Advanced pNET Research Articles

OC-129 Metastatic pancreatic neuroendocrine tumours: does aggressive surgical intervention improve outcome?

IntroductionPancreatic neuroendocrine tumours (PNETS) often present late. At diagnosis 65% of patients have metastases, with median survival of 24 months.1 2 The conventional approach is conservative management. Recent evidence has...

Cost-effectiveness of treating patients with advanced progressive pancreatic neuroendocrine tumors with everolimus versus sunitinib in the United States.

e14525 Background: Everolimus and sunitinib were recently approved to treat patients with advanced, progressive pancreatic neuroendocrine tumors (pNETs). This analysis examined the projected cost-effectiveness of everolimus versus sunitinib in this disease setting from a US payer perspective. Methods: A lifetime (20-year) Markov model was developed to simulate a cohort of advanced, progressive pNET patients and to estimate the cost per life-year (LY) gained and quality-adjusted life-year (QALY) gained when treating with everolimus as compared to sunitinib. Absent head-to-head trials, efficacy data were based on a weight-adjusted indirect comparison of the two agents using the respective phase 3 trial data. Disease or health states considered in the model included: stable disease with no adverse events, stable disease with adverse events, disease progression, and death. Costs of anti-tumor therapies, symptomatic care drugs, and post-progression therapy were based on wholesale acquisition cost. Other costs including physician visits, tests, infusions, hospitalizations, adverse event costs, and end-of-life care costs were obtained from literature and/or standard sources such as the Healthcare Cost & Utilization Project and Medicare reimbursement rates. Utility inputs were based on a time trade-off study conducted in the United Kingdom. Sensitivity analyses were conducted to test the model’s robustness. Results: In the base case analysis, the estimated gain of everolimus over sunitinib was 0.448 LYs (0.304 QALYs) at an incremental cost of $12,673, resulting in an incremental cost-effectiveness ratio (ICER) of $28,281/LY ($41,702/QALY gained), which fell within the cost per QALY range for many other widely used oncology drugs. The ICER was most sensitive to the uncertainty of the sunitinib trial outcomes: however, a probabilistic sensitivity analysis found consistent results across simulations. Conclusions: While the analysis is limited by its reliance on an indirect comparison of two phase 3 studies rather than a single head-to-head trial, everolimus is projected to be cost-effective relative to sunitinib in advanced pNET.

Overall survival with everolimus, sunitinib, and placebo for advanced pancreatic neuroendocrine tumors: A matching-adjusted indirect comparison of randomized trials.

e14621 Background: No randomized trial has compared everolimus (EVE) and sunitinib (SUN) for treatment of advanced pancreatic neuroendocrine tumors (pNET). This study indirectly compared overall survival (OS) with EVE vs. placebo (PBO), and OS and progression-free survival (PFS) with EVE vs. SUN. Methods: Individual patient data were used from the RADIANT-3 trial of EVE 10 mg/day vs. PBO (cutoff: April 2010); published summary data were used from the A6181111 trial of SUN 37.5 mg/day vs. PBO (cutoff: June 2010). To adjust for cross-trial differences, RADIANT-3 patients were subjected to A6181111 exclusion criteria and weighted to match A6181111 baseline demographics, performance status, time since diagnosis, disease sites, distant metastases and prior therapy. After matching, OS was compared between balanced trial populations for EVE vs. the PBO arm from A6181111 (which had access to SUN after progression or early stopping) and vs. the SUN arm. PFS was also compared. Analyses did not adjust for early stopping of A6181111, which may bias towards longer PFS and OS with SUN vs. PBO. Results: 394 patients from RADIANT-3 (after excluding 15 with worse performance status than allowed in A6181111 and 1 missing baseline data) and all 171 patients in A6181111 were included. RADIANT-3 patients differed from A6181111 patients in baseline performance status, prior use of somatostatin analogues, and prior use of systemic chemotherapy before matching. After matching, all baseline characteristics were well-balanced between trials. EVE was associated with significantly prolonged OS vs. PBO in A6181111 (hazard ratio [HR] for death = 0.61, 95% CI = 0.38-0.98, p=0.04), corresponding to a 1-year number needed to treat of 8.3 patients to prevent 1 death. OS and PFS were longer, but not statistically different, with EVE vs. SUN (HR for death = 0.81, 95%CI=0.49-1.31, HR for progression = 0.84, 95% CI=0.46-1.53). Conclusions: After adjusting for cross-trial differences, treatment of advanced pNET with everolimus was associated with significantly prolonged OS compared to placebo. OS and PFS were longer, but not statistically different, with everolimus compared to sunitinib.

Cost-effectiveness of treating patients with advanced progressive pancreatic neuroendocrine tumor with everolimus versus sunitinib in the United States.

