The Antiproliferative Role of Lanreotide in Controlling Growth of Neuroendocrine Tumors: A Systematic Review

Michael Michael; Rocio Garcia‐Carbonero; Matthias M Weber; Catherine Lombard‐Bohas; Christos Toumpanakis; Rodney J Hicks

doi:10.1634/theoncologist.2016-0305

. 2017 Feb 20;22(3):272–285. doi: 10.1634/theoncologist.2016-0305

The Antiproliferative Role of Lanreotide in Controlling Growth of Neuroendocrine Tumors: A Systematic Review

Michael Michael ^a,^*, Rocio Garcia‐Carbonero ^b, Matthias M Weber ^c, Catherine Lombard‐Bohas ^d, Christos Toumpanakis ^e, Rodney J Hicks ^f

PMCID: PMC5344642 PMID: 28220021

The optimal use of lanreotide in the control of neuroendocrine tumors in terms of dosing, timing in relation to local therapies, and its role in combination regimens is unclear. To gain a better understanding of the evidence and identify areas for further research, this systematic review of the published literature was conducted.

Keywords: Lanreotide, Neuroendocrine tumors, Gastroenteropancreatic neuroendocrine tumors, Antiproliferative

Abstract

Background.

Neuroendocrine tumors (NETs) are a heterogeneous group of tumors, with >50% of cases involving the gastrointestinal system or pancreas. Somatostatin analogs (SSAs) are used for treating NET‐related secretory syndromes and, more recently, for their antiproliferative effects. We conducted a systematic review of published literature on the antiproliferative efficacy and safety of the SSA lanreotide Autogel in the management of NETs to gain a fuller understanding of the evidence and identify future areas of research.

Methods.

Searches were conducted in PubMed up to March 16, 2016, and in the proceedings of four congresses from 2013 to 2016.

Results.

Screening of 1,132 publications identified in the searches found 40 relevant publications, including 27 full‐length publications and 13 congress abstracts. Twenty‐four of these publications reported antiproliferative efficacy data for lanreotide Autogel. The CLARINET study showed that 120 mg lanreotide Autogel every 4 weeks improves progression‐free survival (PFS) in patients with gastroenteropancreatic (GEP)‐NETs, with grade 1 or grade 2 (Ki‐67 <10%) disease, providing class I evidence of its antiproliferative effects. The CLARINET open‐label extension study reported a median PFS of 32.8 months with lanreotide Autogel. Other smaller studies generally support CLARINET.

Conclusion.

Current clinical evidence shows that lanreotide Autogel has good antiproliferative activity with favorable safety and tolerability in patients with GEP‐NETs, suggesting it should be considered as an early first‐line treatment in this population. Further studies are needed to assess the potential benefits of higher doses and the use of lanreotide Autogel in combination therapy and as maintenance therapy in the absence of disease progression following other therapies.

Implications for Practice.

This review presents the current clinical evidence for the antiproliferative activity of lanreotide Autogel in patients with midgut or pancreatic neuroendocrine tumors (NETs) and shows its effectiveness, safety, and tolerability in these patient populations. By systematically presenting all the clinical evidence, the review adds to existing publications by discussing results in a broad range of settings. The review also indicates future directions for investigation of the use of lanreotide Autogel in NETs originating in other locations, in combination therapy, or as maintenance therapy in progressive disease.

Introduction

Neuroendocrine tumors (NETs) arise from any cell within the diffuse neuroendocrine system [1], and this gives rise to significant heterogeneity in the characteristics of these tumors and their clinical presentation [2], [3], [4], [5], [6], [7]. The most common anatomical sites for NETs are the gastrointestinal (GI) tract and pancreas, which account for >50% of cases, and the pulmonary system [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]. In patients with grade 1 (G1) or grade 2 (G2) NETs, the site of the primary tumor is a predictor of outcome [2]. NETs can be characterized as functioning tumors, which secrete hormones and peptides that invoke specific clinical syndromes, or nonfunctioning tumors, which produce nonspecific symptoms related to mass effects and malignancy [3]. Due to delayed diagnosis, many patients with NETs present with inoperable disease; therefore, medical treatment is initiated to control disease progression and to relieve symptoms [14], [15].

Somatostatin is an inhibitory neuropeptide, which acts on various targets throughout the body to regulate a variety of physiological functions, including inhibition of endocrine and exocrine secretions as well as the inhibition of normal and tumor cell proliferation. It exerts its effects through interaction with five somatostatin receptor (SSTR) subtypes (SSTR1‐5), which belong to the family of G‐protein‐coupled receptors [16]. Subject to grade, all gastroenteropancreatic (GEP)‐NETs can express multiple SSTR subtypes, but SSTR2 generally predominates [17], [18], [19]. The predominant expression of SSTR2 on pancreatic or midgut NETs is essential for the control of hormonal hypersecretion by the somatostatin analogs (SSAs). As SSTRs are involved in inhibition of the cell cycle in angiogenesis and induction of apoptosis, SSAs are thought to have antiproliferative, antiangiogenic, and proapoptotic effects [16], [17], [19], [20], [21], [22], [23], [24].

