idiopathic

neuroendocrine cell hyperplasia (DIPNECH). In 1972, Arrigoni et al described aggressive lung NETs,

which they termed ‘atypical’, leading to the categories of typical versus atypical NETs. This definition

is still used to describe low grade and intermediate grade lung NETs respectively (8).

The prognosis for metastatic NETs is 24-37 months (2). Over the last decade, treatment options have

been evolving in an effort to improve patient outcomes including further exploration into targeted

therapies such as everolimus, a mammalian target of rapamycin (mTOR) inhibitor. This review will

aim to discuss the treatment options for neuroendocrine tumors of the respiratory and

gastroenteropancreatic systems, particularly focusing on the therapeutic role of everolimus in this

disease group.

Treatment of GEP NETs: where does everolimus fit into current guidance

The ESMO Clinical Practice Guidelines advise on diagnosis, treatment, and follow up of GEP NET

tumors (9). Management of local or locoregional disease should be evaluated in a multidisciplinary

team (MDT) setting including an experienced surgeon, and these patients should be considered as

candidates for curative surgery. It is generally agreed that grade 3 pancreatic NET patients are not

surgical candidates as these tumors are widely metastasized at diagnosis. Cytoreductive surgery

may be considered for patients with a diagnosis of metastatic well-differentiated NET if the

metastatic disease is localized or if >70% of tumor load is thought to be resectable, although in

clinical practice and other studies, surgery is advised against if <90% of the tumor is thought

resectable (10).

Follow up of these patients should include biochemical parameters and conventional imaging. Non-

surgical options for management of non-resectable or symptomatic gastro-enteric NETs include

somatostatin analogues (SSA), chemotherapy, interferon, peptide receptor radiotargeted therapy

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(PRRT) and targeted therapies such as everolimus and sunitinib (Figure 1 and 2) and for functioning

pancreatic NETs, the option of hormone-specific treatment may be considered.

Treatment of well-differentiated lung NETs: where does everolimus fit into current guidance

Expert consensus guidelines were recently published by the European Neuroendocrine Tumor

Society (ENETS) regarding the management of lung NETs (6). It was recommended that all patients

should be reviewed by an MDT with a special interest or expertise in NETs. Pathology is the gold

standard in assessment of pulmonary NETs, and the mitotic count, Ki-67 index, necrosis and

neuroendocrine immunomarkers such as chromogranin A and synaptophysin are also required.

Surgical removal is the treatment of choice, and should be reserved for patients where radical

treatment is possible for all disease sites. Surgical resection of liver metastases can be considered

with curative intent, to aid symptom control or for debulking when >90% of the tumor can be

removed.

The goals of medical therapy in the treatment of lung NETs are to control both hormone-related

symptoms and tumor growth, and can include SSAs, interferon, PRRT, chemotherapy, and

everolimus (Figure 3). In asymptomatic patients, with a low tumor burden and low proliferative

index, a surveillance policy with cross-sectional imaging 3-6 monthly could be considered. Follow up

initially should be at least annually after primary surgery, and needs to be long term to detect

surgically manageable recurrences. For atypical carcinoids, closer monitoring is required and after a

3 month scan, imaging should be 6 monthly for 5 years with biochemical markers.

Systemic therapy for NETs

Somatostatin analogues are standard therapy in functioning NETs of any size, with good evidence for

symptom control benefit (11–13) (Appendix 3). Somatostatin analogues are also recommended as

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first-line therapy in non-functioning as well as functioning progressive G1/G2 GEP NETs, and also in

first-line treatment of patients with advanced lung NETs. Interferon-alpha has been used in patients

with neuroendocrine tumors, however it has a poor toxicity profile with a wide variety of side-effects

including depression with suicidal ideation (14,15).

Chemotherapy is recommended for the treatment of patients with metastatic G2 NET and G3 NEC of

any site, however studies involving chemotherapy in these patients have often involved small

population numbers (16) (Appendix 4). In patients with advanced unresectable progressive lung

NETs, systemic chemotherapy such as temozolomide may be used, which has been the most widely

studied, has a good safety profile and is generally recommended as palliative treatment. Cisplatin is

associated with significant toxicity and should only be considered in patients with aggressive,

advanced pulmonary carcinoids. As limited data is available for patients with primary lung NETs,

recommendations rely on data from GEP NETs and results of clinical trials in patients with lung NETS

are required. There are ongoing clinical trials incorporating the use of everolimus, interferon, PRRT

and certain chemotherapy combinations (Table 1).

The limitations of chemotherapy, interferon and surgery for the treatment of metastatic NETs have

led to the development of targeted therapy options, such as everolimus, sunitinib and pazopanib.

After showing promising antitumor activity in phase II trials (17,18), everolimus in particular has

shown significant clinical benefit in trials and in the real-world setting (16,19,20). A number of trials

investigating the use of everolimus in NETs are currently ongoing (Table 1).

