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Introduction Tumor quantity while receiving cancer therapy is the sum of simultaneous regression of treatment‐sensitive and growth of treatment‐resistant fractions at constant rates. Exponential rate constants for tumor regression/decay (d) and growth (g) can be estimated. Previous studies established g as a biomarker for overall survival; g increases after treatment cessation, can estimate doubling times, and can assess treatment effectiveness in small cohorts by benchmarking to large reference data sets. Using this approach, we analyzed data from the clinical trial CLARINET, evaluating lanreotide depot/autogel 120 mg/4 weeks (LAN) for treatment of neuroendocrine tumors (NETs). Methods and Materials Computed tomography imaging data from 97 LAN‐ and 101 placebo‐treated patients from CLARINET were analyzed to estimate g and d. Results Data from 92% of LAN‐ and 94% of placebo‐treated patients could be fit to one of the equations to derive g and d (p < .001 in most data sets). LAN‐treated patients demonstrated significantly slower g than placebo recipients (p = .00315), a difference of 389 days in doubling times. No significant difference was observed in d. Over periods of LAN administration up to 700 days, g did not change appreciably. Simulated analysis with g as the endpoint showed a sample size of 48 sufficient to detect a difference in median g with 80% power. Conclusion Although treatment of NETs with LAN can affect tumor shrinkage, LAN primarily slows tumor growth rather than accelerates tumor regression. Evidence of LAN efficacy across tumors was identified. The growth‐retarding effect achieved with LAN was sustained for a prolonged period of time. Implications for Practice The only curative treatment for neuroendocrine tumors (NETs) is surgical resection; however, because of frequent late diagnosis, this is often impossible. Because of this, treatment of NETs is challenging and often aims to reduce tumor burden and delay progression. A novel method of analysis was used to examine data from the CLARINET trial, confirming lanreotide depot/autogel is effective at slowing tumor growth and extending progression‐free survival. By providing the expected rate and doubling time of tumor growth early in the course of treatment, this method of analysis has the potential to guide physicians in their management of patients with NETs., Treatment of neuroendocrine tumors is challenging, mainly aiming to reduce tumor burden and delay disease progression. This article reports on the kinetics of tumor growth using a novel method of analysis and data from the CLARINET study.

Purpose The purpose of this analysis of patient-reported outcomes from the ELECT (Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment) trial (NCT00774930) was to explore the effect of lanreotide on symptoms of carcinoid syndrome. Specifically, this post hoc analysis was designed to identify the most important patient-reported outcomes for patients in ELECT. Methods The post hoc analysis of ELECT, a placebo-controlled study of lanreotide in patients with neuroendocrine tumors, evaluated patient-reported outcomes during the double-blind phase of the trial, specifically daily diarrhea and flushing symptoms, octreotide rescue use, and the EORTC QLQ-C30 and QLQ-GINET21 questionnaires at baseline and week 12. Principal component (PC) analysis was applied on baseline data to identify independent variable clusters and clinically meaningful summary measures that highly correlated to these PCs. From those, the minimum clinical important differences were derived so to perform a responder analysis. Results The three largest PCs captured 42.9% of the variation among baseline variables. The C30 summary score (C30-SS), diarrhea burden, and flushing burden were highly correlated with PC1, PC2, and PC3, respectively. Lanreotide patients were more likely to experience an improvement on the C30-SS (risk ratio [RR] 2.42; P=0.023), diarrhea burden (RR 2.85; P=0.005), and flushing burden (RR 1.39; P=0.31) compared to placebo patients. Lanreotide-treated patients have a higher probability of being a responder on at least one of the three domains of C30-SS, diarrhea burden, or flushing burden compared to placebo patients (RR 1.48; P=0.06). Conclusion The higher response rates in the diarrhea burden are consistent with the previously reported effects of lanreotide on octreotide rescue medication use, while the findings of a greater efficacy of lanreotide vs placebo in the quality-of-life domains represent a novel aspect in the benefits of lanreotide. Trial registration ClinicalTrials.gov identifier: NCT00774930.

Background Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) is approved for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. This approval was based on significantly improved median overall survival compared with 5-FU/LV alone (6.1 vs 4.2 months; hazard ratio [HR], 0.67) in the global phase 3 NAPOLI-1 trial. Here, we report the final survival analysis and baseline characteristics associated with long-term survivors (survival of ≥1 year) in the NAPOLI-1 trial. Patients and methods Patients with mPDAC were randomised to receive nal-IRI + 5-FU/LV (n = 117), nal-IRI (n = 151), or 5-FU/LV (n = 149) for the first 4 weeks of 6-week cycles. Baseline characteristics and efficacy in the overall population were compared with those in patients who survived ≥1 year. Through 16th November 2015, 382 overall survival events had occurred. Results The overall survival advantage for nal-IRI+5-FU/LV vs 5-FU/LV was maintained from the original nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1) analysis (6.2 vs 4.2 months, respectively; HR, 0.75; 95% confidence interval: 0.57–0.99). Median progression-free survival, objective response rate and disease control rate also favoured nal-IRI+5-FU/LV therapy. Estimated one-year overall survival rates were 26% with nal-IRI+5-FU/LV and 16% with 5-FU/LV. Baseline characteristics associated with long-term survival in the nal-IRI+5-FU/LV arm were Karnofsky performance status ≥90, age ≤65 years, lower CA19-9 levels, neutrophil-to-lymphocyte ratio ≤5 and no liver metastases. No new safety concerns were detected. Conclusions The survival benefits of nal-IRI+5-FU/LV versus 5-FU/LV were maintained over an extended follow-up, and prognostic markers of survival ≥1 year were identified. Clinical trial registration number NCT01494506 .

Background Chemotherapy dose modification to manage adverse events is commonplace in clinical practice. This exploratory analysis evaluates the impact of liposomal irinotecan dose modification on overall survival (OS) and progression-free survival (PFS) in the NAPOLI-1 clinical trial (NCT01494506). Methods Analysis includes only patients enrolled under protocol version 2 who received at least the first 2 scheduled doses of study drug. Within the liposomal irinotecan +5 fluorouracil/leucovorin (5 FU/LV) arm, patients were grouped according to whether or not they had a dose modification within the first 6 weeks. Dose reduction was defined as any decrease from initial dose; dose delay was any dosing delay >3 days from target date. OS and PFS (Kaplan-Meier estimates) were compared within the liposomal irinotecan+5-FU/LV arm and between treatment arms. Unstratified hazard ratios (HRs) were calculated using Cox regression analysis. Results Of the 93 patients from the liposomal irinotecan+5 FU/LV arm included in the analysis, 53 experienced a dose modification (both delay and reduction, n = 30; delay only, n = 19; reduction only, n = 4). No apparent difference in median OS or PFS was observed between patients who did versus patients who did not have a dose modification (OS: 8.4 vs 6.7 months; HR, 0.89; PFS: 4.2 vs 3.1 months; HR, 0.74). Conclusion An early dose reduction or delay of liposomal irinotecan+5-FU/LV in the first 6 weeks does not significantly impact OS or PFS compared to patients without dose modifications. This finding suggests that tolerability-guided dose modification of liposomal irinotecan does not adversely affect efficacy outcomes.