Due to the short half‐life of native somatostatin, longer‐acting SSAs such as octreotide LAR (Novartis Pharmaceutical Co., East Hanover, NJ) and lanreotide Autogel (Ipsen, Paris France) are now considered the therapy of choice in controlling symptoms associated with GEP‐NETs [25], [26], [27], including carcinoid syndrome‐related diarrhea and flushing and pancreatic islet cell hormonal‐secretory syndromes (i.e., gastrinomas, insulinomas, etc.). A complete or partial clinical response to SSA therapy is generally achieved in at least 50%–90% of patients with carcinoid symptoms [26], [28], [29], [30], [31], [32], and biochemical response ranges up to 50% [29]. Reducing serotonin secretion potentially prevents or delays the development of mesenteric fibrosis and carcinoid heart disease, which are related to sustained secretion of this hormone into the splanchnic and hepatic venous systems, respectively [33].

SSAs can also delay tumor growth. This was first demonstrated for octreotide LAR in a small randomized trial in midgut G1 NETs [34]. The subsequent larger randomized CLARINET study demonstrated the antiproliferative effects of 120 mg lanreotide Autogel in patients with G1 and G2 midgut NETs and pancreatic NETs (pNETs). Other smaller‐scale studies have also been conducted in this setting [14]. Guidelines now include recommendations on the first‐line use of lanreotide Autogel in patients with G1 or G2 GEP‐NETs [35], [36].

The optimal use of lanreotide Autogel in the control of NETs in terms of dosing, timing in relation to local therapies, and its role in combination regimens is unclear. Therefore, to gain a fuller understanding of the evidence and hence identify further areas of research, we conducted a systematic review of the published literature on the antiproliferative efficacy and safety of lanreotide Autogel in the management of NETs.

Materials and Methods

Data and Search Strategy

A search in PubMed was conducted up until March 16, 2016 (no start date was specified), and in four congresses (American Society of Clinical Oncology, European Society for Medical Oncology, European Neuroendocrine Tumor Society [ENETS] and North American Neuroendocrine Tumor Society) from 2013 to 2016. Key words and Medical Subject Headings terms used during the searches are included in supplemental online Appendix 1. No restriction was made on the type of study or publication in the initial searches.

Screening and Selection Criteria

Identified studies were screened for those reporting efficacy relating to the antiproliferative effect of lanreotide in NETs. Two reviewers reviewed titles, abstracts, and full‐length articles. Studies that reported data on lanreotide for the treatment of NETs in human patients and were published in English were included in the review. We included all formulations of lanreotide with the intention of providing the most comprehensive overview of the clinical evidence on lanreotide. The main focus of our discussion of the data is the Autogel formulation, which is currently the most widely studied and available formulation in use, and the only one approved for tumor growth control in the U.S., the European Union, and elsewhere.

Outcome Measures

The selection of relevant studies focused on clinical trial and case study publications; however, selected reviews were included to provide additional information. The outcomes of interest were the antiproliferative efficacy of lanreotide in NETs and its safety and tolerability in studies of its antiproliferative activity. Measures of efficacy included disease markers, tumor response, time to progression (TTP), progression‐free survival (PFS), and overall survival (OS). Measures of safety included the frequency of adverse events (AEs), toxicity, and tolerability.

Results

Description of Included Studies

The results from the PubMed database and congress abstract search and screening are presented in Figure 1. The review consisted of 40 publications, including 27 full‐length publications [14], [32], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61] and 13 congress abstracts (Tables 1 and 2) [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74]. Thirty‐six (90%) of the publications reported on studies performed in Europe, three involved centers in Europe, the U.S., and India (including the two subgroup analyses studies and an open‐label extension [OLE] study from the core CLARINET study), one was performed in the U.S., and one was performed in Israel.

Record search and screening flow chart.

1, Title and abstracts of all identified records were screened by two reviewers; search terms for records are listed in Appendix 1; 2, identified publications were screened for those reporting efficacy and safety and those relating to the antiproliferative effect of lanreotide; 3, the selection of relevant publications focused on clinical trial and case study publications; however, selected reviews were included to provide additional information; 4, publications that reported data on lanreotide for NETs in human patients published in English were included in the review; 5, sixteen of the publications selected were non‐Autogel formulations of lanreotide.

Table 1. Description of publications included in this review.

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In some cases, the exact doses used are undefined. The doses have been included when available.