Everolimus: History of discovery and mechanism

Everolimus is an immunosuppressive macrolide that is derived from sirolimus, also known as

rapamycin. Sirolimus is produced by Streptomyces hygroscopicus, an actinomycete bacteria first

isolated in 1975 from a soil sample from Easter Island, known in the native language as Rapa-nui,

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from where its name derives (21). Initially used as an antifungal agent, it was later discovered to

have immunosuppressive properties and was used as an immunosuppressant in organ

transplantation, triggered by the discovery of a similar compound FK506 (22). Rapamycin and FK506

were found to bind to the same family of intracellular receptors, called FK506 binding proteins

(FKBPs), which are important in mediating the interaction with a protein called mammalian target of

rapamycin (mTOR) (22). Complexes are formed by mTOR with other proteins to form rapamycin

complex 1 (mTORC1), which activates translation of proteins. Rapamycin is a highly selective

mTORC1 allosteric inhibitor (23).

The mammalian target of rapamycin is a phosphatidylinositol-3 kinase-related (PI3K) kinase within

the family of serine-threonine kinases (24), also known as FKBP-RAP associated protein (FRAP1). It is

known to mediate the inhibitory effects of rapamycin in mammalian cells (22), and integrates signals

from multiple pathways to regulate a wide variety of eukaryotic cellular functions, including

translation, transcription, protein turnover, cell growth, differentiation, cell survival, metabolism,

energy balance, and stress response (Figure 4) (23). Disruption of signaling pathways involved in

mTORC1/mTORC2 are commonly observed in many tumors, and cancer cells take advantage of the

roles of these complexes in driving oncogenic protein translation, lipid synthesis, and energy

metabolism, as well as in regulating cytoskeletal organization (23).

The PI3K-Akt-mTOR pathway has been implicated in the development and progression of

neuroendocrine tumors (25). The crucial role of mTOR in cancer biology has therefore stimulated

interest in research into mTOR inhibitors, and several have been developed for use in oncology,

including rapamycin (23). The anti-cancer effects of rapamycin were first reported in 2002 (26), and

since then have been documented in a range of malignancies, and numerous clinical trials have been

performed in cancer patients. Due to its limitations in solubility and pharmacokinetics, analogues

were developed, including the two water-soluble compounds temsirolimus (CCI-779) and everolimus

(RAD001).

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Everolimus was developed in an attempt to improve the pharmacokinetic characteristics of

sirolimus, in particular to improve its oral bioavailability. It blocks growth-driven transduction signals

in the T-cell response to alloantigen and thus acts at a later stage than the calcineurin inhibitors

ciclosporin and tacrolimus. As everolimus and ciclosporin inhibit adjacent steps in the T-cell-

mediated immune response they can be combined for synergistic immunosuppressive activity (27).

Everolimus: Pharmacokinetics and metabolism

Oral everolimus is absorbed rapidly, and reaches peak concentration after 1.3 -1.8 hours. Steady

state is reached within 7 days, and steady-state peak and trough concentrations and area under the

concentration-time curve (AUC) are proportional to dosage (see Table 2). Everolimus is metabolized

mainly by cytochrome P450 (CYP 3A4), 3A5, and 2C8 in the gut and liver (28). Approximately 98% of

everolimus is excreted in the bile in the form of metabolites and 2% is excreted in the urine. The

elimination half-life ranges from 18 to 35 hours (29–31). In adults, pharmacokinetic characteristics

do not differ according to age, sex, or weight. However, bodyweight-adjusted dosages are needed in

children. It is soluble in alcohols, acetonitrile, ethers and halogenated hydrocarbons, and practically

insoluble in water and aliphatic hydrocarbons (32). It has a narrow therapeutic index and variable

oral bioavailability, with the oral bioavailability of everolimus being 16%, higher than that of

sirolimus (10%) (33). In human blood, more than 75% of everolimus is bound to erythrocytes (34).

Everolimus: Clinical evidence and developing evidence

Phase I studies

Minimal data exists on trials investigating the use of everolimus as monotherapy in the phase I

setting for neuroendocrine tumors. However, trial data does exist in the phase I setting utilizing

everolimus in combination with other drugs. Chan et al found clinical benefit and PFS of 79% at 6

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months in 21 patients with a diagnosis of GEP, lung or unknown primary NETs treated with sorafenib

and everolimus, and concluded that sorafenib at 200mg twice daily (BD) with everolimus 10mg once

daily (OD) was the maximum tolerated dose (35). However there were 10 grade 3-4 adverse events,

and 1 grade 5 event (bowel perforation). Chan et al also investigated the use of pasireotide with

everolimus in 22 patients with a diagnosis of GEP, lung or unknown primary NETs (36). A PFS of 76%

at 6 months was demonstrated. Eight patients experienced grade 3-4 hyperglycemia, and 6 patients

grade 3-4 hypophosphatemia (Table 3 and 5).

Phase II studies

When everolimus was introduced, a phase II pilot dose-finding study tested everolimus 5mg and

everolimus 10mg in 60 patients with a diagnosis of low to intermediate grade metastatic NETs (30

with pancreatic NET). Intent-to-treat response rate was 20%, with a PFS of 60 weeks, and the drug

was generally well tolerated (18) (Table 3, Table 5). A further open-label phase II study assessed the

efficacy of everolimus in patients with metastatic pancreatic NETs who progressed on or after

chemotherapy (17). In stratum 1, patients who had not previously been on SSA therapy (n=115), the

objective response rate (ORR) by central radiology review was 9.6% and 10.4% by investigator

assessment, in comparison to patients who had previously been on octreotide, stratum 2 (n=45; ORR

4.4% by central radiology review, 11.1% by investigator review). The median PFS in stratum 1 was

9.7 months, in comparison to 16.7 months in stratum 2. Despite the discrepancy between

radiological and clinical assessment, and the small number of patients in stratum 2, this study did

demonstrate antitumor activity of everolimus in pancreatic NETs, and potentially benefit in

combining everolimus with SSAs (17).