Objective: Neuroendocrine tumors (NETs) are associated with elevated 5-hydroxyindoleacetic acid (5-HIAA) and chromogranin A (CgA) levels. This study aimed to analyze relationships between urinary 5-HIAA and plasma CgA levels and clinical outcomes. Methods: Centrally assessed biomarker levels and correlations with progression-free survival (PFS) and carcinoid syndrome (CS) symptom control were evaluated in a pooled analysis of CLARINET (96-week randomized, double-blind, placebo-controlled) and ELECT (16-week randomized, double-blind, placebo-controlled, 32-week initial open label and ≥2 year long-term extension open label) studies of adults with NETs, with (ELECT) or without (CLARINET) CS at 97 institutions. Patients were treated with subcutaneous lanreotide depot 120 mg monthly. Results: Of 319 pooled patients, 86% and 95% had baseline 5-HIAA and CgA data, respectively, with 47% and 74% having levels greater than the upper limit of normal (ULN). PFS was longer among patients who experienced a dec...

Background Urinary 5-hydroxyindoleacetic acid (5-HIAA) is an established biomarker in neuroendocrine tumors and carcinoid syndrome; however, its role in nonfunctional neuroendocrine tumors is not defined. We present post hoc data on urinary 5-HIAA and plasma chromogranin A (CgA) from the CLARINET study. Methods Patients with well- or moderately differentiated, nonfunctioning, locally advanced or metastatic enteropancreatic neuroendocrine tumors were randomized to deep subcutaneous lanreotide depot/autogel 120 mg or placebo once every 28 days for 96 weeks. Tumor response, evaluated centrally (RECIST 1.0), and progression-free survival (PFS) were assessed by treatment and biochemical response, defined as (a) baseline >upper limit of normal (ULN, 41.6 μmol per day 5-HIAA; 98.1 μg/L CgA) and (b) ≥50% decrease from baseline and to ≤ULN value on study. Results Forty-eight percent (82 of 171; lanreotide, n = 45; placebo, n = 37) and 66% (129 of 195; lanreotide, n = 65; placebo, n = 64) of randomized patients had 5-HIAA and CgA > ULN at baseline. Among patients with >ULN baseline values who did not progress after 96 weeks of treatment, significantly greater reductions in 5-HIAA and CgA were observed in lanreotide-treated versus placebo-treated patients throughout the study (all p < .05). PFS was significantly prolonged among 5-HIAA responders versus nonresponders (median not reached vs. 16.2 months, p < .0001; hazard ratio [HR] = 0.21, 95% confidence interval [CI], 0.09–0.48) and CgA responders versus nonresponders (median not reached vs. 16.2 months, p = .0070; HR = 0.30, 95% CI, 0.12–0.76), regardless of treatment arm. PFS was also significantly prolonged among lanreotide-treated 5-HIAA responders versus nonresponders (p = .0071) but was not significantly different among placebo-treated 5-HIAA responders versus nonresponders. There were no significant differences in PFS between lanreotide-treated CgA responders versus nonresponders or between placebo-treated CgA responders versus nonresponders. Conclusions The 5-HIAA findings are noteworthy because they occurred in patients with nonfunctioning enteropancreatic neuroendocrine tumors. Monitoring 5-HIAA and CgA may be useful when treating patients with nonfunctional neuroendocrine tumors. Implications for Practice Current guidelines focus only on the monitoring of 5-hydroxyindoleacetic acid (5-HIAA) in the diagnosis and management of functional neuroendocrine tumors with carcinoid syndrome. The current post hoc analysis of patients with nonfunctional enteropancreatic neuroendocrine tumors in the CLARINET study demonstrated that measuring and following both 5-HIAA and chromogranin A as biomarkers of disease progression may be useful in the management of patients with nonfunctional neuroendocrine tumors.

This ELECT prospective analysis examined lanreotide depot/autogel for carcinoid syndrome (CS) symptom control in patients with neuroendocrine tumors (NETs) who were responsive to prior octreotide (prior octreotide group) compared with patients who were naïve to prior somatostatin analogue treatment (de novo group).Adults with histopathologically confirmed NET and stable CS (diarrhea and/or flushing) were randomized to subcutaneous (SC) lanreotide 120 mg or placebo every 4 weeks for 16 weeks. Patients reported diarrhea and/or flushing symptom severity and frequency and short-acting SC octreotide rescue therapy daily using an Interactive Voice/Web Response System. To evaluate the efficacy of lanreotide compared with placebo, the novel primary endpoint of patient-determined use of SC octreotide rescue therapy for breakthrough symptoms was used as a surrogate for symptom control. Clinically meaningful patient-reported treatment benefit was examined using daily patient-reported symptoms of diarrhea and flushing.Of the 115 randomized patients, 51 (n = 26 lanreotide, n = 25 placebo) were octreotide-naïve (de novo) and 64 (n = 33 lanreotide; n = 31 placebo) received prior octreotide. Lanreotide versus placebo patients had a lower mean percentage of days of SC octreotide rescue therapy in de novo and prior octreotide groups (least squares [LS] mean difference -19.1, P = .0477 and -6.9, P = .4332, respectively). The mean percentage of days with moderate/severe diarrhea and/or flushing was lower in lanreotide versus placebo patients in de novo and prior octreotide groups (LS mean difference -14.6, P = .0140 and -10.9, P = .0746, respectively). The transition from octreotide to lanreotide was generally well-tolerated.Improvement in CS symptoms occurred with lanreotide treatment, regardless of prior octreotide use.CI = confidence interval CS = carcinoid syndrome DB = double blind ELECT = Evaluation of Lanreotide depot/autogel Efficacy and safety as a Carcinoid-syndrome Treatment IOL = initial open-label IVRS/IWRS = interactive voice/web response system LS = least square NET = neuroendocrine tumor OR = odds ratio SC = subcutaneous SSA = somatostatin analogue SSTR = somatostatin receptor TEAE = treatment-emergent adverse event.

This analysis evaluates the 2-year effectiveness and safety of lanreotide depot/autogel (LAN), as well as treatment convenience and acromegaly symptom relief, from the Somatuline® Depot for Acromegaly (SODA) registry, a post-marketing, open-label, observational, multicenter, United States registry study. Patients with acromegaly treated with LAN were eligible for enrollment. Demographics, LAN dose, extended dosing interval (EDI) (interval of injections ≥42 days), insulin-like growth factor 1 (IGF-1), growth hormone (GH), glycated hemoglobin, adverse events (AEs), injection convenience, and symptom data were collected. As of September 29, 2014, 241 patients were enrolled in SODA. IGF-1 levels below age- and gender-adjusted upper normal limit (ULN) were achieved in 71.2% at month (M) 12 and 74.4% at M24; GH ≤2.5 µg/L in 83.3% at M12 and 80.0% at M24; GH

