Lessons from a multicentre retrospective study of peptide receptor radionuclide therapy combined with lanreotide for neuroendocrine tumours: a need for standardised practice.

PURPOSE: PRELUDE aimed to assess use and effectiveness/safety of lanreotide autogel/depot (LAN) combined with 177Lu-DOTATOC or 177Lu-DOTATATE (LAN-peptide receptor radionuclide therapy [PRRT]) in patients with progressive neuroendocrine tumours (NETs). METHODS: International, non-interventional, retrospective, non-comparative analysis of medical records from patients with progressive metastatic or locally advanced grade 1 or 2 gastroenteropancreatic (GEP)- or lung-NETs. The primary endpoint was progression-free survival (PFS) at end of last LAN-PRRT cycle. Secondary endpoints included PFS at last available follow-up, best overall response, objective response rate (ORR), presence and severity of diarrhoea and flushing, and safety. Post-hoc analyses were conducted to determine pre-treatment tumour growth rate (TGR) cutoffs that best predicted the ORR during treatment. RESULTS: Forty patients were enrolled (GEP-NETs, n = 39; lung-NETs, n = 1). PFS rates were 91.7% at end of last LAN-PRRT cycle and 95.0% at last available follow-up. In the full analysis set, best overall response among patients with GEP-NETs (n = 23) was stable disease (n = 14, 60.9%), partial response (n = 8, 34.8%) and progressive disease (n = 1, 4.3%). The ORR was 27.3% at end of last LAN-PRRT cycle and 36.8% at last available follow-up. Optimal baseline TGR cutoffs for predicting ORR at these time points were 1.18% and 0.33%, respectively. At baseline, 81.0% of patients had diarrhoea or flushing; both remained stable or improved in most cases. No increased adverse drug reactions were reported. CONCLUSION: Despite the major recruitment shortfall for the PRELUDE study, effectiveness data were encouraging in this selected population, highlighting the potential usefulness and feasibility of LAN combined with and after PRRT in patients with GEP-NETs. The study also identified challenges associated with evaluating clinical practice in a rare-disease setting and highlighted the need for standardisation of PRRT procedures. TRIAL REGISTRATION: Trial number: NCT02788578; URL: https://clinicaltrials.gov/ct2/show/NCT02788578.

Prognostic value of the neutrophil/lymphocyte ratio in enteropancreatic neuroendocrine tumors.

Accessible prognostic tools are needed to individualize treatment of neuroendocrine tumors (NETs). Data suggest neutrophil/lymphocyte ratios (NLRs) have prognostic value in some solid tumors, including NETs. In the randomized double-blind CLARINET study (NCT00353496; EudraCT 2005-004904-35), the somatostatin analog lanreotide autogel/depot increased progression-free survival (PFS) compared with placebo in patients with inoperable or metastatic intestinal and pancreatic NETs (grades 1-2, Ki-67 < 10%). The exploratory post-hoc analyses presented here evaluated the prognostic value of NLR in the CLARINET study cohort, in the context of and independently from treatment. Kaplan-Meier PFS plots were generated for patients with available NLR data, in subgroups based on NLR values, and 24-month survival rates were calculated. P values and hazard ratios for prognostic effects were generated using Cox models. 31216222 Baseline characteristics were balanced between lanreotide autogel/depot 120 mg (n = 100) and placebo (n = 101) arms. Irrespective of treatment, raw 24-month PFS rates were comparable across subgroups based on NLR tertiles [37.3% (low), 38.8% (middle), 38.8% (high); n = 67 per group] and NLR cutoff of 4 [38.1% (NLR ≤ 4; n = 176), 40.0% (NLR > 4; n = 25)]. Furthermore, NLRs were not prognostic in Cox models, irrespective of subgroups used. The therapeutic effect of lanreotide autogel/depot 120 mg was independent of NLRs (P > 0.1). These exploratory post-hoc analyses in patients with advanced intestinal and pancreatic NETs contrast with previous data suggesting NLR has prognostic potential in NETs. This may reflect the inclusion of patients with lower-grade tumors or use of higher NLR cutoff values in the current analysis.

Treatment of Advanced BP-NETS with Lanreotide Autogel/Depot vs Placebo: the Phase III SPINET Study.