Combination: LAN ATG + sunitinib; LAN ATG + everolimus; LAN ATG + bevacizumab; LAN ATG + sorafenib; LAN ATG + pazopanib.

Additional treatment included transarterial hepatic embolization, peptide receptor radionuclide therapy, or interferon or a combination.

Abbreviations: 5‐HIAA, 5‐hydroxyindoleacetic acid; AE, adverse event; ATG, Autogel; CgA, chromogranin A; Cape, Capecitabine; CR, complete response; CT, computed tomography; d, days; DS, disease stabilization; EU, European Union; FU, follow‐up; GEP‐NETs, gastroenteropancreatic NETs; GI, gastrointestinal; IFN‐α, interferon alpha; IRF, immediate release form; LAN, lanreotide; LAR, long‐acting release; MD, moderately differentiated; MEN1, multiple endocrine neoplasia type 1; mo, months; MP, microparticle; MTTs, molecular targeted therapies; MU, million units; NA/NR, not applicable/not reported; NENs, neuroendocrine neoplasms; NETs, neuroendocrine tumors; OCT, octreotide; OLE, open‐label extension study; OS, overall survival; PBO, placebo; PD, progressive disease; PFS, progression‐free survival; pNENs, pancreatic neuroendocrine neoplasms; pNETs, pancreatic neuroendocrine tumors; PR, partial response; PS, performance status; pts, patients; QoL, quality of life; SD, stable disease; SSA, somatostatin analogs; SST, somatostatin receptors; std, standard; TS, tumor stabilization; TTP, time to progression; US, United States; VIPoma, Vasoactive intestinal peptide tumor; WD, well‐differentiated; wk, week; yr, year.

Table 2. Safety and tolerability reported in included publications.

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Combination: LAN + sunitinib; LAN + everolimus; LAN + bevacizumab; LAN + sorafenib; LAN + pazopanib.

Abbreviations: AE, adverse event; ASCO, American Society of Clinical Oncology; ATG, Autogel; FU, follow‐up; G1‐4, grade 1‐4; LAR, long‐acting release; mo, month; MP, microparticle; MTT, molecular targeted therapies; NANETS, North American Neuroendocrine Tumor Society; OCT. octreotide; OS, overall survival; PBO, placebo; PD, progressive disease; pNETs, neuroendocrine tumors; pts, patients; QoL, quality of life; SAE, serious adverse event; SAR, severe adverse reactions; std, standard; TREA, treatment‐related adverse event; wk, week.

Non‐Autogel Formulations of Lanreotide

The first published record of the use of lanreotide in humans was in 1989 [75]. The focus of the current review is on the evidence‐base for lanreotide Autogel, but findings with other formulations are summarized briefly here. In 16 of the 40 selected publications, the formulation of lanreotide was not the Autogel formulation (Table 1) [32], [37], [38], [41], [42], [43], [44], [45], [46], [47], [55], [56], [57], [58], [59], [60]. The formulations of lanreotide were described as angiopeptin lanreotide (BIM 23014), lanreotide microparticle (MP), and slow‐ and long‐acting lanreotide. Only lanreotide Autogel was referred to in selected congress abstracts. The studies investigating other lanreotide formulations were generally small scale and/or open label or case studies. Overall, these publications showed that other formulations of lanreotide either decreased or normalized the measured disease markers (Table 1). Tumor size was stabilized in up to 70% of treated patients, and objective responses were generally observed in 5%–10% of patients.

Antiproliferative Efficacy of Lanreotide Autogel

The efficacy of lanreotide Autogel was reported in 24 of the 40 selected publications, involving approximately 913 patients (Table 1). In most publications, the lanreotide Autogel dose examined was 120 mg; however, dosing frequency varied between publications and was either every 4 or 6 weeks. Class I evidence [76] for the antiproliferative effect of lanreotide Autogel at a dose of 120 mg every 4 weeks comes from the CLARINET study, which was the only randomized, placebo‐controlled trial identified [14].

CLARINET was a randomized, double‐blind, placebo‐controlled, multinational phase III trial that investigated 120 mg lanreotide Autogel versus placebo every 4 weeks for 96 weeks in 204 patients with either well‐differentiated or moderately differentiated G1/G2 (Ki‐67 index <10%), nonfunctioning, SSTR‐positive, GEP‐NETs, including pancreas, midgut, or hindgut tumors (Table 1). Patients were observed for 12–24 weeks before randomization; most patients (96%) did not show disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 during this period. At 24 months, the disease had not progressed in 65.1% (95% confidence interval [CI]: 54.0–74.1) of patients who received lanreotide Autogel versus 33.0% (95% CI: 23.0–43.3) in the placebo group: a 53% risk reduction [14]. The median PFS in the placebo arm was 18 months but was not reached in the lanreotide arm [14]. Improvements in PFS with lanreotide Autogel were observed in the midgut NET and pNET subgroups, in patients with G1 tumors or G2 tumors, irrespective of whether the hepatic tumor load was >25% or ≤25%, and in patients of all ages (≤65 or >65 years of age) and BMI categories [14], [68], [77], [78], [79]. In the pNET subgroup of the CLARINET study, 37% of patients had a hepatic tumor load >25% and 77% had received no previous treatment for NETs. The median PFS among lanreotide Autogel patients within the pNETs subgroup was not reached during the core CLARINET study but was 12.1 months in patients receiving placebo [69].

