Clinical utility of lanreotide Autogel^® in gastroenteropancreatic neuroendocrine tumors

Figures & data

Figure 1 Structure of somatostatin 14 (A) and somatostatin 28 (B). The 2 isoforms differ in the amino acids within the red dashed rectangle, as they are missing in somatostatin 14 but are present in somatostatin 28.

Abbreviation: SST, somatostatin.

Figure 2 Structure of the most used somatostatin analogs: octreotide (A), lanreotide (B), vapreotide (C), and pasireotide (D). Lanreotide is an octapeptide that self-assembles into nanotubes when placed in an aqueous environment. It has 3 aromatic residues (d-naphthylalanine, tyrosine, and d-tryptophan) that are involved in the formation of these supramolecular structures.

Figure 3 Mechanisms explaining the inhibitory and antiproliferative effects of SST and SSAs. There are 5 types of SSTRs, which show different tissue distribution. SSTR 2 has 2 different isoforms (2a and 2b) that derive from alternative splicing at the C-terminus of the receptor – between the 2, the SSTR 2a isoform is far more common in human tissues. SST and SSAs bind to SSTRs with different affinities. All SSTRs are G protein-coupled receptors with 7 transmembrane-spanning domains.

Abbreviations: cAMP, cyclic adenosine monophosphate; EGFR, epidermal growth factor receptor; GH, growth hormone; GI, gastrointestinal; SSAs, somatostatin analogs; SST, somatostatin; SSTR, somatostatin receptor.

Table 1 Classifications of GEP-NENs

NEN classification according to embryological origin^Citation37
Foregut	NEN originating from the thymus, respiratory tract, esophagus, stomach, pancreas, duodenum, and ovaries
Midgut	NEN originating from the jejunum, ileum, appendix, cecum, ascending colon, and Meckel’s diverticulum
Hindgut	NEN originating from the transverse, descending, and sigmoid colon
GEP-NEN classification according to grade of differentiation^Citation38,a
Well-differentiated tumors (“carcinoid”)	Mild or no atypia, restricted to the mucosa or submucosa, absence of angioinvasion, tumor size <1 cm, and proliferation rate <2 mitoses/10 HPFs or Ki-67 <2%
Well-differentiated carcinomas (“malignant carcinoid”)	Malignant endocrine tumor cells, moderate atypia, deep invasion of the gut wall, often metastases to regional lymph nodes or liver, tumor size >1 cm, and proliferation rates >2 mitoses/10 HPFs or Ki-67 index >2%
Poorly differentiated carcinomas (“small cell carcinoma”)	Highly atypical, small- to intermediate-sized tumor cells, deep invasion or destruction of the gut wall, often necrosis and angio- and perineural invasion, local and distant metastases, size >1 cm, and proliferation rates of >10 mitoses/10 HPFs or Ki-67 index of >15%
Mixed exocrine–endocrine tumors	Unusual bimorphous tumors. Prominent exocrine cells (acinar or ductal) admixed with at least 30% endocrine component. Biological behavior of the exocrine component
Tumor-like lesion
WHO 2010 classification^Citation35
Neuroendocrine neoplasm typeb	Grade	Ki-67 indexc	Mitotic count (per 10 HPFs)d
Neuroendocrine tumor	G1	≤2%	<2
Neuroendocrine tumor	G2	3%–20%	2–20
Neuroendocrine carcinoma	G3	>20%	>20
Mixed adenoneuroendocrine carcinoma	G1–G3 (mostly G3 component)	All ranges	All ranges

Notes:

a In the WHO 2000 classification of GEP-NENs, large cell carcinomas were mentioned under the stomach, colon, and rectum sections, but no other classification criteria were described.

b The WHO recommends the use of the term “neuroendocrine neoplasm” to indicate low- to high-grade lesions. However, the term “neuroendocrine tumor” is still widely used. The term “neuroendocrine carcinoma” indicates high-grade lesions.

c Ki-67 index: % of 500–2,000 cells in “hot spot areas” stained positive for MIB-1 antibody.

d 10 HPFs =2 mm², based on measurement in at least 50 HPFs in hot spot areas.

Abbreviations: GEP, gastroenteropancreatic; HPFs, high-power fields; NENs, neuroendocrine neoplasms; WHO, World Health Organization.

