Octreotide Long-acting Release Research Articles

A Real-World Observational Study of the Use and Associated Costs of Treating Neuroendocrine Tumors With Somatostatin Analogs in Canada.

Somatostatin analogs (SSAs; lanreotide autogel and octreotide long-acting release) are used to treat neuroendocrine tumors; however, factors that influence SSA use are unclear. This real-world, observational study collected data from private/public pharmacy claims for patients using SSAs in Canada. Data relating to dosing regimens, injection burden, treatment persistence, and costs were retrospectively analyzed for treatment-naive patients. Overall, 1545 patients were included in the analysis of dosing regimens, 908 for injection burden, 453 for treatment persistence, and 903 for treatment-associated costs. Compared with lanreotide, treatment with octreotide long-acting release was more likely associated with treatment above the maximum recommended dose (odds ratio, 16.2; 95% confidence interval, 4.3-136.2; P < 0.0001), higher weighted average long-acting SSA injection burden (13.4 vs 12.5, P < 0.0001), and a higher number of rescue medication claims per patient (0.22 vs 0.03, P < 0.0001). Treatment with lanreotide autogel was associated with greater treatment persistence (hazard ratio, 0.58; 95% confidence interval, 0.42-0.80; P = 0.001) and lower mean annual costs of treatment than octreotide long-acting release (Canadian dollars $27,829.35 vs $31,255.49; P < 0.0001). These findings provide valuable insight into SSA use in clinical settings and may inform treatment selection.

Efficacy and adverse events of octreotide long-acting release in acromegaly: a real-world retrospective study.

BackgroundOctreotide long-acting release (LAR) is a common drug used for acromegaly that aims to normalize serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1). However, only a few studies have evaluated its efficacy and safety in Chinese patients. This retrospective study aimed to assess its efficacy and safety in a cohort of Chinese patients with acromegaly.MethodsA total of 163 patients with acromegaly, who received continuous and regular octreotide LAR treatment at least three times at Peking Union Medical College Hospital between 2010 and 2020, were enrolled. Clinical characteristics, acromegaly activity, and other laboratory tests before and after treatment were collected for analysis.ResultsThe study enrolled 163 patients, including 71 men (43.6%) with a mean age of 40.94±13.00 years. After octreotide LAR treatment, 34.4% of the patients achieved GH control (<2.5 ng/mL), while IGF-1 levels were normalized in 23.3% of the patients. Also, fasting GH levels were downregulated from 4.95 ng/mL [interquartile range (IQR) 2.225, 10.325 ng/mL] at baseline to 3.2 ng/mL (IQR 1.5, 6.6 ng/mL) (P<0.001), and IGF-1/upper limit of the normal (ULN) declined from 1.89 (IQR 1.22, 2.40) to 1.41 (IQR 0.97, 1.89) (P<0.001). In addition, 65 patients experienced moderate adverse events. During the follow-up, none of the patients discontinued octreotide LAR. Further logistic regression showed that comorbidity [odds ratio (OR), 3.19; 95% confidence interval (CI): 1.20–9.27; P=0.025] and previous surgery only (OR, 0.21; 95% CI: 0.08–0.58; P=0.003) were two risk factors for the development of adverse events.ConclusionsOur findings revealed that octreotide LAR treatment is effective in normalizing GH and IGF-1 levels in Chinese patients with acromegaly. In addition, adverse events related to octreotide LAR use were moderate and well tolerated by the patients.

A Randomized Trial Evaluating Patient Experience and Preference Between Octreotide Long-Acting Release and Lanreotide for Treatment of Well-Differentiated Neuroendocrine Tumors.

Somatostatin analogs octreotide long-acting release (octLAR) and lanreotide are equally acceptable in National Comprehensive Cancer Network guidelines for neuroendocrine tumors (NETs). Lanreotide is more expensive and given by deep subcutaneous injection, whereas octLAR is given intramuscularly. We evaluated patient preference between these agents in terms of injection site pain. Randomized, single-blinded study. Patients with NETs received injections every 4 weeks. Arm 1: octLAR × 3, then lanreotide × 3; arm 2: reverse order. Self-reported injection site pain scores (range, 0-10) were obtained after each of the first three injections. Primary end point was comparison of mean pain scores over the first three injections. Secondary end points included patient-reported preference. Fifty-one patients enrolled (26 in arm 1 and 25 arm 2), all evaluable for primary end point. No significant difference was identified in the mean pain score over the first three injections (2.4 ± 1.9 v 1.9 ± 1.5, P = .5). Thirty-four of 51 (67%) patients (15 in arm 1 and 19 in arm 2) completed post-therapy questionnaires and were evaluable for secondary end points. Seven patients (47%) in arm 1 and eight patients (42%) in arm 2 indicated no drug preference at the end of treatment. In the other 19 patients, more patients indicated mild or strong preference for octLAR over lanreotide. We found minimal pain with octLAR and lanreotide and no significant pain score differences between the two. Patients indicating a drug preference trended toward favoring octLAR.