The antitumor efficacy of lanreotide was also confirmed in the CLARINET study when assessed according to tumor response using RECIST version 1.0 criteria: 66% of patients in the lanreotide Autogel group and 43% in the placebo group achieved either a partial response or stable disease [80].

The antitumor efficacy of lanreotide was also confirmed in the CLARINET study when assessed according to tumor response using RECIST version 1.0 criteria: 66% of patients in the lanreotide Autogel group and 43% in the placebo group achieved either a partial response or stable disease.

Although OS did not differ significantly between the placebo and lanreotide Autogel groups, in the CLARINET study, the analysis was complicated by crossover from placebo to lanreotide by patients in the placebo group whose disease had progressed or who had completed 96 weeks without progression and continued into the CLARINET OLE study [14], [61]. In addition, there was uncertainty over subsequent treatments after disease progression [14].

In CLARINET OLE, patients who had received lanreotide Autogel or placebo in the CLARINET study with no disease progression at 96 weeks and patients who had received placebo and had disease progression before 96 weeks could continue or switch to 120 mg lanreotide Autogel every 4 weeks [61]. A total of 88 patients participated, 41 continuing on lanreotide Autogel and 47 switched from placebo [61]. Median PFS with lanreotide Autogel was 32.8 months from start of the core study for patients who received lanreotide in the core study and continued on lanreotide into CLARINET OLE; however, this may represent a highly selected population. Median PFS was 29.7 months for patients with pNETs who received lanreotide Autogel in both the core and the CLARINET OLE studies [69]. The median time to further disease progression was 14.0 months for patients with disease progression and then switching from placebo to lanreotide Autogel [61].

CLARINET is the pivotal study demonstrating the antiproliferative effects of lanreotide Autogel in NETs, but other studies are worth discussing (Table 1) [49], [51], [52]. In a multicenter, open‐label, phase II Spanish study, 30 patients with progressive GEP‐NETs or bronchopulmonary NETs received 120 mg lanreotide Autogel every 4 weeks for up to 94 weeks [51]. Progressive disease at baseline was defined as progression according to RECIST version 1.0 in the 6 months before study inclusion. A median PFS of 12.9 months was reported. The study showed that most patients receiving lanreotide Autogel achieved tumor stabilization (89%) [51]. In a long‐term retrospective study, 76 patients with metastatic midgut NETs (stable disease in the 11 patients with pretreatment data) and carcinoid syndrome received prolonged release lanreotide Autogel over 9 years at a U.K. center; 69 patients had data available [49]. Initially, 23 patients received 60 mg lanreotide Autogel every 4 weeks, 36 patients received 90 mg every 4 weeks, and 7 patients received 120 mg every 4 weeks. Fourteen patients required an increase in lanreotide dose, from 60 mg or 90 mg to 120 mg every 4 weeks, to control radiological or symptomatic progression [49]. The OS of all patients at 1, 3, and 5 years was 96%, 78%, and 72%, respectively. Radiological PFS at 1, 3, and 5 years was 93%, 75%, and 59%, respectively.

In another retrospective study conducted at a center in France, 68 patients with well‐differentiated digestive NETs were treated with lanreotide Autogel (59 patients), lanreotide MP (6 patients), or both (3 patients). The median dose of lanreotide Autogel was 90 mg every 4 weeks [52]. PFS was significantly longer in patients with low‐to‐moderate hepatic tumor involvement (≤25%, PFS >80 months versus 15 months for patients with hepatic tumor involvement >25%, p = .005) and in patients with stable disease before treatment (>46 months in patients with stable disease before treatment versus 6 months with progressive disease before treatment, p = .0005) [52]. A shorter PFS in patients with a higher hepatic tumor load was also demonstrated in CLARINET [81], but both groups of patients benefited from therapy with lanreotide Autogel. Likewise, primary tumor type (pancreas) was identified as an important prognostic factor determining PFS in CLARINET, but these patients gained benefit from lanreotide Autogel treatment [81].