Table 2 Relevant clinical studies of LAN Autogel^® in GEP-NENs

Study	Type of the study	Patients	Aim of the study	Results
Ruszniewski et al^Citation53	6-month, open, non-controlled, multicenter, dose-titration study	71 patients affected by CS treated with LAN. The dose for the first 2 injections was 90 mg. Subsequent doses could be titrated (60 mg, 90 mg, 120 mg) according to symptom response	Efficacy and safety of 28-day PR-LAN in the treatment of CS	Symptom frequency decreased further after the second and third injections. In 6 months, flushing and diarrhea had significantly decreased from baseline. Median urinary 5-HIAA and CgA levels decreased by 24% and 38%, respectively
Bajetta et al^Citation44	Phase III, multicenter, randomized trial	60 patients randomized; 46 completed the study. Comparison between LAN Autogel 120 mg/6 weeks vs LAN microparticles 60 mg/3 weeks	Efficacy of LAN Autogel vs LAN microparticles in sporadic, well-differentiated NENs with a low grade of malignancy	LAN Autogel was not inferior to LAN microparticles for tumor markers (55% and 59%, respectively) and tumor size reduction (68% and 66%, respectively)
Khan et al^Citation58	Retrospective study (9 years)	69 patients treated (initial dose) with LAN 60 mg/28 days (23 patients), 90 mg/28 days in 36 patients and 120 mg in 7 patients	Clinical response and tolerance of LAN in metastatic midgut NENs and CS	94% of patients achieved symptomatic response at first follow-up visit. 46% had loss of symptomatic response, but 44% of these achieved control increasing LAN dose. Overall, symptoms were controlled with LAN in 74% of patients. 26% required additional treatment despite good initial response; 30% showed radiological progression
Bianchi et al^Citation45	Retrospective study (4 years)	23 patients receiving LAN Autogel (120 mg) every 28 days	Relief of disease symptoms, behavior of tumor markers response rate in terms of time to tumor progression, and safety and tolerability of LAN in metastatic well-differentiated NENs	Improvement of flushing and diarrhea in 85.7% and 55.6% of patients, respectively. Complete, partial, or no-changed response in the tumor markers behavior in 42.9%, 22.9%, and 17.1% of cases, respectively. Tumor partial regression: 8.7%; stable disease: 65.3%; tumor progression: 26.0%. No severe adverse reaction
Martín-Richard et al^Citation46	Multicenter, open-label, Phase II trial	30 patients receiving LAN Autogel (120 mg) every 28 days	PFS, response rate, tumor biomarkers, symptom control, QoL, and safety in well-differentiated NENs	PFS time: 12.9 months; disease stabilization: 89% of patients; partial response: 4% of cases. No deterioration in QoL. Treatment-related adverse events (most frequently diarrhea and asthenia): 63%
Palazzo et al^Citation50	Retrospective study	68 patients with well-differentiated NENs treated with LAN	To identify factors associated with tumor control in a group of patients with well-differentiated, malignant GEP-NENs treated with LAN	Tumor progression in 57.4%. Median PFS was 29 months. Ki-67 index of up to 5%, pretreatment stability, and hepatic tumor load of up to 25% were significantly associated with disease stability under LAN therapy
Vinik et al^Citation54	16-week, randomized, double-blind, Phase III trial	LAN 120 mg/28 days, n=59; placebo, n=56	Efficacy of LAN 120 mg/4 weeks in treatment of CS	The percentage days with rescue OCT use is significantly lower in the LAN vs placebo (33.7% vs 48.5%)
Caplin et al^Citation47	96-week, randomized, double-blind, placebo-controlled, multinational study (CLARINET)	LAN Autogel 120 mg/28 days, n=101; placebo, n=103	PFS, overall survival, QoL, and safety in SSAs-positive, G1 or G2 NENs and documented disease-progression status	PFS at 24 months was 65.1% for LAN and 33.0% for placebo group. No significant differences in QoL or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the LAN group and 9% of those in the placebo group)
Orlewska et al^Citation59	National, multicenter, non-interventional, observational study (LANRONET)	52 patients receiving LAN 120 mg/28 days	To examine characteristics and treatment patterns of symptomatic NEN patients treated with LAN Autogel 120 mg for at least 3 months before inclusion, administered as part of routine clinical practice	Primary tumors were GEP-NENs (51.2%); all tumors were metastatic. Most commonly reported symptoms were flushing and diarrhea (55.8%). During the 12-month observation, 28% received LAN Autogel
Ruszniewski et al^Citation55	International, open-label, observational study (SYMNET)	273 patients	Satisfaction with diarrhea control; severity, change in symptoms, and impact on daily life of diarrhea; and satisfaction with flushing control	76% were “completely” or “rather” satisfied with diarrhea control; 79% had improvement in diarrhea with LAN. 75% were unconcerned about the impact of diarrhea on daily life. Satisfaction with flushing control was 73%
Caplin et al^Citation49	Open-label extension of CLARINET study	88 patients. LAN, n=41; placebo, n=47	Long-term safety and additional efficacy	Patients continuing LAN reported fewer adverse events than core study. Placebo-to-LAN switch patients reported similar adverse effects
Faggiano et al^Citation51	Observational multicenter study	106 patients with a histologically confirmed GEP or thoracic NENs or unknown primary NENs, initially treated with LAN Autogel (120 mg/28 days) or OCT LAR (30 mg/28 days). The initial SSA dose has been subsequently changed in 14 patients. OCT was switched to LAN in 6 cases	Evaluate the efficacy of long-acting SSAs in NENs according to Ki-67 index	Tumor response in 11%, stability in 58%, and progression in 31%. No differences between G1 and G2 NENs. PFS was longer but not significantly different in G1 than G2 NENs. The median PFS was significantly longer in NENs showing Ki-67 <5% than in those showing Ki-67 ≥5%

Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; CgA, chromogranin A; CS, carcinoid syndrome; GEP, gastroenteropancreatic; LAN, lanreotide; NENs, neuroendocrine neoplasms; OCT, octreotide; PFS, progression-free survival; PR, prolonged release; QoL, quality of life; SSAs, somatostatin analogs; LAR, long acting repeatable.

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