Methodology of the SORENTO clinical trial: Assessing the efficacy and safety of high exposure octreotide subcutaneous depot in patients with GEP-NETs.

TPS4178 Background: Somatostatin receptor ligands (SRLs) are first-line standard of care therapies for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), showing efficacy in tumor/symptom control with an established safety profile. Yet, disease progression may occur despite standard-dose SRL treatment, requiring more aggressive and toxic therapies. Retrospective/non-randomized data suggest higher-dose SRLs may benefit patients with GEP-NETs who do not respond to standard-dose treatment and provide improved disease control. Octreotide depot (CAM2029) is a novel high-exposure, subcutaneous (SC) formulation. Clinical trials showed ̃500% higher CAM2029 bioavailability versus octreotide long-acting release (LAR) (Tiberg et al. 2015), and maintenance/reduction of NET symptoms (Pavel et al. 2019). Prospective, randomized data are needed to confirm the efficacy/safety of novel SRLs with higher bioavailability such as CAM2029, vs standard-dose SRLs including octreotide LAR and lanreotide Autogel (ATG). Methods: SORENTO is a randomized, multi-center, open-label, active-controlled Phase 3 trial, aiming to enroll 302 adults with GEP-NETs. Key eligibility criteria: advanced, well-differentiated NET of GEP/presumed GEP origin; ≥1 measurable SR positive (by nuclear imaging) lesion according to RECIST 1.1; no or &lt; 6 months consecutive treatment with long-acting SRLs. Notably, patients with Grade 3 GEP-NETs (excluded by CLARINET/PROMID trials) are eligible. Patients will be randomized 1:1 to CAM2029 20 mg Q2W, or active comparator (octreotide LAR 30 mg intramuscular or lanreotide ATG 120 mg SC, Q4W). CAM2029 self/carer administration is allowed after ≥3 successful supervised administrations. Randomization stratified by: histological grade, tumor origin, intended comparator. Primary outcome: progression free survival (PFS; time from randomization to date of first documented disease progression [RECIST 1.1] or death), assessed by a Blinded Independent Review Committee. The study is powered to detect a hazard ratio of 0.65. Key secondary outcomes: overall survival; response rate; rescue medication use; patient satisfaction; adverse events. After primary PFS analysis, patient overall survival will be followed for up to 2 years. If CAM2029 displays superiority in the primary analysis, the comparator group may switch to CAM2029 20 mg Q2W. Patients in any treatment group experiencing progressive disease in the randomized part of the study may proceed to an open-label extension with intensified CAM2029 treatment, to investigate effects of higher frequency dosing. First patient randomized in Nov-2021, with readout (following 194 events) expected by 2024 end. This novel head-to-head superiority trial is anticipated to demonstrate the potential benefits of CAM2029 as a first line-therapy in patients with well-differentiated GEP-NETs. Clinical trial information: NCT05050942.

Real-world injection experience and use of independent injection among patients using lanreotide autogel/depot (LAN) prefilled syringe or octreotide long-acting release (OCT) to treat acromegaly or neuroendocrine tumors (NETs): international PRESTO 2 survey

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

A qualitative study to understand the experience of somatostatin analog treatments from the perspective of patients with neuroendocrine tumors

PurposeNeuroendocrine tumors (NETs) negatively impact patients’ quality of life. Octreotide long-acting release (LAR) and lanreotide depot are somatostatin analogs (SSAs) approved to treat NETs. The study objective was to explore SSA treatment experiences and preferences of patients with NETs.MethodsQualitative interviews were conducted in US adults (≥ 21 years) with NETs who had ≥ 6 months’ treatment with each SSA and transitioned from octreotide LAR to lanreotide depot within the previous year. Participants were asked open-ended questions about their experiences with octreotide LAR and lanreotide depot, treatment preferences, and SSA treatment attributes.ResultsTwenty participants (mean age: 58 years; 90% female; 85% white) completed interviews. The most common reasons for treatment transition were doctor recommendation (70%), treatment not working as expected (55%), and injection type preference (45%). Participants reported 34 unique favorable attributes of SSA treatment and 82 unique unfavorable attributes. Symptom control was the most frequently reported favorable attribute (associated with octreotide LAR by 60% of participants and lanreotide depot by 65%). Painful injection (65%) was most frequently cited unfavorable attribute for octreotide LAR and injection experience dependent on administrator (35%) for lanreotide depot. The three SSA treatment attributes rated as most important were side effects, symptom control, and ability to stabilize tumor.ConclusionOur qualitative data provide valuable insight into the treatment attributes that patients with NETs consider important when making SSA treatment decisions. Factors related to injection administration, side effects, and symptom control are important to patients and should be included in patient-provider communications in clinical contexts.