Combination Therapy Involving Lanreotide Autogel

In a Spanish multicenter cohort study, 133 patients with NETs were treated with lanreotide Autogel in combination with molecular targeted therapies (MTTs) [62]. The principal reason for combining lanreotide with targeted therapies was to achieve antiproliferative synergy (85% of patients). Data from 159 combined treatments were retrospectively collected to evaluate the safety and efficacy of these combinations. Overall, 115 patients received 1 combination (median duration of treatment was 5.1 months) and 18 patients received between 2 and 5 combinations. The results from this cohort study suggested that combining lanreotide with MTTs can enhance efficacy; however, a randomized prospective clinical trial is required. Generally, the safety profile of the combinations in this trial resembled the safety profile of the MTT monotherapy.

An Italian phase II, non‐randomized trial in 30 patients with progressive, well‐differentiated NETs investigated the combination of capecitabine with either lanreotide Autogel or octreotide LAR after the failure of SSAs and/or chemotherapy, everolimus, or Peptide Receptor Radionuclide Therapy (PRRT) [65]. Patients received 1,000 mg capecitabine for 1–14 days and either 120 mg lanreotide Autogel or 30 mg octreotide LAR every 4 weeks until progression. Median PFS was 15.7 months, 4.6 months, and 4.2 months in patients with GI‐NET, pNET, and lung NET, respectively, and median OS was not reached after 50 months. No grade 3‐4 toxicities were reported.

Initial results after 1 year of an ongoing German study combining 120 mg lanreotide Autogel every 4 weeks with the oral chemotherapy agent temozolomide for the treatment of advanced progressive GEP‐NET suggested no tumor progression in 15 patients after ≥4 months [74]. More data from this study will help elucidate the potential role of this combination.

Safety and Tolerability Profile of Lanreotide Autogel

Safety and tolerability during studies of antitumor effects in NET patients was reported in 33 of the 40 publications, of which 23 were full‐length articles and 11 were congress abstracts (Table 2) [62], [64], [65], [66], [67], [68], [69], [71], [72], [73], [74]. A large body of evidence also exists from clinical trials and clinical practice on patients with acromegaly or carcinoid syndrome that supports the safety and tolerability of lanreotide Autogel, but this is outside the scope of this review. In most studies included here, safety and tolerability were measured by the incidence of AEs and causes of death. The most frequently reported AEs were abdominal pain, diarrhea, and cholelithiasis.

In the CLARINET study, similar proportions of AEs were reported in the lanreotide and the placebo groups (88% and 90%, respectively), most of which were mild (17% in each group) or moderate (44% and 43%, respectively). Treatment‐related AEs (TRAEs) among patients receiving lanreotide included diarrhea (26/101 patients), abdominal pain (14/101 patients), cholelithiasis (10/101 patients), and hyperglycemia (5/101 patients) [14]. There were no significant differences between treatments for any individual AEs, and no clinically significant trends were seen in the other safety assessments [82].

In the CLARINET OLE study patients who continued lanreotide Autogel, the incidences of overall and individual AEs (whether considered treatment‐related or not) were generally lower for the OLE study compared with the core study: for example, the incidence of TRAEs in this group was 57.3% (22/41) in the core study and 26.8% (11/41) in the OLE study [61]. This suggests that no major long‐term AEs emerged (up to 72.4 months in CLARINET OLE) with 120 mg lanreotide Autogel.

Preliminary results on the safety of higher‐dose lanreotide Autogel at an Italian center have been presented [73]. In 35 patients with progressive NET (84% with GEP‐NET), 180 mg lanreotide Autogel every 4 weeks for 12 months resulted in two serious TRAEs (cholelithiasis and consequent cholecystitis) [73].

Discussion

Antiproliferative Activity of Lanreotide Autogel

Lanreotide Autogel at a 120 mg dose has been shown to reduce tumor progression in patients with NETs [14], [43], [44], [45], [48], [60]. This review is not a meta‐analysis, and no meaningful comparison of median PFS could be made, as median PFS was not reported in most studies, tumor response was not assessed in a standardized way, the dose was increased in the course of many studies, and study designs and populations varied widely.

Despite the large proportion of patients (96%) in the CLARINET study with no disease progression, according to RECIST version 1.0, in the 3–6 months prior to study entry, significant antitumor effects of lanreotide Autogel were observed in all patient subgroups, including those with >25% liver tumor involvement [14], [15]. The results of CLARINET led to the approval of lanreotide Autogel in many countries as an antiproliferative treatment for patients with GEP‐NETs. The recommended starting dose is 120 mg lanreotide Autogel every 4 weeks in this setting, but further studies may help determine optimum doses in individual patients.