Prospective data are lacking on early somatostatin analog (SSA) therapy in bronchopulmonary neuroendocrine tumors (BP-NETs; typical and atypical carcinoids [TCs and ACs]). SPINET (EudraCT: 2015-004992-62; NCT02683941) was a phase III, double-blind study of lanreotide autogel/depot (LAN; 120 mg every 28 days) plus best supportive care (BSC) versus placebo plus BSC, with an optional open label treatment phase (LAN plus BSC). Patients had metastatic/unresectable, somatostatin receptor (SSTR)-positive TCs or ACs. Recruitment was stopped early owing to slow accrual; eligible patients from the double-blind phase transitioned to open-label LAN. The adapted primary endpoint was progression free survival (PFS) during either phase for patients receiving LAN. Seventy-seven patients were randomized (LAN, n=51 [TCs, n=29; ACs, n=22]; placebo, n=26 [TCs, n=16; ACs, n=10). Median (95% confidence interval [CI]) PFS during double-blind and OL phases in patients receiving LAN was 16.6 (11.3; 21.9) months overall (primary endpoint), 21.9 (12.8, not calculable [NC]) months in TCs and 13.8 (5.4; 16.6) months in ACs. During double-blind treatment, median (95% CI) PFS was 16.6 (11.3; 21.9) months for LAN versus 13.6 (8.3; NC) months for placebo (not significant); corresponding values were 21.9 (13.8; NC) and 13.9 (13.4; NC) months, respectively, in TCs and 13.8 (5.4; 16.6) and 11.0 (2.8; 16.9) months, respectively, in ACs. Patients' quality of life did not deteriorate and LAN was well tolerated. Although recruitment stopped early and the predefined sample size was not met, SPINET is the largest prospective study to date of SSA therapy in SSTR positive TCs and ACs and suggests clinical benefit in TCs.

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.

INTRODUCTION: Long-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. METHODS: Data 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. RESULTS: Patients 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. CONCLUSION: These real-world data suggest potential clinical and economic advantages of LAN over OCT in the management of patients with NETs in the French population.

Efficacy and safety of high-dose lanreotide autogel in patients with progressive pancreatic or midgut neuroendocrine tumours: CLARINET FORTE phase 2 study results.

INTRODUCTION: This prospective, single-arm, phase 2 study assessed the efficacy and safety of lanreotide autogel (LAN) administered at a reduced dosing interval in patients with progressive neuroendocrine tumours (NETs) after LAN standard regimen. METHODS: Patients had metastatic or locally advanced, grade 1 or 2 midgut NETs or pancreatic NETs (panNETs) and centrally assessed disease progression on LAN 120 mg every 28 days. They were treated with LAN 120 mg every 14 days for up to 96 weeks (midgut cohort) or 48 weeks (panNET cohort). The primary end-point was centrally assessed progression-free survival (PFS). PFS by Ki-67 categories was analysed post hoc. Secondary end-points included quality of life (QoL) and safety. RESULTS: Ninety-nine patients were enrolled (midgut, N = 51; panNET, N = 48). Median (95% CI) PFS was 8.3 (5.6-11.1) and 5.6 (5.5-8.3) months, respectively. In patients with Ki-67 ≤ 10%, median (95% CI) PFS was 8.6 (5.6-13.8) and 8.0 (5.6-8.3) months in the midgut and panNET cohorts, respectively. Patients' QoL did not deteriorate during the study. There were no treatment-related serious adverse events and only two withdrawals for treatment-related adverse events (both in the panNET cohort). CONCLUSIONS: In patients with progressive NETs following standard-regimen LAN, reducing the dosing interval to every 14 days provided encouraging PFS, particularly in patients with a Ki-67 ≤ 10% (post hoc); no safety concerns and no deterioration in QoL were observed. Increasing LAN dosing frequency could therefore be considered before escalation to less well-tolerated therapies.

Impact of Diabetes and Metformin Use on Enteropancreatic Neuroendocrine Tumors: Post Hoc Analysis of the CLARINET Study.

The prognostic role of diabetes mellitus (DM) in advanced enteropancreatic neuroendocrine tumors (NETs) is unclear. Progression free survival (PFS) was assessed in post-hoc analyses of the 96-week, phase III, double-blind, placebo-controlled CLARINET study of lanreotide 120 mg in patients with advanced non-functional enteropancreatic NETs with DM (with/without metformin) and without DM. Of 204 patients, there were 79 with DM (lanreotide, n = 42 {metformin, n = 14}; placebo, n = 37 {metformin, n = 10}) and 125 without DM (lanreotide, n = 59; placebo, n = 66). Median PFS was 96.0 and 98.0 weeks with and without DM, respectively (hazard ratio 1.20 {95% confidence interval 0.79 to 1.82}; p = 0.380). No difference in PFS was observed in lanreotide-treated patients with/without DM (p = 0.8476). In the placebo group, median PFS was numerically shorter with versus without DM (p = 0.052) and was significantly longer in patients with DM and metformin (85.7 weeks) versus without metformin (38.7 weeks; p = 0.009). Multivariable Cox analyses showed that DM at baseline was not associated with PFS (p = 0.079); lanreotide was significantly associated with lower disease progression risk (p = 0.017). Lanreotide efficacy was confirmed in patients with advanced enteropancreatic NETs, regardless of diabetic status; DM was not a negative prognostic factor. A potential antitumor effect of metformin was observed in patients receiving placebo.