Tolvaptan vs. somatostatin in the treatment of ADPKD: A review of the literature.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder with an estimated prevalence between 1 : 1,000 and 1 : 2,500. Until a few decades ago, ADPKD was considered an untreatable disease, relentlessly progressing towards end-stage renal disease because of the lack of specific interventions. In the last decade, some aberrant molecular pathways involved in ADPKD development have been identified, and controlled clinical trials have been conducted to investigate the potential role of active drugs on these pathophysiological mechanisms such somatostatin and tolvaptan. Somatostatin analogues have been shown to be effective not only in ADPKD, but also in polycystic liver disease (PLD) with beneficial effect on cardiac function and a better cost/benefit profile; the only somatostatin analogue currently available for clinical use is octreotide long-acting release (octreotide-LAR), and it is approved only in Italy. On the contrary, tolvaptan is authorized worldwide and has received more attention in the last years, even if its clinical use is widely limited by aquaresis tolerability. The aim of this review is to investigate the advantages and drawbacks of somatostatin analogues and tolvaptan in the treatment of ADPKD.

Patterns of Use and Clinical Outcomes with Long-Acting Somatostatin Analogues for Neuroendocrine Tumors: A Nationwide French Retrospective Cohort Study in the Real-Life Setting.

IntroductionLong-acting somatostatin analogues such as lanreotide autogel (LAN) and octreotide long-acting release (OCT) are recommended as first-line treatment for patients with neuroendocrine tumors (NETs). However, only few real-world studies have compared the two medications. This retrospective, observational cohort study used a French claims database to compare patterns of use with LAN vs. OCT in patients with NETs.MethodsData on LAN and OCT patterns of use were obtained retrospectively from the National System of Health Data (SNDS), a national French claims database. Patients 18 years of age or older who initiated treatment for NETs between 2009 and 2016, and who received at least six subsequent dispensings of first-line LAN or OCT during the first year of treatment, were included. A subgroup analysis was performed on patients with gastroenteropancreatic (GEP)-NETs.ResultsPatients receiving LAN (n = 2327) vs. OCT (n = 2090) had greater median treatment duration (31.8 months vs. 22.1 months, respectively; p < 0.0001; log-rank test) and were less likely to discontinue treatment; adjusted hazard ratio (HR) 0.74 (95% confidence interval [CI] 0.69–0.80). In year 1, a significantly lower percentage of patients receiving LAN vs. OCT switched treatments (10.4% vs. 22.2%, respectively; p < 0.0001), received an average monthly dose per trimester above recommended dose (3.0% vs. 7.3%, respectively; p < 0.0001), and used rescue medication (3.1% vs. 10.0%, respectively; p < 0.0001). Dispensing of pancreatic enzymes was significantly higher in patients receiving LAN than OCT (16.4% vs. 13.9%, respectively). In the subgroup of patients with GEP-NETs, those receiving LAN (n = 1478) vs. OCT (n = 1278) had greater treatment duration and less treatment discontinuation, switching, dosage above the recommended dose, and rescue medication use, but no significant difference in dispensing of pancreatic enzymes or time to second-line treatment.ConclusionThese real-world data suggest potential clinical and economic advantages of LAN over OCT in the management of patients with NETs in the French population.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02060-1.

Comparing Somatostatin Analogs in the Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors

Background: The 2 approved somatostatin analogs (SSAs) in the first-line treatment of advanced, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are octreotide long-acting release (Sandostatin LAR) and somatuline depot (Lanreotide). The study’s objective was to compare progression-free survival (PFS) and overall survival (OS) of patients (pts) with GEP-NETs treated with somatuline or octreotide LAR. Pts and Methods: Pts with advanced well-differentiated GEP-NET who received either SSA at Emory University between 1995 and 2019 were included after institutional review board approval. The primary end point was PFS, defined as time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.1, or clinical progression) or death. The secondary end point was OS. Kaplan-Meier curves were generated, and log-rank tests were conducted to compare the survival outcomes. Results: A total of 105 pts were identified. The mean age was 62.1 years (SD ± 11.8). The male-to-female ratio was 51:54. The majority (N = 69, 65.7%) were white. Most pts had grade 2 (G2) disease (N = 44, 41.9%). Primary location was small bowel in 58 (55.2%), pancreas in 27 (25.7%), and other in 20 (19.0%). Functional tumors were defined in 32 pts distributed equally between the 2 groups. Distribution of treatment was similar in the 2 groups, with 54 receiving octreotide LAR and 51 receiving somatuline depot. The median PFS for the octreotide LAR and somatuline depot groups was 12 months (95% CI, 6–18 months) and 10.8 months (95% CI, 6–15.6 months), respectively, and the difference was not statistically significant (p = 0.2665). For pts with G1 disease, the median PFS for the octreotide LAR and somatuline depot was 8.4 versus 32.4 months, respectively, and the difference was not statistically significant (p = 0.159). For G2 disease, the difference in median PFS between octreotide LAR and somutaline depot groups was statistically significant (12 vs. 7.2 months, respectively; p = 0.0372). The mean follow-up time for octreotide LAR was 21.6 months versus 11.3 months for somatuline depot. Conclusions: Overall, there was no difference in PFS between octreotide LAR and somatuline depot for pts with well-differentiated, metastatic GEP-NETs. A prospective study is worth designing selecting for G.