In 2014, a phase II Italian study of everolimus in 50 patients with GEP or lung NETs was reported,

with a primary endpoint of ORR (37). The ORR was 18% in the intent-to-treat population, and 19.6%

in the 46 patients who received everolimus per-protocol. The percentage of response did not differ

between patients with pancreatic (n=14) and non-pancreatic (n=36) NETs. This study therefore

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demonstrated that non-pancreatic NETs also appear to benefit from everolimus. However, the

results need to be interpreted with caution due to the small population size.

A phase II study investigating the efficacy and safety of everolimus in pancreatic NETs in a Chinese

population, comparing everolimus (n=44) with placebo (n=35) was published in 2014 (38). The study

met its primary endpoint, with a PFS of 15.47 months in patients receiving everolimus compared to

4.29 months in patients receiving placebo. Although the drug was clinically effective there was a

100% rate of adverse events in patients receiving everolimus, including pneumonitis in 61% of

patients (38).

Phase II trials have also been performed investigating the use of everolimus in combination with

other targeted therapy. An example is the recent study by Kulke et al which randomized 150 patients

with advanced pancreatic NETs to everolimus alone or everolimus plus bevacizumab, a vascular

endothelial growth factor inhibitor (39). Treatment with both agents was found to have a

significantly higher response rate (31% compared to 12%; p=0.005) and a slight increase in PFS (16.7

months versus 14 months; HR=0.80; 95% CI: 0.55, 1.17; 1-sided p=0.12) and overall survival (OS)

(36.7 months versus 35 months; HR=0.75; 95% CI: 0.42-1.33; 1-sided p=0.16). However, the rate of

adverse events was also significantly higher in patients who received both agents. As this study

demonstrates, the use of everolimus in combination with other agents is an exciting area for

research with the potential for clinical benefit, but needs more investigation.

Phase III studies

The Radiant II study was an international randomized, double-blind, placebo-controlled phase III trial

of everolimus plus octreotide for the treatment of patients with advanced NET associated with

carcinoid syndrome (19). The study included patients with low-grade or intermediate-grade

advanced neuroendocrine tumors including GEP and lung primary tumor origin, which were

functional in nature. The study met its primary endpoint, demonstrating an increase in PFS in

patients receiving everolimus (median PFS 16.4 months compared to 11.3 months), and everolimus

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was associated with a 23% reduction in the estimated risk of progression. There was a consistent

benefit across most subgroups of patients, and irrespective of prior chemotherapy, WHO

performance status, age, sex, tumor grade, and primary tumor site. Despite the confounding factor

of patients on the placebo arm having the opportunity to cross over to the open label everolimus

arm (n=124), the study demonstrated that everolimus had efficacy in a significant number of

patients with non-pancreatic NETs.

Sub-group analysis comparing patients within the RADIANT-II study who had previously received

SSAs (n=339) with the patients who were SSA-naïve found that previous SSA exposure did not

influence PFS in this study (40). Analysis of the patients with colorectal NETs included in RADIANT-II

found a 66% risk reduction for progression in this population, and a benefit in PFS from everolimus

(29.9 months, n=19) compared to the patients receiving placebo (PFS 6.6 months, n=20) (41). Among

the 44 patients with lung NETs included in RADIANT-II, there was a 28% risk reduction of progression

associated with everolimus, and benefit in PFS from 5.59 months in the placebo arm to 13.63

months in the everolimus arm (42). Although these numbers are small, they do show that there is a

benefit to using everolimus in patients with non-pancreatic NETs, and that these are avenues of

research worth pursuing.

Radiant III was also an international randomized double-blind, placebo-controlled phase III study

comparing oral everolimus (10mg/day) with placebo in patients with advanced, low-grade or

intermediate-grade pancreatic neuroendocrine tumors with PFS as the primary endpoint. More than

80% had well-differentiated disease, and more than 90% had liver metastases. The median PFS for

patients receiving everolimus was 11.0 months, compared to 4.6 months in the placebo group,

representing a 65% reduction in the estimated risk of progression. This benefit was significant

irrespective of prior chemotherapy, WHO performance status, age, sex, race, geographical origin,

prior SSAs or tumor grade. One hundred and forty eight patients crossed over to open-label

everolimus from placebo after progression. The results after adjusting for crossover bias were

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presented at the Annual Society of Clinical Oncology conference in 2015, with everolimus

demonstrating a 6.3 month prolongation in median OS compared with placebo (44.02 months vs

37.68 months; HR = 0.94; P = 0.3) (43).