Background: Octreotide has been used for decades in the United States (US) and Europe to treat patients with advanced neuroendocrine tumors (NETs). Lanreotide was approved in 2014 to improve progressionfree survival (PFS) in patients with unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic NETs. Therefore, clinicians and patients may consider sequencing therapy from octreotide to lanreotide. However, current real-world outcomes data on patients who have made this transition is limited. Methods: We conducted a multicenter, noninterventional, retrospective medical record review of patients with locally advanced or metastatic gastroenteropancreatic NETs (NCT03112694). Included patients had been treated with long-acting octreotide monotherapy for ≥90 days before transitioning to lanreotide monotherapy and continued on lanreotide for ≥90 days. Abstractors entered patient demographic and clinical data into a customized, web-based case report form. We assessed clinically defined PFS and other tumorrelated outcomes while patients were treated with lanreotide. Outcomes were analyzed according to level of response at the time of transition from octreotide to lanreotide: progressive disease, nonprogressive disease, or unknown. Statistical analyses were descriptive. Clinically defined PFS and duration of treatment with lanreotide were estimated using the Kaplan-Meier method. Results: Data were abstracted for 91 patients with gastroenteropancreatic NETs who received long-acting octreotide followed by lanreotide at six US based sites. At initial diagnosis, 71.4% of patients had stage IV disease. Small intestine (63.7%) and pancreas (14.3%) were the most common primary tumor sites. Mean [standard deviation (SD)] duration of follow-up from diagnosis was 70.6 (41.3) months. Patients received long-acting octreotide for a mean (SD) of 38.4 (32.8) months. When patients transitioned to lanreotide, 57.1% had nonprogressive disease on octreotide, 30.8% had progressive disease, and the remainder had unknown disease status. The most common reasons for switching from octreotide to lanreotide were progressive disease (22.0%), formulary change (15.4%), and patient preference (9.9%). Patients received lanreotide for a median (95% CI) duration of 24.7 (16.7–59.9) months. At the end of follow-up, 74% of patients remained on lanreotide monotherapy. Progression occurred in 24.2% of patients during lanreotide treatment. Overall median (95% CI) clinician-defined PFS following the transition to lanreotide was estimated to be 23.7 months [20.2 months–NE (not estimable)]. Patients with nonprogressive disease when they transitioned to lanreotide experienced a median clinician-defined PFS of 24.7 (17.0–NE) months. Among patients reported to have progressive disease when they transitioned to lanreotide, median (95% CI) clinician-defined PFS was estimated to be 15.2 (11.4–NE) months. There were no material differences in adverse events recorded during the long-acting octreotide and lanreotide treatment periods. Conclusions: Our study suggests that lanreotide monotherapy is well tolerated and may contribute to stabilization of disease in a subset of patients with locally advanced or metastatic gastroenteropancreatic NETs previously treated with long-acting octreotide.

Irinotecan liposomal; Pacients grans; Càncer de pàncrees Irinotecán liposomal; Pacientes mayores; Cáncer de páncreas Liposomal irinotecan; Older patients; Pancreatic cancer Objectives Pancreatic cancer is a highly lethal disease predominantly affecting older patients. Characterization of outcomes in these patients may help optimise treatment decisions. The global, phase 3 NAPOLI-1 trial ( NCT01494506 ) demonstrated an overall survival (OS) benefit with liposomal irinotecan and 5-flurouracil/leucovorin (nal-IRI + 5-FU/LV) versus 5-FU/LV. This subgroup analysis explored impact of age on outcomes in NAPOLI-1 patients, and nal-IRI + 5-FU/LV efficacy and safety in older patients. Materials and Methods This exploratory, post-hoc analysis of the NAPOLI-1 trial included patients aged ≥eighteen years (no upper limit) with metastatic pancreatic adenocarcinoma that had progressed on gemcitabine-based therapy. Patients were stratified by age (cut-offs at 65, 70, and 75 years); OS and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Results Of 417 randomized patients, 192 (46%), 110 (26%) and 43 (10%) were aged ≥65, ≥70 and ≥ 75 years, respectively. Mortality risk and risk of disease progression were similar in older and younger patients independent of treatment (HRs for median [m]OS/mPFS comparisons were 0.88/0.95 [ .25). Reduced mortality/morbidity risk with nal-IRI + 5-FU/LV in older subgroups was in line with the wider population. No additional toxicities with nal-IRI + 5-FU/LV were observed in older patients: 86% of patients ≥75 years versus 69%

Purpose Metastatic neuroendocrine tumors (mNETs) are rare, heterogeneous tumors that present diagnostic and treatment challenges, with limited data on the management of mNETs in clinical practice. The present study was designed to identify current diagnostic and treatment patterns in mNET patients treated in the US community oncology setting. Methods Patient-level data was collected from medical records of adults with mNETs from the Vector Oncology Data Warehouse, a comprehensive US community oncology network database. Results Of the 263 patients included (median follow-up, 22 months; range, 0.1–193.9), 30.4% (80/263) had intestinal tumors, 11.0% (29/263) had pancreatic, and 58.6% (154/263) had tumors of other or unknown location. Progression-free survival (PFS) from the start of first-line therapy differed significantly by tumor grade (log rank P = 0.0016) and location (P = 0.0044), as did overall survival (OS) (grade, P P = 0.0068). Median PFS and OS for patients with undocumented tumor grade were shorter than for patients with G1/G2 tumors and longer than patients with G3 tumors. Median PFS and OS for patients with other or unknown tumors were shorter than for patients with intestinal tumors. Conclusions While potentially confounded by the high number of patients with other or unknown tumor locations, this retrospective study of patients in a US community oncology setting identified the importance of awareness of tumor grade and tumor location at diagnosis, as these were direct correlates of PFS and OS.

Neuroendocrine tumors (NETs) are associated with elevated 5-hydroxyindoleacetic acid (5-HIAA) and chromogranin A (CgA) levels. This study aimed to analyze relationships between urinary 5-HIAA and plasma CgA levels and clinical outcomes.Centrally assessed biomarker levels and correlations with progression-free survival (PFS) and carcinoid syndrome (CS) symptom control were evaluated in a pooled analysis of CLARINET (96-week randomized, double-blind, placebo-controlled) and ELECT (16-week randomized, double-blind, placebo-controlled, 32-week initial open label and ≥2 year long-term extension open label) studies of adults with NETs, with (ELECT) or without (CLARINET) CS at 97 institutions. Patients were treated with subcutaneous lanreotide depot 120 mg monthly.Of 319 pooled patients, 86% and 95% had baseline 5-HIAA and CgA data, respectively, with 47% and 74% having levels greater than the upper limit of normal (ULN). PFS was longer among patients who experienced a decrease in biomarker levels at week 12, with statistical significance reached in the CgA cohort (not reached vs. 14.4 months; P.0001). A large proportion (87%) of patients without symptoms of CS in the CLARINET study had detectable levels of 5-HIAA (48%ULN). In ELECT, patients with CS who received lanreotide and experienced a biochemical response (≥50% decrease from baseline) achieved greater symptom control.This pooled analysis of two randomized, placebo-controlled trials demonstrated that 5-HIAA and CgA are secreted as biochemical biomarkers in many patients with NETs, regardless of clinical syndromes. Significant biochemical response was associated with improved clinical outcomes, as measured by improved PFS or improved CS symptom control.5-HIAA = 5-hydroxyindoleacetic acid; CgA = chromogranin A; CI = confidence interval; CLARINET = Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors; CS = carcinoid syndrome; ELECT = Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment; HR = hazard ratio; ITT = intention-to-treat; NET = neuroendocrine tumor; PanNET = pancreatic NET; PFS = progression-free survival; PPI = proton pump inhibitor; SSA = somatostatin analogue; ULN = upper limit of normal.