Octreotide-LAR is a Useful Alternative for the Management of Diazoxide-Responsive Congenital Hyperinsulinism.

The data on the congenital hyperinsulinism (CHI) in Asian Indian patients is limited. Diazoxide is often unavailable in India, which poses challenge in managing CHI. The study was aimed to present our experience with CHI with a special focus on the effectiveness and cost-effectiveness of octreotide long-acting release (OCT-LAR) among diazoxide-responsive CHI. The data of 14 index cases with CHI registered at our center were retrospectively analyzed. The diagnosis of CHI was based on elevated serum insulin (3.4-32.5 μIU/ml) and C-peptide (0.58-1.98 ng/ml) at the time of symptomatic hypoglycemia (BG≤41 mg/dl). Fourteen patients (13 males) presented at a median (range) age of 3 (1-270) days, seizures being the most common mode of presentation (78.6%). Ten patients were diazoxide-responsive, two were partially responsive, while two were unresponsive. Genetics was available for eight patients; ABCC8 (n=3, 1 novel) and HADH (n=2, both novel) were the most commonly mutated genes. OCT-LAR was offered to eight patients including four with diazoxide-responsive disease and was universally effective. We propose a cost-effective approach to use OCT-LAR in the management of CHI, which may also make it more cost-effective than diazoxide for diazoxide-responsive disease. Five of the 11 (45.5%) patients had evidence of neurological impairment; notably, two patients with HADH mutations had intellectual disability despite diazoxide-responsiveness. We report three novel mutations in CHI-associated genes. We demonstrate the effectiveness of and propose a cost-effective approach to use OCT-LAR in diazoxide-responsive CHI. Mutations in HADH may be associated with abnormal neurodevelopmental outcomes despite diazoxide-responsiveness.

Safety and efficacy of peptide receptor radionuclide therapy with 177Lu-DOTA0-Tyr3-octreotate in combination with amino acid solution infusion in Japanese patients with somatostatin receptor-positive, progressive neuroendocrine tumors

PurposePeptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA0-Tyr3-octreotate (177Lu-DOTATATE) is one of the most reliable treatments for unresectable, progressive neuroendocrine tumors (NETs) with somatostatin receptor expression. We have, for the first time, reported the results of the tolerability, safety, pharmacokinetics, dosimetry, and efficacy of this treatment for Japanese patients with NET.MethodsPatients with unresectable, somatostatin receptor scintigraphy (SRS)-positive NETs were enrolled in this phase I clinical trial. They were treated with 29.6 GBq of 177Lu-DOTATATE (four doses of 7.4 GBq) combined with amino acid solution infusion plus octreotide long-acting release (LAR) 30 mg. The primary objective of this study was to evaluate the tolerability, safety, pharmacokinetics, and dosimetry of a single administration of this treatment in patients with SRS-positive NETs.ResultsSix Japanese patients (three men and three women; mean age 61.5 years; range 50–70 years) with SRS-positive unresectable NETs were recruited. 177Lu-DOTATATE was eliminated from the blood in a two-phase manner. Cumulative urinary excretion of radioactivity was 60.1% (range 49.0%–69.8%) within the initial 6 h. The cumulative renal absorbed dose for 29.6 GBq of 177Lu-DOTATATE was 16.8 Gy (range 12.0–21.2 Gy), and the biological effective dose was 17.0 Gy (range 12.2–21.5 Gy). Administration of 177Lu-DOTATATE was well tolerated, with no dose-limiting toxicities. Grade 3 lymphopenia occurred in two (33.3%) cases, but there were no other severe toxicities. Four patients achieved partial response (objective response rate, 66.7%), one patient had stable disease, and one patient had progressive disease.ConclusionPRRT with 177Lu-DOTATATE was well-tolerated and showed good outcomes in Japanese patients with unresectable NETs. Peptide receptor radionuclide therapy, 177Lu-DOTA0-Tyr3-octreotate .

177Lu-DOTATATE Plus Radiosensitizing Capecitabine Versus Octreotide Long-Acting Release as First-Line Systemic Therapy in Advanced Grade 1 or 2 Gastroenteropancreatic Neuroendocrine Tumors: A Single-Institution Experience.