The other SSA that is used for antiproliferative effect in G1 midgut NETs is octreotide. This is based on the PROMID trial, which included patients with G1 midgut NET only [34]. Therefore, although octreotide may have antiproliferative action against pNETs or G2 midgut NET (Ki‐67 <10%), there is currently no other randomized controlled trial data to confirm the exact extent of the effect in such patients. Although these two SSAs share some common features, their different drug formulations and administered doses mean that care should be taken in assuming that the data on one drug can be extrapolated entirely to the other. This is reflected in current labeled indications for these two SSAs in many countries, which differ in the NET setting, or in some countries such as the U.S., where octreotide is not approved for antiproliferative effects.

In the CLARINET trial, patients were recruited only if their tumors were SSTR‐positive. Of the five different SSTR subtypes (SSTR1‐5), SSTR2 is expressed in approximately 90% of GI‐NETs and almost 80% of pNETs [83].The actions of the SSAs are mediated mainly through SSTR2 and SSTR5 [84]. There has been some discussion on the effectiveness of lanreotide Autogel or octreotide LAR in the treatment of Octreoscan‐negative or SSTR2‐negative NETs [84], [85]. The lack of expression of SSTR2 in GEP‐NETs treated with lanreotide Autogel or octreotide LAR is a prognostic indicator of the likelihood of tumor recurrence [86], [87]. However, the ENETS 2016 guidelines for the management of intestinal, pancreatic, bronchial, and unknown primary NETs state that SSAs may be considered for the treatment of tumor growth in patients with Octreoscan‐negative low tumor burden NETs [36]. SSAs are not recommended for the treatment of Octreoscan‐negative G3 NETs that have an aggressive phenotype [88]. Octreoscan has been shown to have suboptimal sensitivity compared to ⁶⁸Ga SSA‐labeled positron emission tomography (PET) in the detection of small‐volume disease [89]. Therefore, increasing adoption of ⁶⁸Ga SSA‐labeled imaging may facilitate a clearer indication of Octreoscan‐negative patients who may benefit from SSAs.

Watchful Waiting Versus Early Initiation of Lanreotide Autogel

Watchful waiting, until there is evidence of rapid disease progression and/or symptoms develop, has been suggested as an option in patients with nonprogressive low‐grade GEP‐NETs [35]. The most recent ENETS guidelines suggest watchful waiting as an alternative to an SSA in patients with G1 GEP‐NETs with a low tumor burden and stable disease [36]. There appear to be two alternative viewpoints on the role of watchful waiting. Positive results for initiating 120 mg lanreotide Autogel as a first‐line antiproliferative treatment in patients with metastatic midgut NETs and pNETs are provided by the CLARINET study. If the placebo arm of the CLARINET study is considered as a surrogate watchful waiting arm, there are clear benefits in terms of significantly greater PFS with lanreotide Autogel [14], [15]. The minor impact of TRAEs associated with lanreotide Autogel, combined with its antiproliferative effects, potentially justifies its early use even in the absence of specific symptoms. Furthermore, many patients with NETs are only diagnosed when nonspecific symptoms trigger further investigations—hence treatment to prevent progression is justified.

On the other hand, there is limited evidence that withholding treatment with lanreotide Autogel until there is objective evidence of disease progression has an adverse impact on OS, and this supports a watchful waiting approach. Although the CLARINET and CLARINET OLE trials showed improvements in PFS, no difference in OS was observed between treatment arms. This is not entirely unexpected, as the slowly progressive nature of NETs and the effect of other treatments during long‐term follow‐up make measuring differences in OS between treatments problematic or impractical [90], [91]. Furthermore, the cost impact of introducing a long‐acting SSA instead of allowing a period of watchful waiting is unknown, and this should be assessed before recommending treatment for all patients.

More studies are needed to determine if the delayed progression (and potentially delaying the worsening of associated symptoms) means that lanreotide Autogel is the best option for all patients with GEP‐NETs. In the meantime, clinical judgement and informed patient preference will continue to drive management decisions on an individualized basis for patients with stable or slowly progressing GEP‐NET.

Measuring Treatment Response in NETs

Alternative and more sensitive measures of disease progression in GEP‐NETs may be useful in future trials. In the CLARINET study, tumor growth was assessed using structural imaging. However, the technique used and, in particular, the timing of contrast enhancement can significantly impact response assessment [92]. Functional imaging with ⁶⁸Ga DOTA PET is more sensitive and specific for staging than structural imaging and may be a more appropriate technique for assessing suitability for treatment and response. However, this technique is not globally available or approved at present. Another technique, fluorodeoxyglucose (FDG) PET, has exhibited excellent predictive value for early tumor progression in NET—especially as it is a surrogate of more aggressive disease—and has prognostic value in metastatic GEP‐NETs. FDG PET and SSTR scintigraphy results correlate with PFS and OS in patients with metastatic NETs [93], [94], [95].