In clinical research involving acromegalic patients naïve to somatostatin-receptor ligands (SRLs), 19 and 31% of those receiving the SRLs octreotide LAR and pasireotide LAR, respectively, achieved GH 2.5 ng/mL + normalized IGF-1 concentrations. The proportions achieving control appeared higher in the post-surgery compared with the de-novo setting with pasireotide, but more similar with octreotide. Using pooled data from multicenter clinical trials, we examined the biochemical efficacy of lanreotide depot/Autogel in similar settings.Inclusion criteria: Ipsen-sponsored, 48-52-week trials in SRL-naïve acromegalic populations receiving lanreotide depot (60-120 mg); patients were included if de novo (no prior acromegaly treatment) or post-surgery (no medical treatment; radiotherapy allowed unless within previous 3 years). Efficacy endpoints included normalized IGF-1 levels and GH 2.5 ng/mL + normalized IGF-1 at study end/last value available.all patients (analysis #1) and subset with baseline GH 5 ng/mL (analysis #2).Three studies were included. Analysis #1: normalized IGF-1 was achieved by 42% (71/171) of patients overall (post-surgery, 46% [21/46]; de-novo, 40% [50/125]); GH 2.5 ng/mL + normalized IGF-1 was achieved by 35% (59/171) (39% [18/46] and 33% [41/125], respectively). Analysis #2: normalized IGF-1 levels, 39% (46/118) (post-surgery, 40% [10/25]; de-novo, 39% [36/93]); GH 2.5 ng/mL + normalized IGF-1, 31% (36/118) (28% [7/25] and 31% [29/93], respectively).In these pooled analyses of SRL-naïve patients receiving lanreotide depot, 39-42% achieved IGF-1 control and 31-35% achieved GH and IGF-1 control. Control rates within post-surgery cohorts did not differ markedly from those in corresponding de-novo cohorts.

Introduction: In the NAPOLI-1 phase 3 study of patients with mPDAC who progressed following gemcitabine-based therapy (NCT01494506), nal-IRI+5-FU/LV significantly increased median overall survival (mOS) vs 5-FU/LV control (6.1 vs 4.2 months; unstratified hazard ratio [HR] 0.67 [0.49–0.92]; P = 0.012). Best response to prior therapy may influence treatment outcomes, prognosis and subsequent therapy choices. Methods: This post-hoc analysis explored outcomes in NAPOLI-1 patients based on best response to prior anticancer therapy. Treatment response groups were: complete response/partial response as prior best response (CR/PR) vs not CR/PR, and complete response/partial response/stable disease as prior best response (CR/PR/SD) vs not CR/PR/SD. Results: Prior to study entry, 55/417 patients (13%) had CR/PR on prior anticancer therapy, and 211 (51%) had CR/PR/SD. In the overall intent-to-treat (ITT) population, trends towards improved outcomes were observed in CR/PR vs not CR/PR patients (mOS 5.6 vs 4.8 months, HR = 0.73, P = 0.08; median progression-free survival [mPFS] 3.8 vs 2.4 months, HR = 0.73, P = 0.06; objective response rate [ORR] 13% vs 6%, P = 0.085). mOS, mPFS and ORR were similar in CR/PR/SD vs not CR/PR/SD patients (mOS 4.9 vs 4.9 months, HR = 0.95, P = 0.68; mPFS 2.5 vs 2.6 months, HR = 1.00, P = 0.95; ORR 7% vs 7%, P = 1.00). In the nal-IRI+5-FU/LV arm, a trend towards improved mOS, mPFS and ORR was observed in patients with CR/PR (n = 11) vs not CR/PR (n = 106) (mOS 9.3 vs 6.1 months, HR = 0.64, P = 0.34; mPFS 4.2 vs 3.0 months, HR = 0.53, P = 0.13; ORR 27% vs 15%). mOS, mPFS and ORR were similar in patients with CR/PR/SD (n = 58) vs not CR/PR/SD (n = 59) (mOS 6.2 vs 6.1 months, HR = 1.04, P = 0.88; mPFS 4.0 vs 3.3 months, HR = 1.18, P = 0.45; ORR 14% vs 19%, P = 0.62). Patients with CR/PR numerically benefited from treatment with nal IRI+5 FU/LV (n = 11) vs 5 FU/LV (n = 21) (mOS 9.3 vs 5.1 months, HR = 0.46, P = 0.14; mPFS 4.2 vs 1.4 months, HR = 0.33, P = 0.03; ORR 27% vs 0, P = 0.03). Patients with not CR/PR also benefited from treatment with nal IRI+5-FU/LV (n = 106) vs 5-FU/LV (n = 98) (mOS 6.1 vs 4.0 months, HR = 0.69, P = 0.03; mPFS 3.0 vs 1.5 months, HR = 0.58, P

460 Background: We report a post hoc, exploratory analysis of pts with BL ML number and LL data who received nal-IRI+5-FU/LV, nal-IRI or 5-FU/LV in NAPOLI-1, a pivotal, phase 3 trial (NCT01494506). nal-IRI+5-FU/LV increased median OS (mOS) vs 5-FU/LV (6.1 vs 4.2 mo [HR=0.67; p=0.012]). Methods: ML (1, 2, 3, >3) and LL were recorded (local investigator) at BL. Pts with >1 LL were counted for each location. Results: 354 of 417 ITT pts had measurable BL ML and 1,080 LL were recorded. There was no clear trend in the percentage of pts with KPS ≥80 in 1- >3 ML (range 87%-95%) or LL (range 89%-94%) subgroups. ML 1 (n=81), 2 (n=65) and 3 (n=24) subgroups were small. nal-IRI+5-FU/LV significantly improved mOS vs. 5-FU/LV in pts with 2/>3 ML (n=184/24); nal-IRI+5-FU/LV had numerically higher mOS vs. 5-FU/LV for all LL (Table). nal-IRI+5-FU/LV had favourable median PFS (mPFS) vs. 5-FU/LV in pts with 1–>3 ML (range 2.0-4.2 vs. 1.4-1.9 mo; HR range 0.35-0.88) and for all LL (range 2.8-4.2 vs. 1.4-2.0 mo; HR range 0.39-0.55). Conclusions: Low pt numbers across groups and repeat counting of pts in LL subgroups preclude firm conclusions on treatment efficacy, pending further analyses. Allowing for these limitations, we detected no clear prognostic effect on outcomes of higher BL ML number or LL in NAPOLI-1 ITT pts. nal-IRI+5-FU/LV improved mOS vs. 5-FU/LV in some ML groups and across LL groups; improvement in mPFS vs. 5-FU/LV in the ITT population was maintained in all subgroups. Clinical trial information: NCT01494506. [Table: see text]

Introduction: In NAPOLI-1 (NCT01494506), treatment with liposomal irinotecan + 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) significantly increased median overall survival (mOS) vs. 5-FU/LV (6.1 vs. 4.2 months; unstratified hazard ratio [HR]=0.67, 95% confidence interval [CI] 0.49–0.92; P = 0.012) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had progressed following gemcitabine-based therapy. We investigated the effect of metabolism and nutrition disorders (MNDs) on survival in NAPOLI-1 patients. Methods: This post-hoc analysis explored outcomes in patients with vs. without MNDs (based on MedDRA v14.1), including diabetes mellitus (DM), decreased appetite (DA; which included anorexia, poor appetite, lack of appetite, loss of appetite), hypercholesterolemia (HC), and dyslipidemia. Results: At baseline, 267/417 intent-to-treat (ITT) patients had any MND. Differences in baseline characteristics were observed in some MND subgroups vs. the ITT population: e.g. Karnofsky performance status (DA), gender and race (HC), albumin (DA, HC). Both mOS (3.6 vs. 5.3 months; HR = 1.65, 95% CI 1.25–2.18; P