PURPOSETo compare the efficacy and safety of 177Lu-DOTATATE plus radiosensitizing capecitabine and octreotide long-acting release (LAR) as first-line systemic therapy in advanced well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs).MATERIALS AND METHODSData of consecutive patients of advanced inoperable or metastatic grade 1 or 2 GEP-NETs treated with first-line 177Lu-DOTATATE plus radiosensitizing capecitabine or octreotide LAR from September 2012 to December 2019 were collected and analyzed for response, toxicity, and survival outcomes.RESULTSSeventy-six patients (median age: 53 years; range 14-81 years) with treatment-naïve advanced grade 1 or 2 GEP-NETs were included. Thirty-six patients received a median cumulative dose of 27.3 GBq of 177Lu-DOTATATE intravenously at 8-12 weeks' intervals along with 1,250 mg/m2 oral capecitabine on days 0-14 of each cycle of 177Lu-DOTATATE, whereas 40 patients were administered 30 mg octreotide LAR intramuscularly every 4 weeks. Using response evaluation criteria in solid tumor 1.1, the objective response rate was 38% in the 177Lu-DOTATATE arm compared with 15% in the octreotide LAR arm (P = .025), whereas the disease control rates were 88% and 67% in 177Lu-DOTATATE and octreotide LAR arms, respectively (P = .035). The median durations of progression-free survival in the 177Lu-DOTATATE and octreotide LAR arms were 54 months and 16 months, respectively (P = .017), whereas the median overall survival was not reached and not significantly different across both the arms. Of the treatment-related adverse events, no major difference was observed in the occurrence of grade 3 or 4 toxicities between the two treatment arms.CONCLUSIONFirst-line systemic 177Lu-DOTATATE plus radiosensitizing capecitabine achieved better radiologic response and longer progression-free survival compared with octreotide LAR in patients with advanced grade 1 or 2 GEP-NETs. Future randomized controlled trials are, however, required to determine the best treatment sequence for the treatment-naïve patients with advanced GEP-NETs.

Estimation of Health-Related Utilities for 177Lu-DOTATATE in GEP-NET Patients Using Utilities Mapped from EORTC QLQ-C30 to EQ-5D-3L and QLU-C10D Utilities.

BackgroundGastroenteropancreatic neuroendocrine tumours (GEP-NET) are a rare, life-threatening type of cancer. The survival benefit of 177Lu-DOTATATE has been demonstrated in GEP-NET patients. Health technology assessment bodies require data on health-related utility impacts of treatment. A cancer-specific instrument, EORTC QLQ-C30, was used to collect the data for 177Lu-DOTATATE within clinical studies, but utility-based instruments were not included.ObjectiveThe main aim of this study was to compare EQ-5D-3L and QLU-C10D utilities obtained from EORTC QLQ-C30 using two different approaches. A secondary aim was to analyse the EQ-5D-3L and QLU-C10D utilities of patients treated with 177Lu-DOTATATE versus best supportive care. A supplementary aim was to evaluate the effect of 177Lu-DOTATATE on patients’ health-related utility over time.MethodsThree datasets were used for the analysis. NETTER-1 is a clinical trial, whilst ERASMUS and Guy’s and St. Thomas (GStT) are real-world datasets. Two mapping algorithms (response mapping and ordinary least square regression) were applied to generate EQ-5D-3L utilities from EORTC QLQ-C30. An algorithm was used to obtain QLU-C10D utilities from EORTC QLQ-C30.ResultsIn all studies, EQ-5D-3L utilities were higher than QLU-C10D utilities at most time points measured, although the magnitude of the differences was small. In NETTER-1, EQ-5D-3L and QLU-C10D utilities were higher in the 177Lu-DOTATATE arm compared with the octreotide long-acting release (LAR) arm, overall and pre-progression. In all studies, patients’ health-related utilities seem to be maintained over time.ConclusionThere were small differences between EQ-5D-3L and QLU-C10D utilities, but these did not translate to relative differences over time or between groups. In NETTER-1, patients in the 177Lu-DOTATATE arm had higher health-related utilities than patients in the octreotide LAR arm. Health-related utility may at least remain maintained in patients with GEP-NET receiving 177Lu-DOTATATE.

Gender-Specific Efficacy Revealed by Head-to-Head Comparison of Pasireotide and Octreotide in a Representative In Vivo Model of Nonfunctioning Pituitary Tumors.