A retrospective analysis of all patients with NETs treated with everolimus in a real-world setting of a

compassionate-use program was recently published (20). One hundred and sixty nine patients were

enrolled, including 85 patients with pancreatic NETs and 84 with non-pancreatic NETs which mainly

consisted of small bowel or lung. Similar to trial criteria, patients had an Eastern Co-operative

Oncology Group performance status of 0 to 2. One hundred and sixty four patients (97%) started

everolimus at 10mg daily, while 5 patients (3%) started at 5mg. One hundred and twenty eight

(75.7%) patients demonstrated a response to everolimus, with stable disease in 114 (67.5%)

patients, partial response in 13 (7.7%) patients, and complete response in 1 (0.5%) patient according

to Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 imaging criteria. Interestingly the Ki-67

value of 12% was identified as a better cut-off between responders and non-responders. Median PFS

was 12 months, with similar values in patients with pancreatic and non-pancreatic NETs (11 and 12

months respectively). Median OS was 32 months. This was not significantly different according to

tumor site, in contrast to other studies which have found pancreatic NETS to be more aggressive.

This may be due to other factors such as high median age, and longer interval between initial NET

diagnosis and everolimus treatment in non-pancreatic NETS, and the heterogeneity of primary

tumors in the non-pancreatic tumor group (20).

RADIANT IV was a large placebo-controlled phase III study evaluating the efficacy and safety of

everolimus in advanced, nonfunctional progressive lung or gastrointestinal NETs. The 302 patients

were randomized 2:1 to everolimus 10mg daily or placebo, and treated until disease progression,

intolerable adverse events or consent withdrawal. The study demonstrated a 52% relative risk

reduction of progression or death with everolimus,(HR = 0.48, 95% CI 0.35-0.67; p = <0.00001). The

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PFS was 11 months in patients treated with everolimus vs 3.9 months in those treated with placebo

by central review, and 14 months vs 5.5 months by investigator review (44).

Safety and tolerability

In the RADIANT-II, RADIANT-III and RADIANT-IV studies, the most common adverse events of

everolimus were stomatitis, rash, diarrhea, fatigue and infections (16,19,44). The majority of these

were grade 1-2. The incidence of serious toxicity in RADIANT-II was 57%, and the incidence of drug-

related pneumonitis, a known complication of everolimus was 8% (18 patients) (19), 12% in

RADIANT-III (16) and 16% in RADIANT-IV with 2% grade 3-4 pneumonitis (44).

A randomized phase II study of 79 Chinese patients with pancreatic NETs comparing everolimus with

placebo reported that adverse events occurred in 100% of patients, the majority were grade 1-2 and

the most common included rash, stomatitis, infections, epistaxis, anemia and more concerningly

pneumonitis, which occurred in 27 patients (61%) (38). A multi-center phase II trial assessing

everolimus in advanced NETs with a variety of histotypes, with and without carcinoid syndrome,

found everolimus in combination with octreotide LAR to be well tolerated. The majority of adverse

events were grade 1 or 2, and the most common included mucositis/stomatitis, rash, or diarrhea.

Pneumonitis occurred in only 3 patients (6%) (37) (Table 5).

These clinical trial findings differ from the real-world data produced by Panzuto et al (20). Although,

interstudy comparison cannot be reliably made, in the study by Panzuto et al, significantly lower

rates of adverse events such as stomatitis (occurring in 21.9% compared to 61.8% in RADIANT-II and

64.2% in RADIANT-III), rash (occurring in less than 10% compared with 37.2% in RADIANT-II and 49%

in RADIANT-III) and diarrhea (occurring in less than 10% compared with 27.4% in RADIANT-II and

34% in RADIANT-III) were found (16,19). The authors proposed this could be explained by the

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retrospective nature of the study and also differences in awareness of the physicians involved in

reporting these toxicities.

Panzuto et al also found higher rates of grade 3-4 AEs of pneumonitis (18.9%), thrombocytopenia

(21.9%) and renal impairment (16.6%). During a median follow up period of 12 months, 47 patients

died, resulting in a mortality rate of 27.8%. Two patients died following a diagnosis of pneumonitis

during everolimus therapy. Both had previously received PRRT. The risk of any severe toxicity was in

fact increased 12-fold in patients who had received both PRRT and chemotherapy prior to

everolimus (86.8% of these patients, compared to 34.3% of other patients). It was therefore

suggested that everolimus might be more appropriate before chemotherapy and PRRT in the

sequencing of treatments in patients with metastatic NETs (20). Seventeen deaths occurred during

everolimus treatment, none of which were directly attributed to the drug.

Review of toxicity profiles could inform a clinician’s decision regarding the most appropriate therapy

for a patient with advanced pancreatic NET in the absence of clear guidance. For example,

everolimus may be favored in patients with heart disease, uncontrolled hypertension, bleeding risk

or esophageal varices, whereas an alternative targeted therapy, sunitinib, may be preferred in

patients with uncontrolled diabetes mellitus or severe lung disease.