226 Background: Everolimus and sunitinib were recently approved to treat patients with advanced, progressive pancreatic neuroendocrine tumors (pNETs). This analysis examines the projected cost-effectiveness of everolimus versus sunitinib in this setting from a US payer perspective. Methods: A lifetime Markov model was developed to simulate a cohort of advanced, progressive pNET patients and to estimate the cost per incremental life-years gained (LYG) and quality-adjusted life years (QALYs) gained when treating with everolimus as compared to sunitinib. Absent head-to-head trials, efficacy data were based on a weight-adjusted indirect comparison of the two agents using the respective phase 3 trial data. Disease or health states considered in the model included: stable disease without adverse events, stable disease with adverse events, disease progression, and death. Costs of anti-tumor therapies, symptomatic care drugs, and post-progression therapy were based on wholesale acquisition cost. Other costs including physician visits, tests, infusions, hospitalizations, adverse event costs, and end-of-life care costs were obtained from literature and/or standard sources such as the Healthcare Cost and Utilization Project and Medicare reimbursement rates. Utility inputs were based on a UK time trade-off study. Sensitivity analyses were conducted to test the model’s robustness. Results: In the base case analysis, the estimated gain of everolimus over sunitinib was 0.448 LYs (0.304 QALYs) at an incremental cost of $12,673, resulting in an incremental cost-effectiveness ratio (ICER) of $28,281/LYG ($41,702/QALY gained), which fell within the cost per QALY range for many other widely used oncology drugs. The analysis was sensitive to the uncertainty of the sunitinib trial results; however, a probabilistic sensitivity analysis showed the results were consistent across simulations. Conclusions: While the analysis is limited by its reliance on an indirect comparison of two phase 3 studies rather than a single head-to-head trial, everolimus is expected to be cost-effective relative to sunitinib in advanced pNET.

Overall survival with everolimus, sunitinib, and placebo for advanced pancreatic neuroendocrine tumors: A matching-adjusted indirect comparison of randomized trials.

237 Background: Everolimus and sunitinib are approved in the US and EU for treating advanced pancreatic neuroendocrine tumors (pNET). No randomized trial has directly compared these treatments for pNET. This study indirectly compared overall survival (OS) with everolimus vs. 1) placebo and 2) sunitinib. Methods: Individual patient data were used from the RADIANT-3 trial of everolimus 10 mg/day vs. placebo (cutoff: April 4, 2010); published summary data were used from the A6181111 trial of sunitinib 37.5 mg/day vs. placebo (cutoff: June 1, 2010). To adjust for cross-trial differences, RADIANT-3 patients were subjected to exclusion criteria used in A6181111 and then re-weighted to match A6181111 in terms of baseline demographics, performance status, time since diagnosis, disease sites, distant metastases and prior therapy. After matching, OS was compared between balanced trial populations for everolimus in RADIANT-3 vs. 1) the placebo arm in A6181111, which had access to sunitinib after early stopping, and 2) the sunitinib arm in A6181111. Progression-free survival (PFS) was also assessed, but was confounded by early stopping of A6181111. Results: Analyses included 394 patients from RADIANT-3 (after excluding 15 with worse performance status than allowed in A6181111 and 1 with missing baseline data) and all 171 patients in A6181111. Before matching, patients in RADIANT-3 had better performance status, more prior use of somatostatin analogues and less prior use of systemic chemotherapy. After matching, these and all other baseline characteristics were well-balanced between trials. Everolimus was associated with prolonged OS vs. placebo in A6181111 (hazard ratio [HR] for death = 0.61, 95% CI = 0.38-0.98, p=0.04). No statistically significant difference was observed with everolimus vs. sunitinib in OS (HR for death = 0.81, 95%CI=0.49-1.31) or in PFS (HR for progression = 0.84, 95% CI=0.46-1.53). Conclusions: After adjusting for cross-trial differences, treatment of advanced pNET with everolimus was associated with prolonged OS compared to treatment with placebo.

Health plan budget impact of introducing everolimus for treatment of advanced progressive pancreatic neuroendocrine tumors in the United States.