Simple SummaryNo effective medical therapy exists for residual/recurrent nonfunctioning pituitary tumors (NFPTs). First-generation somatostatin analogs (SSAs) like octreotide targeting somatostatin receptor type 2 (SSTR2) are the mainstay therapy for functioning PTs, but have shown little effect in NFPTs. This is in agreement with an SSTR profile characterized by low SSTR2, and high SSTR3 levels in the latter. Pasireotide a multi-SSTR-preferring SSA, should be effective against NFPTs. To test this hypothesis, we conducted a head-to-head comparison of octreotide and pasireotide in the only spontaneous in vivo model of NFPTs (MENX rats), which recapitulates the human disease. Pasireotide showed a superior anti-tumor effect vs. octreotide, especially in females. Interestingly, Sstr3 levels were higher in female vs. male NFPTs. A sex-related SSTR3 expression may extend to human NFPTs, thereby representing a tool for patient stratification. Our results have translational relevance for the medical treatment of patients with residual/recurrent NFPTs currently lacking efficacious therapeutic options.Invasive nonfunctioning pituitary tumors (NFPTs) are non-resectable neoplasms associated with frequent relapse and significant comorbidities. Current treatments, including somatostatin receptor 2 (SSTR2)-directed somatostatin analogs (SSAs), often fail against NFPTs. Thus, identifying effective therapies is clinically relevant. As NFPTs express SSTR3 at high levels, pasireotide, a multireceptor-targeted SSA, might be beneficial. Here we evaluated pasireotide in the only representative model of spontaneous NFPTs (MENX rats) in vivo. Octreotide long-acting release (LAR), pasireotide LAR, or placebo, were administered to age-matched, tumor-bearing MENX rats of both sexes for 28 d or 56 d. Longitudinal high-resolution magnetic resonance imaging monitored tumor growth. While tumors in placebo-treated rats increased in volume over time, PTs in drug-treated rats displayed significant growth suppression, and occasional tumor shrinkage. Pasireotide elicited stronger growth inhibition. Radiological responses correlated with tumors’ proliferation rates. Both SSAs, but especially pasireotide, were more effective in female vs. male rats. Basal Sstr3 expression was significantly higher in the former group. It is noteworthy that female human NFPTs patients also have a trend towards higher SSTR3 expression. Altogether, our studies provide the rationale for testing pasireotide in patients with residual/recurrent NFPTs. If confirmed, the sex-related SSTR3 expression might be used as criteria to stratify NFPTs patients for treatment with pasireotide.

Randomized blinded study comparing injection site pain from octreotide long-acting-release (LAR) versus lanreotide during the treatment of well differentiated neuroendocrine tumors (WDNETs).

e16204 Background: The somatostatin analogs (SSAs) octreotide LAR and lanreotide are equally acceptable in the NCCN guidelines to treat WDNETs. Average Sales Price for 1 year of lanreotide at 120mg is $106,802 versus $53,471 for 1 year of octreotide LAR 20mg and $80,206 for 1 year of 30mg. Lanreotide is given by “deep subcutaneous injection” while octreotide LAR is given intramuscularly. We conducted a randomized, blinded trial evaluating patient (pt) experience, as measured by injection site pain, with octreotide LAR and lanreotide, during the treatment of advanced, nonfunctional, WDNETs. We also investigated drug preference and financial toxicity in this pt population. Methods: This randomized single-blinded pilot study enrolled 51 pts recommended to begin SSA therapy. Pts received injections q 4 weeks and received 6 injections on study; Arm 1: octreotide LAR for 3 injections then lanreotide for 3 injections; Arm 2: lanreotide for 3 injections then octreotide LAR for 3 injections. Pts were blinded as to which agent they received throughout the study. Self-reported injection site pain scores were obtained after each of the first 3 injections using a 0 to 10 scale (0: “I didn’t feel it”; 10: “worst pain ever”). Primary endpoint was comparison of mean pain scores over the first 3 injections of octreotide LAR (Arm 1) or lanreotide (Arm 2). Secondary endpoints, evaluated with descriptive statistics, included pt-reported preference of octreotide LAR versus lanreotide, and willingness to pay for the preferred therapy, both assessed after 6 months of therapy by questionnaire. Results: 51 pts were enrolled (Arm 1: N = 26, Arm 2: N = 25). All pts were evaluable for the study primary endpoint. All pts received lanreotide at a dose of 120mg monthly; among those pts (49) receiving octreotide LAR, 30 (61%) received 20mg, 18 (37%) received 30mg, 1 (2%) received 10mg. No significant difference was identified in mean pain scores over the first 3 SSA injections; Arm 1: mean 2.4, standard deviation 1.9 versus Arm 2: mean 1.9, standard deviation 1.5 (p = 0.5). 34/51 (67%) pts (15 pts in Arm 1; 19 pts in Arm 2) were evaluated for secondary endpoints and completed post-therapy questionnaires. 7 (47%) in Arm 1 and 8 (42%) in Arm 2 indicated no drug preference at the end of the 6 months. There was a trend towards preference for octreotide LAR versus lanreotide in both arms, with more pts indicating mild or strong preference for octreotide LAR. 7 (50%) and 10 (56%) of pts in Arms 1 and 2, respectively, were unwilling to pay more for their preferred SSA; the rest of the cohort was willing to experience increased financial toxicity to receive their preferred SSA. Conclusions: This randomized, blinded study evaluating pt comfort with SSAs found minimal pain with both agents and no significant differences in pain scores between octreotide LAR versus lanreotide. Clinical trial information: NCT03289741.

Therapeutic advances in ADPKD: the future awaits.

Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder included in ciliopathies, representing the fourth cause of end stage renal disease (ESRD), with an estimated prevalence between 1:1000 and 1:2500. It is mainly caused by mutations in the PKD1 and PKD2 genes encoding for polycystin 1 (PC1) and polycystin 2 (PC2), which regulate differentiation, proliferation, survival, apoptosis, and autophagy. The advances in the knowledge of multiple molecular pathways involved in the pathophysiology of ADPKD led to the development of several treatments which are currently under investigation. Recently, the widespread approval of tolvaptan and, in Italy, of long-acting release octreotide (octreotide-LAR), represents but the beginning of the new therapeutic management of ADPKD patients. Encouraging results are expected from ongoing randomized controlled trials (RCTs), which are investigating not only drugs acting on the calcium/cyclic adenosin monoposphate (cAMP) pathway, the most studied target so far, but also molecules targeting specific pathophysiological pathways (e.g. epidermal growth factor (EGF) receptor, AMP-activated protein kinase (AMPK) and KEAP1-Nrf2) and sphingolipids. Moreover, studies on animal models and cultured cells have also provided further promising therapeutic strategies based on the role of intracellular calcium, cell cycle regulation, MAPK pathway, epigenetic DNA, interstitial inflammation, and cell therapy. Thus, in a near future, tailored therapy could be the key to changing the natural history of ADPKD thanks to the vigorous efforts that are being made to implement clinical and preclinical studies in this field. Our review aimed to summarize the spectrum of drugs that are available in the clinical practice and the most promising molecules undergoing clinical, animal, and cultured cell studies.

Use of Oral Concomitant Medications in Patients With Acromegaly

Background: Acromegaly is a rare condition characterized by excess GH and IGF-I levels.1 Injectable somatostatin analogs (SSAs) are recommended as first-line medical treatment.2 Comorbidities including diabetes, hypertension and hypopituitarism reduce quality of life in patients with acromegaly; 3,4 treatment for these includes oral medications. We assessed the most common oral medications used by patients with acromegaly during treatment with lanreotide autogel 120 mg (LAN). Methods: This post-hoc analysis reports data from the PRIMARYS5 (NCT00690898) and LEAD6 (NCT00701363) open-label trials in which adult patients with acromegaly received LAN. PRIMARYS patients were SSA/surgery-naïve with uncontrolled acromegaly, LEAD patients were previously treated with octreotide long-acting release with normal age-adjusted IGF-I levels for two consecutive measurements. Results: PRIMARYS included 90 patients: mean (standard deviation [SD]) age 49.5 (12.4) years; 47.8% male; mean (SD) baseline IGF-I 809.9 (300.0) µg/L, 97.8% had IGF-I >1.3xULN. LEAD included 124 patients: mean (SD) age 55.4 (10.9) years; 37.1% male. Median (range) time since diagnosis was 99.0 (27.0-1,261.0) days (PRIMARYS) and 7.1 (0.5-27.0) years (LEAD). 51.1%, 24.4% and 3.3% of participants in PRIMARYS had a history of cardiovascular disorders (including hypertension), diabetes/glucose intolerance, and hypopituitarism/hypothalamic disorders; the corresponding values in LEAD were 69.4%, 33.9% and 18.5%. 83.3% of participants in PRIMARYS and 86.3% in LEAD used ≥1 concomitant oral medication with LAN. Of these participants, >50% used >3 types (PRIMARYS: 53.3%; LEAD: 61.7%). Out of participants in both studies who used concomitant oral medication with LAN, this was commonly indicated for cardiovascular disorders including: renin-angiotensin agents (PRIMARYS: 33.3%; LEAD: 45.8%); antithrombotic agents (PRIMARYS: 10.7%; LEAD: 19.6%); beta-blocking agents (PRIMARYS: 22.7%; LEAD: 19.6%) and calcium channel blockers (PRIMARYS: 16.0%; LEAD: 22.4%). Diuretics (PRIMARYS: 16.0%; LEAD: 20.6%) and lipid modifying agents (PRIMARYS: 20.0%; LEAD: 39.3%) were also common concomitant oral medications, as were medications used in diabetes (PRIMARYS: 17.3%; LEAD: 20.6%) and for thyroid therapy (PRIMARYS: 28.0%; LEAD: 31.8%). Conclusions: In this analysis, most patients with acromegaly receiving LAN, regardless of prior therapy, used ≥1 concomitant oral medication. An awareness of the ongoing burden of comorbidities requiring oral medications should help physicians in managing acromegaly. Funding: This study was sponsored by Ipsen.1. Lavrentaki A Pituitary 2017;20:4-92. Melmed S Nat Rev Endocrinol. 2018;14:552-613. Lesén E Eur J Endocrinol. 2017:176:203-124. Vilar L Pituitary 2017;20:22-325. Caron PJ J Clin Endocrinol Metab. 2014;99:1282-906. Neggers SJ Eur J Endocrinol. 2015;173:313-23

Economic evaluation of orphan drug Lutetium-Octreotate vs. Octreotide long-acting release for patients with an advanced midgut neuroendocrine tumour in the Netherlands