Introduction: In NAPOLI-1 (NCT01494506), treatment with liposomal irinotecan + 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) significantly increased median overall survival (mOS) vs. 5-FU/LV (6.1 vs. 4.2 months; unstratified hazard ratio [HR]=0.67, 95% confidence interval [CI]:0.49–0.92; P = 0.012) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had progressed following gemcitabine-based therapy. A potential prognostic impact of primary tumor location on metastatic pancreatic cancer outcomes has been reported. We investigated the effect of primary tumor location on survival following inclusion in the NAPOLI-1 study. Methods: This post-hoc analysis explored outcomes in patients with primary tumor locations of the pancreatic head only (H only), body only (B only), tail only (T only), and multiple locations including (H_incl) and excluding (H_excl) the head. Results: Of 417 patients, 239 (57%) had a primary tumor location of H only, 54 (13%) B only, 62 (15%) T only, 17 (4%) H_incl and 30 (7%) H_excl. Karnofsky performance status was lower in patients with a primary tumor location of T only versus the intent-to-treat population. The mOS (HRs: 0.87–1.06) and median progression-free survival (mPFS) (HRs: 0.82–0.98) were similar across primary tumor location subgroups and no clear prognostic signal for OS was detected. The mOS and mPFS in patients with a primary tumor location of H only were 5.0 and 2.7 months, respectively, versus 5.4 and 2.8 months, respectively, for those with B only (mOS: HR = 1.06, 95%CI:0.75–1.50, P = 0.737; mPFS: HR = 0.98, 95%CI:0.70–1.37, P = 0.925). For patients with T only, mOS and mPFS were 4.3 and 1.7 months respectively (mOS H only vs. T only: HR = 0.89, 95%CI:0.64–1.23, P = 0.469; mPFS H only vs. T only HR = 0.89, 95%CI:0.66–1.22, P = 0.471). For patients with H_incl, mOS and mPFS were 5.7 and 2.3 months respectively, while for H_excl patients they were 4.6 and 1.4 months, respectively. For the comparison of mOS between the H only and B only+T only+H_excl subgroup (mOS=4.4, mPFS=1.7 months), HR = 0.88 (95%CI:0.69–1.11, P = 0.285) while for mPFS HR = 0.83 (95%CI:0.66–1.05, P = 0.116). For the comparison of mOS between the H only and B only+T only+H_excl+H_incl subgroup (mOS=4.6, mPFS=1.7 months), HR = 0.91 (95%CI:0.72–1.15, P = 0.421), while for mPFS HR = 0.87 (95%CI:0.70–1.09, P = 0.233). For the comparison of mOS between the H only+H_incl and B only+T only+H_excl subgroup HR = 0.87 (95%CI:0.69–1.10, P = 0.240), while for mPFS HR = 0.82 (95%CI:0.65–1.03, P = 0.084). Both mOS and mPFS were higher in patients treated with nal IRI+5 FU/LV vs. 5 FU/LV across primary tumor location subgroups (mOS: HRs: 0.39–0.88; two groups with n

OBJECTIVE This study was conducted to understand treatment patterns and clinical outcomes in metastatic gastroenteropancreatic neuroendocrine tumor patients treated in a large community oncology network. METHODS This retrospective study used the McKesson Specialty Health/US Oncology Network iKnowMed electronic health record database with supplemental chart review. Eligibility criteria included a metastatic neuroendocrine tumor diagnosis between January 1, 2008, and to December 31, 2012; at least 2 US Oncology Network visits; and age at least 18 years. Follow-up was through October 31, 2014. RESULTS Among the 229 patients identified, median age was 64.0 years, 52.4% were male, 69.4% were white, and 62.9% were overweight/obese. Primary tumor sites included small bowel (47.6%), pancreas (31.4%), and stomach/colorectum (21.0%). There were 16.2% under observation without treatment, 52.4% received only somatostatin analogs (SSAs), and 31.4% received chemotherapy/targeted therapy during treatment. In the first-line setting (n = 192), 77% received SSAs, 12% received chemotherapy, and 10.9% received targeted therapy. Fifty percent of patients receiving octreotide had a relative dose intensity of less than 85%, and 16.7% received above-label dose. Toxicities of SSAs included diarrhea (18.2%), abdominal pain (16.9%), and fatigue (13.5%). Median overall survival from diagnosis was 68.0 months (95% confidence interval, 57.1 to not reached). CONCLUSIONS Most metastatic gastroenteropancreatic neuroendocrine tumor patients received systemic treatment with SSAs. Patient treatment used an individualized dosing approach. Overall survival and toxicity were consistent with the published literature.

Purpose This 2-year analysis assessed frequency of comorbidities and comorbidity screening in the Somatuline® (lanreotide, LAN) Depot for Acromegaly (SODA) registry. Methods Patient data collected included pituitary hormone deficiencies, sleep studies, echocardiograms, gallbladder sonographies, colonoscopies, and glycated hemoglobin (HbA1c) levels. Insulin-like growth factor-1 (IGF-1) and growth hormone levels in patients with (DM) and without (non-DM) diabetes mellitus were analyzed. Results There were 241 patients enrolled. Pituitary hormone deficiencies were reported more frequently at enrollment in male (56.9%) vs female patients (32.0%; p

Background In the double-blind (DB) ELECT study, lanreotide depot/autogel significantly reduced versus placebo the need for short-acting octreotide for symptomatic carcinoid syndrome (CS) control in neuroendocrine tumor (NET) patients. Here we present patient-reported symptom data during DB and initial open-label (IOL) treatment. Materials and Methods Adults with NETs and CS history, with/without prior somatostatin analog use, were randomized to 16 weeks’ DB lanreotide 120 mg subcutaneous or placebo every 4 weeks, followed by 32 weeks’ IOL lanreotide. Patients recorded diarrhea and/or flushing frequency and severity daily by Interactive Voice (Web) Response System for 1 month prior to randomization and throughout the study. Results Of 115 patients randomized (n = 59 lanreotide, n = 56 placebo), 56 lanreotide and 45 placebo patients enrolled in the IOL phase. During DB treatment, least square (LS) mean percentages of days with moderate/severe diarrhea and/or flushing were significantly lower for lanreotide (23.4%) versus placebo (35.8%; LS mean difference [95% confidence interval]: −12.4 [−20.73 to −4.07]; p = .004). For DB lanreotide patients, average daily composite (frequency × severity) diarrhea scores improved significantly between DB and IOL treatment (mean difference: −0.71 [−1.20 to −0.22]; p = .005), and remained stable for diarrhea and/or flushing. For DB placebo patients, composite scores for diarrhea, flushing, and diarrhea and/or flushing improved significantly between DB and IOL treatment (mean differences: −1.07 [−1.65 to −0.49]; −1.06 [−1.93 to −0.19]; and −2.13 [−3.35 to −0.91]; all p ≤ .018). Conclusion Improved diarrhea and flushing control in CS patients during 16-week lanreotide treatment was sustained during maintenance of lanreotide treatment for the 32-week IOL phase (48 weeks total). Implications for Practice This study prospectively collected daily patient-reported data on diarrhea and flushing from the ELECT trial to evaluate the direct impact of lanreotide depot on patients’ relief of carcinoid syndrome symptoms. Treatment with lanreotide depot was associated with significant reductions in the percentages of days patients reported symptoms of diarrhea and flushing, as well as reductions in the frequency and severity of daily symptoms compared with placebo during 16 weeks of double-blind treatment. These improvements were sustained for 32 additional weeks of open-label lanreotide treatment (i.e., through week 48 of treatment), resulting in clinically meaningful, long-term symptom reduction.