Regulatory affairs in relation to everolimus

Everolimus is approved in over 85 countries for use in the treatment of patients with pancreatic

NETs (45). The European Medicines Agency report from the Committee for Medicinal Products for

Human Use (CHMP) assessed everolimus and granted a marketing authorization making it available

in the European Union for well- or moderately-differentiated progressive pancreatic NETs which are

metastatic or locally advanced. Everolimus was approved by the Food and Drug Administration (FDA)

on 5th May 2011 for the treatment of progressive pancreatic NETs in patients with unresectable,

15

locally advanced or metastatic disease (46), following the results of the RADIANT-II trial. It is

available in the United States for this indication. It was approved in Japan by the Pharmaceuticals

and Medical Devices Agency on the 22nd November 2011. However, everolimus is no longer licensed

in the UK or available through the Cancer Drugs Fund (CDF) for well-differentiated pancreatic NETs

(since 12th March 2015) or moderately-differentiated pancreatic NETS (since 21st July 2015). It may

be accessed through application to the manufacturing pharmaceutical company on a Named Patient

Supply basis.

Areas of unmet need

Larger trials are needed to better assess the use of chemotherapy in patients with NETs. The role of

surgery in metastatic disease is also unclear (9). Another area for current and future research is the

role of adjuvant therapy in GEP and lung NETs, as surgery remains the initial treatment of choice for

the majority of NETs (6,9,47).

The rarity of the condition, requiring significant co-ordination between oncological and surgical

departments across different countries for larger prospective studies, especially when considering

adjuvant treatment, and the trend for current research into targeted and immunological agents may

be factors contributing to the challenges posed in trial initiation.

However, a trial is currently ongoing investigating the use of adjuvant everolimus in patients with a

diagnosis of pancreatic NETs with liver metastases (clinicaltrials.gov NCT02031536), and a phase III

trial by Eba et al (48) is investigating the role of adjuvant irinotecan and cisplatin versus etoposide

and cisplatin following complete resection of lung high grade NEC.

Targeted agents in the market, aside from everolimus, include the tyrosine kinase inhibitors sunitinib

and pazopanib. A phase II multicenter study of 107 patients with GEP non-resectable NETs treated

with sunitinib demonstrated an ORR of 16.7%, and a median time to progression of 10.2 months for

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patients with gastro-enteric tumors and 7.7 months for patients with pancreatic tumors. One year

survival rates were 83.4% and 81.1% respectively (49). A randomized, double-blind, placebo-

controlled phase III study of sunitinib in 171 patients with advanced, well-differentiated pancreatic

NETs compared sunitinib with placebo, but was discontinued early due to a significant increase in

progression-free survival (PFS) in the sunitinib group and higher incidence of adverse events and

deaths in the placebo group (50). Median PFS was 11.4 months in the sunitinib group compared to

5.5 months in the placebo group (HR 0.42; 95% CI 0.26 to 0.66, p<0.001). The ORR was 9.3% in the

sunitinib group vs 0% in the placebo group. This study led to approval of sunitinib for the treatment

of well-differentiated pancreatic neuroendocrine tumors world-wide.

An increasing area of research over the last few years is the use of PRRT in the treatment of NET

patients. The majority of trials have shown 15-35% ORR (51), and a large phase II trial of 1109

patients found 34.1% of patients experienced morphological response, with a median survival from

diagnosis of 94.6 months (52). However, PRRT can be difficult to access for patients not treated at a

major cancer center and is associated with adverse events such as nephrotoxicity, hypertension and

anemia (51,53). In the UK, PRRT will come off the list of agents covered by the cancer drug fund in

November 2015. Randomized controlled trials are needed to compare treatment modalities and

determine appropriate sequencing (54). A prospective multicenter phase III study comparing

treatment with 17-Lu-Dototate plus octreotide LAR to a high dose of octreotide LAR alone in patients

with inoperable, progressive, somatostatin receptor positive, midgut carcinoid tumors found a

statistically significant increase in PFS in the PRRT group. At time of analysis PFS was 8.4 months for

the patients treated with octreotide LAR but not yet reached for the patient group receiving 17-Lu-

Dototate (HR 0.21, 95% CI 0.13-0.34) (55). The authors also found that the safety profile observed in

the study was consistent with the safety information generated in phase I – II clinical trials.

The use of multimodality therapy and the sequencing of treatment options is another area of unmet

need; at present there is no clear evidence regarding which treatments work best first-line or

17

subsequently in non-resectable NET patients. The SEQTOR trial, taking place in over 8 countries in

Europe aiming to recruit 180 patients and anticipated to be completed by September 2018, will

compare everolimus followed by streptozotocin-based chemotherapy with streptozotocin-based

chemotherapy followed by everolimus in patients with advanced pancreatic NETs and may help

clarify this issue.

In relation to sequencing, the RECORD-3 trial was a crossover-design phase II trial in patients with

metastatic renal cell carcinoma, comparing first-line everolimus followed by sunitinib with first-line

sunitinib followed by everolimus. The results of this study supported the use of first-line sunitinib

followed by everolimus in this disease group (56). However, these results cannot be reliably applied

across disease sites. Indeed, a real world study of everolimus in 169 patients (20) found that the risk

of serious toxicities was increased 12-fold if patients had received chemotherapy and/or PRRT

previously, and therefore everolimus may be more appropriate as a first-line therapy in systemic

treatment-naïve patients with a diagnosis of NET.