Evaluation of Nurse Preferences Between the Lanreotide Autogel New Syringe and the Octreotide Long-Acting Release Syringe: An International Simulated-Use Study (PRESTO).

INTRODUCTION: Somatostatin analogues are used to treat symptoms and slow tumour progression in patients with neuroendocrine tumours (NETs) and carcinoid syndrome and to reduce hormone secretion and pituitary tumour volume in patients with acromegaly. A new syringe for lanreotide autogel/depot (LAN) was developed following feedback from a human factors study to improve ease of injection compared with previous syringes. PRESTO aimed to assess preferences of nurses between the LAN new syringe and the octreotide long-acting release (LAR) syringe. METHODS: PRESTO, a multinational, multicentre, prospective, noninterventional, simulated-use study, enrolled nurses with ≥ 2 years' experience injecting LAN and/or octreotide LAR in patients with NETs and/or acromegaly. Nurses administered injections into pads using the LAN new syringe and octreotide LAR syringe in a randomised sequence. In an anonymous web-based questionnaire, nurses reported their overall preference ('strong' or 'slight'; primary endpoint) and rated and ranked the importance of nine attributes for each syringe (1 [not at all] to 5 [very much]). RESULTS: Overall, 90 nurses attended sessions and completed valid questionnaires. Most nurses (97.8%) expressed a preference (85.6% 'strong', 12.2% 'slight') for the LAN new syringe versus the octreotide LAR syringe (P < 0.0001). Attribute performance ratings (1 [not at all] to 5 [very much]) were consistently higher for the LAN new syringe versus the octreotide LAR syringe, with the greatest differences in 'fast administration' and 'confidence the syringe will not be clogged' (mean difference [SD]: 2.6 [1.2] and 2.3 [1.5], respectively; P < 0.0001). The attribute ranked most important was 'confidence the syringe will not be clogged' (24.4%); least important was 'convenience of syringe format, including packaging, from preparation to injection' (34.4%). CONCLUSIONS: Nurses preferred the user experience of the LAN new syringe compared with the octreotide LAR syringe, with a particular preference for attributes related to product delivery with the LAN new syringe.

Correction to: Co-Creation of a Lanreotide Autogel/Depot Syringe for the Treatment of Acromegaly and Neuroendocrine Tumours Through Collaborative Human Factor Studies.

In the Original Article, there is an error in the "participants" section of Results. The correct sentence is "A total of 213 participants took part in the studies, including 34 patients with acromegaly and 28 patients with NETs".

Co-Creation of a Lanreotide Autogel/Depot Syringe for the Treatment of Acromegaly and Neuroendocrine Tumours Through Collaborative Human Factor Studies.

INTRODUCTION: Although the previous lanreotide autogel/depot syringe had been well received, feedback indicated that improvements could be made to make it more user-friendly. Additionally, the view that patients should have greater involvement in the research and development process is echoed by the International Neuroendocrine Cancer Alliance. A series of studies aimed to develop and validate a new syringe that works better for patients, caregivers and healthcare professionals (HCPs) by involving these groups at key stages in the development and testing process. METHODS: The multicentre, international, human factor studies, consisted of four formative studies and one validation study. The formative studies collected patient, caregiver and HCP feedback on the lanreotide autogel/depot syringe on the market at the time, and on newly designed prototypes. The validation study was conducted to evaluate the final syringe to confirm that it can be used effectively and safely in the intended environment, by the intended user, for the intended purpose. RESULTS: Overall, 213 individuals participated in the studies; 145 contributed to the formative studies and 68 to the validation study. The validated new-generation syringe included several important updates compared with the lanreotide autogel/depot syringe currently on the market, including the flanges, which are now larger and have a better grip; the overcap, which is white, ridged, opaque and bigger; the plunger supports and the thermoformed tray. No participant hurt themselves or others during the validation study (although several misuses were reported), and all participants succeeded in delivering a complete dose and activating the safety system. CONCLUSION: With collaboration, a new syringe was developed to meet the needs of patients, caregivers and HCPs, whilst ensuring lanreotide was delivered effectively and safely. These studies highlight the importance of involving patients, caregivers and HCPs in clinical evaluation studies to develop medical products that address their concerns and meet their needs. FUNDING: Ipsen. Plain language summary available for this article.