Jesse D Ortendahl,1 Sonia J Pulgar,2 Beloo Mirakhur,3 David Cox,3 Tanya GK Bentley,1 Alexandria T Phan4 1Health Economics, Partnership for Health, LLC, Beverly Hills, CA, USA; 2Health Economics and Outcomes Research, Ipsen Biopharmaceuticals, Basking Ridge, NJ, USA; 3Medical Affairs, Oncology, Ipsen Biopharmaceuticals, Basking Ridge, NJ, USA; 4GI Medical Oncology, University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA Objective: With the introduction of new therapies, hospitals have to plan spending limited resources in a cost-effective manner. To assist in identifying the optimal treatment for patients with locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors, budget impact modeling was used to estimate the financial implications of adoption and diffusion of somatostatin analogs (SSAs). Patients and methods: A hypothetical cohort of 500 gastroenteropancreatic neuroendocrine tumor patients was assessed in an economic model, with the proportion with metastatic disease treated with an SSA estimated using published data. Drug acquisition, preparation, and administration costs were based on national pricing databases and published literature. Octreotide dosing was based on published estimates of real-world data, whereas for lanreotide, real-world dosing was unavailable and we therefore used the highest indicated dosing. Alternative scenarios reflecting the proportion of patients receiving lanreotide or octreotide were considered to estimate the incremental budget impact to the hospital. Results: In the base case, 313 of the initial 500 gastroenteropancreatic neuroendocrine tumor patients were treated with an SSA. The model-predicted per-patient cost was US$83,473 for lanreotide and US$89,673 for octreotide. With a hypothetical increase in lanreotide utilization from 5% to 30% of this population, the annual model-projected hospital costs decreased by US$488,615. When varying the inputs in one-way sensitivity analyses, the results were most sensitive to changes in dosing assumptions. Conclusion: Results suggest that factors beyond drug acquisition cost can influence the budget impact to a hospital. When considering preparation and administration time, and real-world dosing, use of lanreotide has the potential to reduce health care expenditures associated with metastatic gastroenteropancreatic neuroendocrine tumor treatments. Keywords: health economics, oncology, model, costs, real-world evidence, lanreotide

Background: In a randomized phase III study (BREAK-3), dabrafenib showed prolonged progression-free survival (PFS) (median 5.1 versus 2.7 months; hazard ratio = 0.30; 95% confidence interval 0.18–0.53; P < 0.0001) compared with dacarbazine (DTIC) in patients with BRAF V600E metastatic melanoma. Assessing how these results are transformed into a real health benefit for patients is crucial. Methods: The EORTC QLQ-C30 questionnaire assessed quality of life (QoL) at baseline and follow-up visits. Results: For DTIC, all functional dimensions except role dimension worsened from baseline at follow-up. For dabrafenib, all functionality dimensions remained stable relative to baseline or improved at week 6; mean change in seven symptom dimensions improved from baseline, with appetite loss, insomnia, nausea and vomiting, and pain showing the greatest improvement. In the DTIC arm, symptom dimensions were unchanged or worsened from baseline for all symptoms except pain (week 6), with the greatest exacerbations observed for fatigue and nausea and vomiting. Mixed-model-repeated measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements from baseline in favor of dabrafenib for emotional and social functioning, nausea and vomiting, appetite loss, diarrhea, fatigue, dyspnea, and insomnia at weeks 6 and/or 12. After crossing over to dabrafenib upon progression (n = 35), improvements in all QoL dimensions were evident after receiving dabrafenib for 6 (n = 31) to 12 (n = 25) weeks. Conclusions: This first reported QoL analysis for a BRAF inhibitor in metastatic melanoma demonstrates that the high tumor response rates and PFS superiority of dabrafenib over DTIC is not only a theoretical advantage, but also transforms in a rapid functional and symptomatic benefit for the patient. Clinical Trials.gov identifier NCT01227889.

NAPOLI-1; Liposomal irinotecan; Survival outcomes NAPOLI-1; Irinotecan liposòmic; Resultats de supervivència NAPOLI-1; Irinotecan liposomal; Resultados de supervivencia NAPOLI-1 (NCT01494506) was a phase III study of liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. This post hoc analysis of NAPOLI-1 aimed to develop a predictive nomogram for overall survival (OS) at 6 and 12 months. Analyses were derived from all patients in NAPOLI-1 randomized to receive nal-IRI+5-FU/LV, nal-IRI monotherapy, or 5-FU/LV combination therapy. OS was associated with baseline factors using univariate and multivariable Cox analyses. A predictive nomogram was derived and validated using a concordance index and calibration plots. The univariate analyses identified 21 independent factors that contributed to OS, with eight factors significantly associated with OS. The Karnofsky Performance Score contributed the largest number of points (100), followed by presence of liver metastasis (98) and randomization to nal-IRI+5-FU/LV (96). The other baseline factors showing effects were albumin (g/dL), neutrophil/lymphocyte ratio, carbohydrate antigen 19-9 (U/mL), disease stage at diagnosis, and body mass index (kg/m2). The nomogram was used to predict the 6- and 12-month survival probability. The mean absolute errors between the observed and predicted probabilities for OS at 3, 6, and 9 months were 0.07, 0.08, and 0.07, respectively. This nomogram, based on NAPOLI-1, provides additional insight to aid decision-making for patients with mPDAC after previous gemcitabine-based therapy. This study (NCT01494506) was supported by Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA. Analysis sponsored by Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ, USA.

Summary Background Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a manageable safety profile in studies of phase 1 and 2 in patients with BRAF V600 -mutated metastatic melanoma. We studied the efficacy of dabrafenib in patients with BRAF V600E -mutated metastatic melanoma. Methods We enrolled patients in this open-label phase 3 trial between Dec 23, 2010, and Sept 1, 2011. This report is based on a data cutoff date of Dec 19, 2011. Patients aged 18 years or older with previously untreated, stage IV or unresectable stage III BRAF V600E mutation-positive melanoma were randomly assigned (3:1) to receive dabrafenib (150 mg twice daily, orally) or dacarbazine (1000 mg/m 2 intravenously every 3 weeks). Patients were stratified according to American Joint Committee on Cancer stage (unresectable III+IVM1a+IVM1b vs IVM1c). The primary endpoint was investigator-assessed progression-free survival and was analysed by intention to treat; safety was assessed per protocol. This study is registered with ClinicalTrials.gov, number NCT01227889. Findings Of the 733 patients screened, 250 were randomly assigned to receive either dabrafenib (187 patients) or dacarbazine (63 patients). Median progression-free survival was 5·1 months for dabrafenib and 2·7 months for dacarbazine, with a hazard ratio (HR) of 0·30 (95% CI 0·18–0·51; p Interpretation Dabrafenib significantly improved progression-free survival compared with dacarbazine. Funding GlaxoSmithKline.