The development of reliable biomarkers for response to treatment is also an area of ongoing

investigation. Chromogranin A has been generally accepted as the most useful biomarker, however

there are substantial concerns regarding sensitivity and discrepancies in measurement techniques

(57). Several studies are investigating alternative biomarkers such as soluble vascular endothelial

growth factor 2 (sVEGFR2), p-mTOR and Insulin-like growth factor 1 receptor (IGF1R) (57).

Interleukin-8, sVEGFR-3 and stromal derived factor-1 alpha (SDF-1α) have been recently identified as

predictors of sunitinib-related clinical outcome in patients with pancreatic NETs (58).

A challenge to all clinical trials involving NET patients is the nature of the disease; the variable clinical

course and rarity of the condition which makes designing a logistically feasible study of adequate

power and duration difficult, in addition to the variable imaging and biochemical assessments of

metastatic disease (59,60).

18

Discussion

Neuroendocrine tumors are a heterogeneous group of cancers that frequently present at an

advanced stage. There are still unanswered questions in the treatment of NETs, including the role of

adjuvant therapy, and the optimal sequencing of treatment options. Other areas of ongoing

investigation include clarification of the best imaging modality to monitor response to treatment of

patients with a diagnosis of a NET. There may be a disparity between response rates using RECIST

imaging criteria and clinical response. For example, in one phase II study investigating everolimus in

patients with pancreatic NETs it was reported that in one group of patients, ORR by central radiology

review was 4.4%, but by investigator assessment 11.1% (61). Additionally, well-differentiated NETs

are hypervascular coexisting with central areas of necrosis, and response to VEGFR inhibitors such as

sunitinib has been detected as a decrease in tumor density, as opposed to changes in tumor size.

Therefore, assessment by RECIST criteria may underestimate response (62). Alternative assessment

imaging using modified RECIST criteria (63) or Choi criteria which considers both size and density of

tumors as parameters for response (64) may be indicated.

It is also unclear what the ideal dose reduction levels are when administering targeted therapies and

which should be mandated for everolimus. In a phase III study which investigated the use of

everolimus in the treatment of well-differentiated pNETs, dose reductions from 10mg to 5mg daily

were initially recommended, and then 5mg on alternate days (16,20). This amounts to an initial 50%

dose reduction, which is not standard for dose reductions in chemotherapy and may change dose

intensity and possibly efficacy.

The future of treatments in patients with a diagnosis of a NET may involve the application of

personalized therapy and tumor profiling, an area which has recently been under investigation. A

recent study reported that a number of micro-RNAs (miRNAs) were highly significantly deregulated

in pulmonary NETs, and also discriminated between different subtypes; the authors suggest that

analysis of specific sets of miRNAs could be used as diagnostic and/or predictive markers in these

19

patients (65). Another study found positive predictive values of 92.5% for small bowel NETs and

93.8% for pancreatic NETs in identifying primary tumors from liver metastases using a gene

expression algorithm (66). A recent comprehensive integrated molecular analysis of small bowel

NETs has also been published, which identifies new molecular subtypes with significantly different

survival outcomes (67). Further study involving tumor profiling may lead to exciting insights in to the

biology of NETs and help direct the ever-changing therapeutic pathway more accurately.

Conclusion

Targeted therapies are an ongoing area of research, some of which have been shown to have

significant benefit. At present, everolimus is only licensed for the treatment of patients with

pancreatic NETs, and is now only available on a named-patient basis in the UK. However, the recent

results of RADIANT-IV add to a growing body of data demonstrating a significant prolongation of PFS

in a wider group of patients, including those with advanced nonfunctional lung and gastrointestinal

neuroendocrine tumors.

Conflicts of Interest

Dr Nicola Flaum: No Conflicts of Interest

Professor Juan Valle: Honoraria: Merck

Consultant or Advisory Role: Ipsen, SIRTex, Celgene, Novartis, AstraZeneca,

AAA

Speaker’s Bureau: Pfizer, Novartis, Abbott, Celgene, Ipsen, SIRTex

Research Funding: AstraZeneca, Novartis

Dr Wasat Mansoor: Honoraria: Lilly, Nordic

20

Consultant or Advisory Role: Novartis, Nordic pharma, Lilly

Speaker’s Bureau: Nordic pharma, Lilly

Dr Mairéad McNamara: Speaker’s Bureau: Pfizer

Research Funding: NuCana

Travel and/or accommodation: Bayer, Ipsen

Legends

Figure 1 - Suggested algorithm for management of gastro-enteric neuroendocrine tumors including

role of everolimus

Figure 2 – Suggested algorithm for management of pancreatic neuroendocrine tumors including

role of everolimus

Figure 3 – Suggested algorithm for management of lung neuroendocrine tumors

Figure 4 – Simplified overview of the mTOR pathway showing point of action of everolimus

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28

Table 1 - Examples of some ongoing/closed to recruitment phase II and III clinical trials in gastro-

enteropancreatic and lung neuroendocrine tumors including everolimus as a treatment arm

Study Dates of

recruitment

Trial

phase

Tumor

primary

Regimen Estimated

number of

patients

Primary

endpoint

NCT01229943 2010-2014 II Pancreatic Everolimus + octreotide

vs everolimus +

octreotide +

bevazicumab

150 PFS

COOPERATE-2

NCT01374451

2011-2015 II Pancreatic Everolimus vs

everolimus +

pasireotide LAR

160 PFS

LUNA

NCT01563354

2013-2016 II Advanced

lung/ thymus

Everolimus vs

pasireotide LAR vs

everolimus +

pasireotide

120

(40:40:40)

PFS at 9

months

NCT02031536 2014-2017 II Pancreatic

with liver

metastases

Adjuvant everolimus 150 Disease free

survival at 5

years

MetNET1

NCT02294006

2014-2017 II Pancreatic Metformin + octreotide

LAR + everolimus

43 PFS at 12

months

NCT02315625 2014-2021 II GI/ pancreas Surgery-sunitinib vs

surgery-everolimus.