229 Background: Everolimus was recently approved for treatment of patients with advanced progressive pancreatic neuroendocrine tumors (pNET) based on a clinically meaningful and statistically significant increase in progression-free survival. To understand the financial impact of introducing everolimus into the market, a model was developed to simulate a typical health plan in the United States (US). Methods: A cross-sectional budget impact model with a one-year time horizon was developed. Disease prevalence and drug usage data were derived from a real-world data source. Costs for anti-tumor therapy and underlying care included concomitant medications, physician visits, treatment infusion, surgical procedures, tests, hospitalizations, and adverse event (AE) management. Resource utilization rates were derived from a physician survey-based resource utilization study; treatment-related AE rates were taken from secondary literature. Drug costs were Wholesale Acquisition Costs (2011). Medical procedure and hospitalization costs were based on Medicare fee schedules for current procedure terminology and diagnosis-related group codes. AE costs were obtained from the literature. The model assessed the initial annual budget impact, under the assumption that everolimus and sunitinib, another recently approved targeted therapy, replace most currently available chemotherapy treatments. Results: Based on published prevalence rates, for a health plan with 1,000,000 members, an annual count of 12 advanced pNET patients was projected. The model estimated a $22,657 budget increase ($0.0019 per member per month or $0.0227 per member per year [PMPY]). The largest percent increase in budget was associated with anti-tumor treatments; infusions and surgical procedures represented the largest percent decrease in costs. Scenario analyses indicated that increasing the percentage of everolimus use (by reducing that of sunitinib) resulted in a decrease in the overall budget compared to baseline. Conclusions: Our model predicts that treating pNET patients with everolimus will have a minimal budget impact on US health plans, amounting to about $0.027 PMPY.

Chromogranin A and Neuron-Specific Enolase as Prognostic Markers in Patients with Advanced pNET Treated with Everolimus

Everolimus, an oral inhibitor of mammalian target of rapamycin, significantly prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumors (pNET). Chromogranin A (CgA) and neuron-specific enolase (NSE) are considered general biomarkers of these tumors. The objective of the study was to evaluate the prognostic value of CgA and NSE in patients with pNET treated with everolimus. Patients with low- to intermediate-grade advanced pNET enrolled in two phase 2 studies [RAD001 in Advanced Neuroendocrine Tumors (RADIANT-1) and single institution phase II study at The University of Texas M. D. Anderson Cancer Center] received everolimus. Blood samples were collected and analyzed by a central laboratory at baseline and monthly thereafter. PFS and overall survival (OS) were evaluated in patients with elevated and nonelevated baseline CgA/NSE levels. In RADIANT-1, elevated vs. nonelevated baseline CgA was associated with shorter median PFS (8.34 vs. 15.64 months; P = 0.03) and OS (16.95 months vs. not reached; P < 0.001). Elevated vs. nonelevated baseline NSE resulted in shorter median PFS (7.75 vs. 12.29 months; P = 0.01) and OS (13.96 vs. 24.90 months; P = 0.005). Median PFS was prolonged in patients with early CgA or NSE response (11.0 vs. 5.0 months) compared with those without early biomarker response. More patients with CgA (87 vs. 50%) or NSE (81 vs. 14%) response experienced tumor shrinkage compared with those without response. CgA response data from the single-institution phase II study at The University of Texas M. D. Anderson Cancer Center study are consistent with data from the RADIANT-1 study. Elevated baseline CgA/NSE provided prognostic information on PFS and survival; early CgA/NSE responses are potential prognostic markers for treatment outcomes in patients with advanced pNET.

Everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET): Updated results of a randomized, double-blind, placebo-controlled, multicenter, phase III trial (RADIANT-3).

4009 Background: In the RADIANT-3 trial, everolimus, an oral inhibitor of mTOR, significantly prolonged progression-free survival (PFS) in pts with advanced pNET (ESMO 2010, Abstract #LBA9). Updated safety and exploratory biomarker analyses from this trial are presented. Methods: Pts with progressive, advanced low- or intermediate-grade pNET were randomized to everolimus 10 mg/d orally (n=207) or placebo (n=203); both arms received best supportive care. The primary endpoint was PFS (RECIST v1.0). Results: Median PFS by investigator assessment with everolimus was 11.0 mo vs with 4.6 mo with placebo (HR=0.35; 95% CI, 0.27-0.45; p<0.0001), resulting in a 65% reduction in the risk for progression. Everolimus compared with placebo resulted in a rapid and significant (p<0.001) reduction in baseline biomarkers, including chromogranin A, neuron-specific enolase, gastrin, and glucagon. Treatment arms were well balanced with respect to on-study somatostatin analog (SSA) use (39%, everolimus arm; 40%, placebo arm). An improvement in median PFS was observed with everolimus vs placebo in pts who received on-study SSA (11.4 mo vs 3.9 mo; HR=0.40; 95% CI, 0.29-0.56) and those without on-study SSA (10.8 mo vs 4.6 mo; HR=0.35; 95% CI, 0.24-0.50). Median safety follow-up is now 20.1 mo. Most common drug-related adverse events (AEs) with everolimus vs placebo were stomatitis (52.9% vs 12.3%), rash (48.5% vs 10.3%), diarrhea (34.3% vs 10.3%), and fatigue (32.4% vs 14.3%). The most common grade 3-4 AEs were anemia (5.9% vs 0%), hyperglycemia (5.9% vs 2.5%), stomatitis (4.9% vs 0%), and thrombocytopenia (3.9% vs 0%). Conclusions: In the RADIANT-3 trial, the largest randomized controlled trial ever completed in pts with progressive advanced pNET, everolimus provided a significant increase in median PFS, irrespective of SSA use, and significant reductions in tumor and secretory biomarkers. Oral stomatitis represented the most common drug-related AE; however, grade 3-4 somatitis was rare. These emerging data, including longer follow-up safety data, support the use of everolimus as a standard of care for pts with progressive, advanced pNET.