Introduction: In the NAPOLI-1 phase 3 study of patients with mPDAC who progressed following gemcitabine-based therapy (NCT01494506), nal-IRI+5-FU/LV significantly increased median overall survival (mOS) vs 5-FU/LV control (6.1 vs 4.2 months; unstratified hazard ratio [HR]=0.67 [0.49–0.92]; P = 0.012). Biliary stenting is used to treat malignant obstructive jaundice and associated complications, allowing bile efflux resulting in normalised bilirubin levels. Patients with a biliary stent were allowed to enter the NAPOLI-1 study if plasma bilirubin was normal. Methods: This post-hoc analysis explored outcomes in patients in the NAPOLI-1 study population with or without biliary stent at baseline (BL). Results: Prior to study entry, 37/417 (9%) patients had a biliary stent. A higher proportion of patients with a BL stent had a primary tumour located in the head of the pancreas at diagnosis vs patients without a BL stent (89% vs 58%). In the overall intent-to-treat (ITT) population, mOS and median progression-free survival (mPFS) were similar for patients with or without a BL stent (mOS: 5.3 vs 4.8 months, HR = 0.97, P = 0.90; mPFS: 3.5 vs 2.4 months, HR = 0.82, P = 0.32). Patients with a BL stent demonstrated a higher objective response rate (ORR) (16% vs 6%; P = 0.03) and a greater proportion of cancer antigen 19-9 (CA19-9) responses (37% vs 20%; P

e16174Background: Somatostatin analogs (SSA), such as OCT and LAN, are used to treat GEP-NETs. LAN is effective for carcinoid syndrome (CS) control in both SSA-experienced and -naive patients (pts)...

e16204Background: NAPOLI-1 (NCT01494506) was a global phase 3 study in pts with mPDAC previously treated with gemcitabine-based therapy that showed a significant improvement in overall survival (OS...

e16233Background: Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and are ineligible for potentially curative surgical resection. Oncologists are face...

e24329Background: Tumor size following cancer-related therapy is the result of regression of the treatment-sensitive fraction and growth of the treatment-resistant fraction, occurring simultaneousl...

459 Background: Results from NAPOLI-1 (NCT01494506), a phase 3 study in pts with mPDAC previously treated with gemcitabine-based therapy, demonstrated an improvement in OS (primary endpoint), progression-free survival, and objective response rate with nal-IRI+5-FU/LV vs 5-FU/LV. The MPACT study reported a nomogram to predict OS using baseline pt variables in previously untreated mPDAC. We conducted an exploratory post hoc analysis of NAPOLI-1 variables to develop a nomogram to predict OS in the post-gemcitabine setting. Methods: In NAPOLI-1, pts were randomized to receive nal-IRI 80 mg/m2 q2w + 5-FU/LV, nal-IRI 100 mg/m2 q3w, or 5-FU/LV. Univariate and multivariate analyses determined factors significantly predictive of OS. A multivariable Cox model was created using these factors to develop a nomogram that assigned points equal to the weighted sum of relative significance of each variable. Predictive accuracy of the nomogram as measured by the concordance index (c-index) was evaluated by internal bootstrap validation. Results: Data from the 417-pt univariate analysis and 399-pt multivariate analysis (18 pts excluded for missing baseline data) were used. Eight of 21 variables were retained in the multivariate analysis (p < 0.01 except BMI [p=0.08]). Conclusions: In NAPOLI-1, predictors of OS were nal-IRI+5-FU/LV treatment, KPS, NLR, albumin level, baseline CA19-9, stage 4 at diagnosis, BMI, and presence of liver metastasis. The nomogram, which will distinguish between risk groups and may aid in clinical decision making, will be presented in the poster. Clinical trial information: NCT01494506. [Table: see text]

388 Background: In NAPOLI-1 (NCT01494506), a randomized phase 3 study in patients with metastatic pancreatic cancer previously treated with gemcitabine-based therapy, nal-IRI+5-FU/LV improved overall survival (OS; primary endpoint) vs 5-FU/LV (6.1 mos vs 4.2 mos; HR = 0·67, 95% CI 0.49–0.92; P = 0.012). This exploratory analysis examined the impact of dose modifications or delays used to manage adverse events (AEs) on OS. The study protocol allowed ≤2 dose reductions for nal-IRI and 5-FU and for up to 3 weeks. Methods: Patient who had a dose delay or reduction within the planned first 6 weeks of the study were included. Delays were defined as any delay in dosing > 3 days from target dosing date and dose reductions were defined as any reduction in dose from initial administered dose. OS was compared within the nal-IRI+5-FU/LV arm and with the 5-FU/LV arm. Comparisons were made using the cohort of 5-FU/LV and nal-IRI+5-FU/LV patients enrolled under protocol version 2. Median OS was based on Kaplan-Meier estimates and Cox regression analysis was used to calculate HRs. Results: More patients in the nal-IRI+5-FU/LV treatment group experienced AEs that required dose delay and/or reduction than in the 5-FU/LV treatment group (62% vs 33%). Within the nal-IRI+5-FU/LV arm, median OS was numerically but not significantly different between patients who did (n = 34) vs did not (n = 83) have a dose reduction (9.3 vs 5.4 mos; HR = 0.66 [95% CI 0.43, 1.01]) and for those who did (n = 49) vs did not (n = 68) have a dose delay (8.4 vs 5.6 mos; 0.82 [95% CI 0.56, 1.23]). Between treatment arms, OS was greater in the nal-IRI+5-FU/LV arm regardless of dose delay or reduction (Table). Conclusions: Dose modifications in the nal-IRI+5-FU/LV arm did not significantly impact OS compared with those who did not need a dose modification, and OS remained greater than in 5-FU/LV-treated patients. This suggests that appropriate dose modification of nal-IRI+5-FU/LV for AEs may not adversely affect outcomes. Clinical trial information: NCT01494506. [Table: see text]

347 Background: In the ELECT study, mean percentage of days with rescue octreotide (OCT) use was significantly lower in lanreotide depot/autogel (LAN) 120 mg vs. placebo (PBO) group during 16-week double blind (DB) phase. We examined prospective data on use of subcutaneous (sc) OCT or other medications as rescue during DB and initial open label (IOL) treatment periods of the ELECT trial to evaluate the direct impact of LAN on patients’ relief of CS symptoms for prolonged periods. Methods: Adults with neuroendocrine tumors (NETs) and CS history, with/without prior SSA use, were randomized to 16 weeks DB LAN 120 mg sc or PBO every 4 weeks, followed by a 32-week IOL LAN phase. Prospectively collected data recorded via Interactive Voice (Web) Response System on the use of sc OCT or other rescue medications during screening, DB and IOL treatment periods was analyzed. Results: During the 16-week DB phase, treatment with LAN was associated with less frequent rescue sc OCT use (least squares mean percentage of usage days (MPUD): 33.7% LAN vs. 48.5% PBO; p = 0.02). Through the 32-week LAN IOL period, rescue sc OCT use in the DB LAN group further decreased to 27.1% MPUD. Following crossover from PBO to active treatment, sc rescue OCT MPUD in the DB PBO group decreased from 48.5% to 20.9% during the IOL period. MPUD of other rescue medications at baseline were: 12.9% LAN; 8.3% PBO and no significant decreases were observed with LAN treatment during the DB phase (8.9% LAN vs. 6.3% PBO). MPUD of the DB LAN group remained relatively unchanged through the IOL phase (8.9% LAN DB; 8.8% LAN IOL). Following crossover from PBO to active treatment, the PBO group exhibited a decrease in MPUD of other rescue medications from 6.3% to 3.1% during the IOL period. Stratified by prior SSA therapy cohorts (naïve vs. prior SSA therapy), no apparent differences were observed in the use of sc OCT or other rescue medications between the two cohorts. Trends in MPUD of rescue medications of the individual cohorts were also similar to the overall group. Conclusions: The results of this study demonstrated that LAN is effective for the prolonged control of CS symptoms in SSA-naïve or experienced patients with NETs. Clinical trial information: NCT00774930.