120 PFS

SEQTOR

NCT02246127

2014-2018 III Pancreatic Everolimus and STZ-5FU

in alternate sequencing

180 Second PFS up

to 84 weeks

*= primary endpoint, PFS = progression free survival.

29

Table 2 – Data regarding main pharmacokinetic characteristics of everolimus

Study Dosage/day Cmax (ng/mL) Tmax (hours) AUC (ng-h/mL) T1/2 (hours)

Neumayer et al, 1999

(31)

2.5mg 45 1.3 344 25

Kahan et al, 1999

(30)

2.5mg 33 1.8 211 18

Kovarik et al, 2002

(34)

4mg 44 0.5 219 32

O’Donnell et al, 2008

(77)

5mg 32 1 238 26

Xu et al, 2011 (78) 5mg 29 3 316 -

Levy et al, 2001 (29) 7.5mg 53 2.5 735 32

O’Donnell et al, 2008

(77)

10mg 61 1 514 38

Xu et al, 2011 (78) 10mg 17 2 589 -

30

Table 3 – Examples of reported phase I and II trials of everolimus in patients with

gastroenteropancreatic and lung neuroendocrine tumors

Authors Year Phase Primary tumor

location

Regimen Number

of

patients

Response

assessment

PFS Median

OS

(months)

Chan et al

(35)

2013 I Carcinoid (small

bowel, bronchus,

unknown

primary) or

pancreatic

Sorafenib +

everolimus

21 1 PR, 13 SD, 3 PD.

62% disease

shrinkage. 26% CGA

decrease.

79% at 6

months

-

Chan et al

(36)

2012 I Carcinoid (small

bowel, bronchus,

unknown

primary) or

pancreatic

Pasireotide +

everolimus

22 90% SD, 81% some

degree of tumor

shrinkage. 21% CGA

decrease.

76% at 6

months

65% at 12

months

-

Chan et al

(79)

2013 I/II Grade 1/2

pancreatic

Everolimus 5mg

or 10mg +

temozolomide

43 16 (40%) PR, 53% SD,

7% PD. 45% CGA

decrease.

15.4 * Not

reached

Kulke et al

(39)

2015 II Pancreatic Everolimus +

octreotide vs

everolimus +

bevacizumab +

octreotide

150 Response rate 31%

vs 12%

16.7 vs

14 *

OS 36.7 vs

35.0

Yao J et al

(38)

2014 II Pancreatic Everolimus vs

placebo

79 72% risk reduction 15.47 vs

4.29*

Not

reached

Bajetta et

al (37)

2014 II GEP + lung Everolimus +

octreotide LAR

first line

50 18% ORR *

2% CR, 16% PR, 74%

SD, 6% PD

Not

reached

by 277

days

Not

reached

by 277

days

Yao et al

(61)

2010 II Pancreatic Everolimus in

octreotide naïve

pts (stratum 1)

Everolimus +

octreotide - pts

on octreotide

for 3/12

(stratum 2)

160 9.6% (Radiological

assessment), 10.4%

(Ix assessment )ORR*

4.4% (radiological

assessment), 11.1

(investigator

assessment ) ORR

9.7, 8.5

16.7, 15.2

OS – 24.9

24month

survival

54.7%

Yao et al 2008 II GEP, thymus, Everolimus 5mg

or 10mg +

60 ORR 20% 22% PR, 60 weeks 1 yr – 83%

2 yr – 81%

31

(18)

RADIANT-I

lung, renal octreotide LAR 70% SD, 8% PD 3 yr – 78%

*= primary endpoint

PR = Partial response; SD = stable disease; PD = progressive disease; CGA = chromogranin A; ORR

= objective response rate; OS = overall survival; PFS = progression-free survival; pts = patients

32

Table 4 – Examples of reported phase III trials involving everolimus in patients with lung,

gastroenteropancreatic, and other neuroendocrine tumors

Authors Year Tumor type Regimen Number of

patients

Objective response PFS (months)

Yao et al (44)

(RADIANT IV)

2015 Advanced

nonfunctional

lung and GI

NETs

Everolimus 1mg vs

placebo

302 52% risk reduction for

progression or death

11.0 vs 3.9 (central

review

14.0 vs 5.5

(investigator review)

Anthony et al

(40)

(RADIANT-II

sub-analysis)

2015 Functional

advanced

NETs

Everolimus 10mg +

octreotide vs placebo

+ octreotide.