Chromogranin‐A (CgA) and SSTR imaging are the most sensitive indicators of disease burden in NETs. CgA is the most helpful prognostic and diagnostic biomarker, as it is elevated in 90% of patients with metastatic NETs [96]. Lanreotide treatment can achieve normalization of CgA levels in a reasonable proportion of patients with GEP‐NET [40], and decreases in the release of CgA are associated with clinical benefits [29], [97]. However CgA can be elevated by several non‐NET sources, including SSA therapy [98]. The potential role of other novel biochemical markers has yet to be determined [99], [100].

Another method that has been proposed for assessment of treatment response is the tumor growth rate (percentage variation of tumor volume per month), which has been applied to other solid tumors [101] and may have promise in NETs [102]. Hence, in NETs, response assessment criteria need to be redefined with functional and structural imaging [103].

Ongoing Studies of Lanreotide Autogel as Maintenance Therapy and in Combination

The strategy of continuing SSA therapy when patients progress and commence other systemic therapies may be essential in SSTR‐positive disease, but more data are needed on the important question of treatment sequencing, maintenance therapy, and combination therapy.

Continuation of lanreotide Autogel use when other drugs (such as MTTs or capecitabine) are introduced appears to reduce disease progression and may be associated with more prolonged PFS (up to 89% of patients at 6 months) [62], [65], but more studies are needed to assess and validate the ongoing benefits of lanreotide when disease progresses (for example, the international SUNLAND study of lanreotide Autogel plus either sunitinib or placebo [NCT01731925, EudraCT 2012‐001098‐94]). The initial results from the German SONNET trial also indicate the potential value of lanreotide Autogel plus temozolomide in advanced progressive GEP‐NET [74], but longer‐term data will help determine the impact of this combination on PFS.

The value of lanreotide Autogel as maintenance therapy when disease has been stabilized by cytotoxic chemotherapy or by everolimus or sunitinib treatment is being assessed in the international REMINET study in non‐resectable duodeno‐pNET patients (NCT02288377, EudraCT 2013‐004069‐14). Maintenance therapy with lanreotide Autogel following initial PRRT is another treatment sequence that needs to be assessed in future clinical studies. The prolonged PFS recently reported within the NETTER‐1 study in patients receiving PRRT compared with high‐dose octreotide LAR further complicates the choice of optimal therapy in patients with low grade midgut NETs who have progressived disease with standard dose SSAs [104].

The prolonged PFS recently reported within the NETTER‐1 study in patients receiving PRRT compared with high‐dose octreotide LAR further complicates the choice of optimal therapy in patients with low grade midgut NETs who have progressived disease with standard dose SSAs.

Ongoing Studies of Lanreotide Autogel Antiproliferative Efficacy in Other NETs

The antiproliferative activity of lanreotide Autogel has also been shown in NETs originating in locations other than the midgut and pancreas. The CLARINET study included patients with NETs originating in the hindgut; however, patient numbers were too small to draw any accurate conclusions. Other publications of smaller studies have reported potential antiproliferative activity of lanreotide in NETs originating in the testes, respiratory system (including the lungs and bronchus), liver, hindgut, and foregut [14], [32], [37], [38], [40], [43], [44], [45], [46], [47], [51], [52], [54], [58], [59], [60], [62], [64], [65], [66], [71]. Larger‐scale studies are also ongoing in some of these settings (e.g., the international SPINET study in lung NET [NCT02683941] and a phase II study of 120 mg lanreotide Autogel versus placebo in advanced lung or thymus NETs [105]).

Ongoing Studies of Higher Doses or Alternative Dose Regimens of Lanreotide Autogel

The potential for using higher doses of lanreotide is being assessed prospectively in the ongoing international CLARINET FORTE study of 120 mg lanreotide Autogel every 2 weeks in GEP‐NET patients who have progressed radiologically (RECIST version 1.1) on 120 mg lanreotide Autogel every 4 weeks. There is also an ongoing Italian phase II study investigating the use of 180 mg lanreotide Autogel every 4 weeks in patients with progressive NETs following standard doses of SSAs (EudraCT 2012‐005222‐30) [73]. These studies will provide information on both the potential benefits of higher doses to achieve an antiproliferative response and on the AE profile of such higher doses in patients with GEP‐NETs.

Safety and Tolerability of Lanreotide Autogel

The CLARINET study, the CLARINET OLE study, and other studies identified in this review have demonstrated the favorable overall safety and tolerability profile of lanreotide Autogel. This is consistent with the wider experience of safety and tolerability in studies and clinical practice over many years for acromegaly and carcinoid symptom control. Ongoing studies will help establish the safety profile of higher dose lanreotide Autogel; initial experience suggests no additional toxicity concerns with increased doses of lanreotide.