4088 Background: In ELECT, LAN significantly reduced the need for short-acting OCT rescue therapy for symptomatic control of CS in NET patients (pts) vs placebo (PBO) (primary result). Here we present flushing and diarrhea symptom data and biochemical response for pts with or without prior OCT use from ELECT. Methods: Adults with histopathologically-confirmed NET and history of stable CS (diarrhea and/or flushing) who were OCT-naive or responsive to OCT long-acting release (LAR) (≤30 mg q4W) or short-acting OCT (≤600 μg daily) were randomized to LAN 120 mg (SC q4W) or PBO for 16 wks. Pts administered SC OCT if needed and recorded daily frequency and severity of symptoms using Interactive Voice/Web Response System for 1 month pre-randomization and throughout the study. 24-hr urinary 5-hydroxindoleacetic acid (5HIAA) and plasma chromogranin A (CgA) were assessed at baseline and wk 12. Results: Of 115 pts randomized, 51 were OCT-naive and 64 received prior OCT. The least squares (LS) mean percentages of days with moderate/severe diarrhea and/or flushing were lower in both naive and prior OCT LAN pts vs naive and prior OCT PBO pts; LS mean difference (LAN-PBO) was significant in the naive group (Table). By week 12, 5HIAA and CgA levels dropped by ≥30% to normal in 35.3% and 15.8% of naive LAN pts and 28.6% and 4.5% of prior OCT LAN pts; 5HIAA and CgA reductions were seen in 15.4% and 21.4% of naive PBO pts and 5HIAA in 7.1% of prior OCT PBO pts. Conclusions: Pts showed improvement in CS symptoms of flushing and diarrhea and reduction in 5HIAA levels with LAN treatment, indicating efficacy of LAN regardless of prior OCT use. Transition from OCT to LAN was well tolerated among prior OCT pts in ELECT. Clinical trial information: NCT00774930. [Table: see text]

4095 Background: 5HIAA or CgA are biomarkers in some GEP NETs. We present posthoc analyses using prospectively collected urinary 5HIAA and serum CgA data from CLARINET. Methods: Adults with moderately or well differentiated, nonfunctioning (no symptoms of carcinoid syndrome), locally advanced or metastatic GEP NETs were randomized to LAN 120mg or placebo (PBO) every 4 weeks (wks) for 96 wks. Tumor response evaluated centrally (RECIST 1.0) and PFS were assessed by treatment. Biochemical response was defined as baseline > upper limit of normal (ULN, 41.6µmol/d 5HIAA; 98.1µg/L CgA) and ≥50% decrease from baseline to ≤ULN value on study. CgA analyses excluded gastrinoma patients (pts). Results: 48% (82/171) (45LAN; 37PBO) and 66% (129/195) (65LAN, 64PBO) of pts had > ULN baseline 5HIAA and CgA. In those pts with no radiologic progression, significantly greater reductions in 5HIAA (Table) and CgA were observed in LAN vs PBO pts at all assessments (all P< 0.05). PFS was significantly prolonged in LAN 5HIAA responders vs nonresponders (median not reached vs 22.1 months, P= 0.0076) but was not significantly different in PBO 5HIAA responders vs nonresponders. There were no significant differences in PFS by CgA response (responders vs nonresponders) in either LAN or PBO pts. Conclusions: These data suggest that serotonin is secreted by nonfunctioning tumors, but does not reach the threshold required for clinical carcinoid symptoms. Monitoring 5HIAA and CgA may be useful during LAN treatment of nonfunctional GEP NETs. Clinical trial information: NCT00353496. [Table: see text]

BACKGROUND: There are currently many approved agents for the treatment of metastatic melanoma (MM), the most aggressive form of skin cancer. Treatments may include systemic therapies such as ipilimumab, dacarbazine, temozolomide, high-dose interleukin 2, interferon α, dacarbazine- or temozolomide-based combination chemotherapy/biochemotherapy, paclitaxel, paclitaxel/cisplatin, and paclitaxel/carboplatin, as well as the targeted therapies vemurafenib, dabrafenib, and trametinib for patients with BRAF V600 mutation. However, all treatment options are associated with different adverse events (AEs) and, in some instances, considerable toxicity. The occurrence of such treatment-related AEs can lead to higher health care resource utilization and increasing treatment and patient management costs. An understanding of the economic burden of these AEs will therefore enable better management of health care expenditures, not just for existing therapies, but also for new and novel treatments in development. OBJECTIVE: To estimate the incremental health care costs of specific AEs among patients with MM treated with paclitaxel, vemurafenib, ipilimumab, dacarbazine, temozolomide, high-dose interleukin 2, or interferon α, along with AEs known to be associated with dabrafenib and trametinib. METHODS: This cohort study employed a retrospective administrative claims-based analysis of MarketScan commercial and Medicare supplemental databases from July 1, 2004, to April 30, 2012. Patients included those aged ≥ 18 years who had diagnosed melanoma (ICD-9-CM code 172.xx) with ≥ 1 diagnosis of metastasis and ≥ 1 claim for any of the 7 study treatments. Health care encounters for AEs of interest were based on ICD-9-CM diagnosis/procedure codes. Incremental cost per AE was determined by comparing the 30-day expenditures in patients with the event to patients without the event based on a shadow event date. Multivariate generalized linear models (GLMs) with a log-link function and gamma distribution were utilized to control for baseline differences between groups. RESULTS: A total of 2,621 patients with MM were included. Mean age was 56.0 years (SD ± 13.0); 64% were male; and 24% had a diagnosis of primary or secondary brain cancer at the time of MM diagnosis. GLM-based estimate of 30-day incremental costs by AE category were metabolic, $9,135 (95% CI = $6,404-$12,392); hematologic/lymphatic, $8,450 (95% CI = $6,528-$10,633); cardiovascular, $6,476 (95% CI = $4,667-$8,541); gastrointestinal, $6,338 (95% CI = $4,740-$8,122); skin/subcutaneous, –$900 (95% CI = –$1,899-$237); central nervous system/psychiatric, $5,903 (95% CI = $3,842-$8,313); and pain, $5,078 (95% CI = $3,392$7,012). CONCLUSIONS: Incremental costs associated with many MM treatmentrelated AEs are substantial. New approaches to prevent and/or better manage these events may reduce overall health care costs.

Mollaret meningitis is a rare form of meningitis that is recurrent, aseptic, mild, and self-limiting. When initially described by Mollaret, this form of aseptic meningitis had no identifiable infecting agent.[1][1] New sophisticated diagnostic tools have now identified Herpes simplex type 2 virus as