Comparison of

previous SSA

exposure with none

429 (339

previous SSA

exposure)

No sig difference in PFS

relating to SSA

O+E+SSA 14.3

O+E 25.2

P+O+SSA 11.1

P+O 13.6

Lombard-

Bohas et al

(80)

(RADIANT-3

sub-group)

2015 Pancreatic Everolimus vs placebo

comparing prior

chemo with chemo-

naïve

410 (204 =

50% were

chemo-naïve)

ORR 4.8% vs 2% in prior

chemo, 4.9% vs 2% in

chemo-naïve

Prior chemo 11 vs 3.2

Chemotherapy-naïve

11 vs 5.4 *

Castellano et

al (41)

(RADIANT-II

sub group

analysis)

2013 Colorectal Everolimus +

octreotide vs placebo

+ octreotide

39 66% risk reduction for

progression

29.9 vs 6.6 *

Fazio et al

(42)

(RADIANT-II

sub group

analysis)

2013 Lung Everolimus +

octreotide vs placebo

+ octreotide

44 28% risk reduction for

progression

13.63 vs 5.59 *

Pavel et al

(19)

(RADIANT-II)

2011 G1-2

functional

NETs – GEP,

liver, lung,

other

Everolimus +

octreotide vs placebo

+ octreotide

429 23% risk reduction for

progression

16.4 vs 11.3 *

Yao et al (16)

(RADIANT-III)

2011 Pancreatic Everolimus 10mg OD

vs placebo

410 (18

countries)

65% risk reduction of

progression or death

11 vs 4.6*

*= primary endpoint

SSA = somatostatin analogue; ORR = objective response rate; PFS = progression-free survival.

33

Table 5 – Toxicities reported in trials involving patients receiving everolimus as a treatment

option*

Trial Yao et al 2011

(16)

Total % of AE

(% of grade 3-4

AE)

Pavel et al 2011

(19)

Total % of AE

(% of grade 3-4

AE)

Panzuto et al

2014 (20)

Total % of AE

(% of grade 3-4

AE)

Bajetta et al

2014 (37)

Total % of AE

(% of grade 3-

4 AE)

Yao et al 2014

(38)

Total % of AE

(% of grade 3-4

AE)

Total patient number 204 215 169 50 79

Anorexia 19.6 (0) 13.5 (0) - - -

Asthenia 12.7 (0.9) 10.2 (0.9) 17.8 (1.8) - -

Diarrhea 33.8 (3.4) 28.9 (6.37) - 60 (22) 17.7 (1.3)

Dysgeusia 17.2 (0) 16.7 (0.5) - - 24.1 (1.3)

Edema 20.1 (0.5) 13.0 (0) 17.2 (3.6) - -

Fatigue 31.4 (2.4) 31.2 (6.5) - - 12.7 (0)

Headache 19.1 (0) - - - 24.1 (2.5)

Hypercholesterolemia - - 13.6 (0) 26 (0) -

Hyperglycemia 13.2 (3.9) 12.1 ( 5.1) 16.6 (1.2) 18 (0) 20.3 (3.8)

Infection 22.5 (2.4) 20.6 ( 5.1) - - 41.8 (12.7)

Stomatitis 64.2 (6.9) 61.9 (6.9) 21.9 (2.4) - 38.0 (13.9)

Nausea 20.1 (2.5) 19.5 (0.5) - - -

Mucositis - - - 62 (10) -

Pneumonitis 17.2 (2.5) 8.8 (1.4) 18.9 (8.3) 6 (0) 34.2 (5.1)

Pruritis 14.7 (0) 10.7 (0) - - -

Pyrexia 10.8(0) - - - 15.2 (1.3)

Rash 48.5 (0.5) 37.2 (0.9) - 48 (2) 48.1 (0)

Renal impairment - - 16.6 (3.6) - -

Vomiting 15.2 (0) 10.7 (0.5) - - 21.5 (3.8)

Weight loss 15.7 (0) 14.9 (0.5) - - -

Anemia 17.2 (5.9) 15.3 (1.4) 19.5 (2.4) 8 (2) 27.8 (6.3)

Neutropenia - - - 6 (2) 19.0 (6.3)

Thrombocytopenia 13.2 (3.9) 14.0 (4.7) 21.9 (7.7) 12 (0) -

*All studies reported are individual stand-alone studies with different inclusion and exclusion criteria

with different patient populations and therefore direct comparisons cannot be made. AE = adverse

event.

34

35

* - Use in this setting is currently investigational.

Diagram adapted from guidelines from Öberg et al 2012 (9), Kanti et al 2012 (72), Caplin et al, 2014 (68).

Figure 1

36

* - Use in this setting is currently investigational.

** - Everolimus currently not on Cancer Drugs Fund approved list in the United Kingdom for well-

differentiated or moderately-differentiated pancreatic neuroendocrine tumors.

Diagram adapted from guidelines by Öberg et al 2012 (9) and the National Comprehensive Cancer Network

Guidelines Version 1.2015 – Neuroendocrine Tumors of the Pancreas, Management of locoregional

unresectable disease and/or distant metastases.

Figure 2

37

* - Use in this setting is currently investigational.

Diagram adapted from Caplin et al 2015 (6), and Filosso et al 2015 (76).

Figure 3

38