Limitations of the Review

One of the limitations to the conclusions of this systematic review was that many of the studies identified were small and retrospective, which can be subject to recall bias. However, the evidence base is considerably strengthened by the CLARINET study, which is the largest study of SSA use for tumor control to date and offers high‐level evidence that confirms and extends the other literature. Other limitations were that the studies varied in design, patient population, definitions of outcomes, and NETs origin (e.g., lung, metastatic GI, digestive, etc.), and data were reported in several ways; hence, a direct comparison between studies was not possible. Ongoing large prospective studies may have more standardized designs for outcome assessments, which may go some way to addressing this issue.

Conclusion

This systematic literature review shows that current clinical evidence for lanreotide Autogel indicates important antiproliferative activity with favorable safety and tolerability in patients with midgut NETs and pNETs. This suggests that this agent should be considered first‐line early treatment in this population, as recommended in the 2016 ENETS guidelines [36]. Further studies are required on the use of lanreotide Autogel in NETs originating in other locations, including hindgut and bronchopulmonary NETs. The optimal dose, the utility of combination therapy, and the potential role of lanreotide Autogel as backbone or maintenance therapy in progressive disease will be addressed with ongoing studies. These studies may also better utilize functional imaging and biomarkers to optimize treatment.

See http://www.TheOncologist.com for supplemental material available online.

Acknowledgments

Medical writing support was provided by ESP Bioscience, Crowthorne, U.K., and funded by Ipsen. Ipsen provided information to the authors on its clinical program. The authors were responsible for the concept and all content, were involved at all stages of manuscript development, and provided approval of the final version for submission.

Author Contributions

Conception/Design: Michael Michael, Rocio Garcia‐Carbonero, Matthias M. Weber, Catherine Lombard‐Bohas, Christos Toumpanakis, Rodney J. Hicks

Provision of study material or patients: Michael Michael, Rocio Garcia‐Carbonero, Matthias M. Weber, Catherine Lombard‐Bohas, Christos Toumpanakis, Rodney J. Hicks

Collection and/or assembly of data: Michael Michael, Rocio Garcia‐Carbonero, Matthias M. Weber, Christos Toumpanakis, Rodney J. Hicks

Data analysis and interpretation: Michael Michael, Rocio Garcia‐Carbonero, Matthias M. Weber, Catherine Lombard‐Bohas, Christos Toumpanakis, Rodney J. Hicks

Manuscript writing: Michael Michael, Rocio Garcia‐Carbonero, Matthias M. Weber, Catherine Lombard‐Bohas, Christos Toumpanakis, Rodney J. Hicks

Final approval of manuscript: Michael Michael, Rocio Garcia‐Carbonero, Matthias M. Weber, Catherine Lombard‐Bohas, Christos Toumpanakis, Rodney J. Hicks

Disclosures

Michael Michael: Ipsen, Pfizer, Novartis (H), Novartis (RF); Rocio Garcia‐Carbonero: Ipsen (C/A); Matthias M. Weber: Novartis, Pfizer, Ipsen (C/A, H), Novartis, Ipsen (RF); Catherine Lombard‐Bohas: Pfizer, Ipsen, Novartis, Keocyt (C/A), Novartis, Ipsen (RF); Christos Toumpanakis: Ipsen, Lexicon (C/A), Ipsen, Novartis (H), Ipsen, Novartis (RF); Rodney J. Hicks: Ipsen (C/A).

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board

Supplementary Information

Supplemental Data

supp_22_3_272__index.html^{(780B, html)}

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PERMALINK

The Antiproliferative Role of Lanreotide in Controlling Growth of Neuroendocrine Tumors: A Systematic Review

Michael Michael

Rocio Garcia‐Carbonero

Matthias M Weber

Catherine Lombard‐Bohas

Christos Toumpanakis

Rodney J Hicks

Abstract

Background.

Methods.

Results.

Conclusion.

Implications for Practice.

Introduction

Materials and Methods

Data and Search Strategy

Screening and Selection Criteria

Outcome Measures

Results

Description of Included Studies

Figure 1.

Table 1. Description of publications included in this review.

Table 2. Safety and tolerability reported in included publications.

Non‐Autogel Formulations of Lanreotide

Antiproliferative Efficacy of Lanreotide Autogel

Combination Therapy Involving Lanreotide Autogel

Safety and Tolerability Profile of Lanreotide Autogel

Discussion

Antiproliferative Activity of Lanreotide Autogel

Watchful Waiting Versus Early Initiation of Lanreotide Autogel

Measuring Treatment Response in NETs

Ongoing Studies of Lanreotide Autogel as Maintenance Therapy and in Combination

Ongoing Studies of Lanreotide Autogel Antiproliferative Efficacy in Other NETs

Ongoing Studies of Higher Doses or Alternative Dose Regimens of Lanreotide Autogel

Safety and Tolerability of Lanreotide Autogel

Limitations of the Review

Conclusion

Acknowledgments

Author Contributions

Disclosures

Supplementary Information

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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