ObjectivesMultiple studies showed positive effects of Lutetium-Octreotate (LO) treatment in neuroendocrine tumours. LO has been used in the Netherlands since the 1980s and recently received the orphan status shortly after the acquisition by Novartis. Since then, the official list price has increased sixfold. From a value-based pricing perspective, we analysed the impact of the increase in price on the incremental cost-effectiveness ratio (ICER) of LO treatment compared to optimal best supportive care, a high dose of Octreotide long-acting release (O-LAR), using the clinical data of the NETTER-1 trial.MethodsA Markov model was developed to evaluate the costs per quality-adjusted life-year (QALY) for LO treatment compared to O-LAR from the healthcare perspective. A scenario analysis was conducted to compare the cost-effectiveness with the initial and increased price level of the LO-treatment.ResultsAt the increased price level, the cost-effectiveness analysis rendered a deterministic ICER of €53,500 per QALY, while at the initial pricing, the ICER was €19,000 per QALY. The probabilistic sensitivity analysis (PSA) showed that LO had a high probability of being cost-effective at both the increased and initial price level, considering a cost-effectiveness threshold of €80,000.ConclusionsEven at the increased price level, LO treatment can still be considered cost-effective using the applicable Dutch willingness-to-pay threshold of 80,000 euro per QALY. Considering the public scrutiny in relation to this price increase, these outcomes raise the question whether traditional cost-effectiveness methods are sufficient in fully capturing the societal acceptance of prices of new medicines.

Octreotide long-acting release (LAR) in combination with other therapies for treatment of neuroendocrine neoplasia: a systematic review.

In the last decades, the incidence of neuroendocrine neoplasia (NEN) increased from 1 to 5 new diagnoses/100,000 persons/year. The synthetic somatostatin analogues (SSAs) represent the first-choice treatment for both functionally active and inactive gastro-enteric-pancreatic NEN. This systematic review examines the role of octreotide long-acting release (LAR) in combination with other therapies for NEN management. Primary outcomes were the disease control rate and the progression free survival (PFS), defined as the time between treatment initiation and progression of disease. Secondary outcomes were overall survival (OS) and safety. This systematic review identified 13 studies, concerning the use of octreotide LAR in association with other therapies in advanced NENs and included 1,206 patients. Patients were treated with octreotide LAR in combination with other drugs, mainly with everolimus (404 patients, 35%), but even with Peptide Receptor Radionuclide Therapy, bevacizumab, interferon or fluoride-derivatives. Disease control was observed in 85% cases with SSAs in combination with other therapies; PFS ranged from 15 to 16.4 months and OS from 25 to 61.9 months. SSAs are very well tolerated drugs, with few side effects which are usually mild, not requiring drug withdrawn. The review summarizes the effectiveness and available safety data on octreotide LAR in combination with other therapies in patients with NEN and may provide suggestions to address the therapeutic strategy. Further comparative head-to-head studies are needed to understand which is the best combination treatment for patients with progressive NEN after failure of first-line therapy.

Patient and Healthcare Provider Perspectives of First-Generation Somatostatin Analogs in the Management of Neuroendocrine Tumors and Acromegaly: A Systematic Literature Review.

IntroductionSomatostatin analogs (SSAs) are used to treat neuroendocrine tumors (NETs) and acromegaly. Two first-generation SSAs, octreotide long-acting release (OCT LAR) and lanreotide autogel/depot (LAN), are available. A systematic literature review (SLR) was conducted to investigate which characteristics beyond efficacy are most important in patient and healthcare practitioner (HCP) experience of LAN and OCT when used to treat acromegaly and NETs.MethodsMEDLINE, Embase, the Cochrane Library, and Database of s of Reviews of Effect were searched from database inception to January 2019 with terms for first-generation SSAs, NETs, acromegaly, preferences, decision-making, and human factors. Key congresses in 2016–2018 and SLR bibliographies were hand-searched. Two independent reviewers screened articles at title/abstract and full-text stage. Publications fulfilling pre-specified inclusion criteria reported patient or HCP perspectives of LAN or OCT, or any factors affecting treatment perspectives for NETs or acromegaly.ResultsA total of 1110 unique records were screened, of which 21 studies were included, reporting from the perspectives of patients (n = 18) and/or HCPs (n = 9). Perspectives were collected using shared decision-making frameworks, questionnaires, informal patient opinion, and a Delphi panel. Where patient preference was specifically reported, LAN was preferred in 4/5 studies and OCT LAR in 1/5. Common factors underlying treatment experience included technical problems with injections and associated pain, emotional quality/anxiety of injections, time and convenience of treatment administration, and independence. Immediate aspects of injections appeared most important to patients, though the possibilities of extended dosing intervals and self-/partner-injection with LAN were also notable factors.ConclusionsStudy outcomes favored LAN in this SLR, with factors surrounding injection administration most influential in treatment experience. The findings of this SLR provide a basis that could inform development of decision-making criteria, with patient and HCP treatment perspectives considered. Future studies should utilize a common method to report preference and associated drivers.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-020-01600-x.