Impact of prior chemotherapy on progression-free survival in patients (pts) with advanced pancreatic neuroendocrine tumors (pNET): Results from the RADIANT-3 trial.

4103 Background: In the phase III RADIANT-3 trial, everolimus (EVE), an oral mTOR inhibitor, demonstrated superior progression-free survival (PFS) with a median of 11.0 vs 4.6 mo for placebo (PBO) (HR=0.35; 95% confidence interval, 0.27-0.45; P<0.0001) in pts with advanced pNET (ESMO 2010, Abstract #LBA9). An exploratory analysis of prior chemotherapy use and PFS from the RADIANT-3 trial is presented. Methods: Pts with progressive advanced low- or intermediate-grade pNET were randomized to EVE 10 mg/d orally (n=207) or PBO (n=203); both arms received best supportive care. The primary endpoint was PFS per central review (RECIST v1.0). Pts were stratified by use of prior vs no prior chemotherapy. Results: Overall, 206/410 (50%) pts received prior chemotherapy. Prior chemotherapy use was balanced in both arms: 104/207 (50%) EVE pts vs 102/203 (49%) PBO pts. No difference was observed in baseline characteristics (age, sex, race, tumor type, histologic grade) and baseline tumor biomarker levels for pts receiving prior chemotherapy vs those without. Time since initial diagnosis was >2 years for 147 (71%) pts with prior chemotherapy vs 98 (48%) pts without prior chemotherapy. A higher proportion of pts with prior chemotherapy also had received prior somatostatin therapy (54% prior chemotherapy vs 45% no prior chemotherapy). A positive treatment effect with EVE was observed in pts both with and without prior chemotherapy. EVE significantly prolonged PFS vs placebo in pts with prior chemotherapy (HR=0.34; P<0.0001) and those without prior chemotherapy (HR=0.42; P<0.001). Median PFS with EVE for pts with prior chemotherapy was 11.0 mo vs 11.4 mo for those without prior chemotherapy (HR=1.120; 95% CI, 0.768-1.634; P=0.56). Median PFS with PBO for pts with prior chemotherapy was 3.2 mo vs 5.4 mo for those without prior chemotherapy (HR=1.3; 95% CI, 0.990-1.828; P=0.054). Conclusions: EVE demonstrated significantly longer median PFS than PBO in pts with advanced pNET, regardless of prior chemotherapy use. These results suggest that EVE should be considered a treatment option for pNET pts, including those without prior chemotherapy.

Everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET): Multivariate analysis of progression-free survival from the RADIANT-3 trial.

e21091 Background: In the phase III RADIANT-3 trial, everolimus, an oral mTOR inhibitor, demonstrated superiority in progression-free survival (PFS) with a median of 11.0 versus 4.6 months for placebo (HR=0.35; p<0.0001) in patients with advanced pNET (ESMO 2010, abstract LBA9). In order to determine the factors that significantly influence PFS, a prespecified multivariate analysis was performed. Methods: Patients with progressive advanced low- or intermediate-grade pNET were randomized to receive everolimus 10 mg/d orally (n=207) or placebo (n=203); both arms received best supportive care. Primary endpoint was PFS. Multivariate analysis using a Cox-proportional hazards model was performed on the following factors: treatment; age; sex; WHO performance status; geographic region; prior somatostatin use; baseline CgA; baseline NSE; Ki67; years since diagnosis; liver, bone, or extrahepatic involvement; and number of organs involved. Significant factors (p<0.05) were determined after a stepwise elimination of nonsignificant factors from the model. Results: Multivariate analysis indicated that significant prognostic factors of PFS were treatment (everolimus vs placebo) (p<0.001), WHO performance status (p<0.001), baseline NSE level (p<0.001), and liver involvement (p=0.048). Conclusions: Multivariate analysis of the RADIANT-3 trial has allowed, for the first time, evaluation of prognostic factors associated with PFS in a large phase III, placebo-controlled trial in patients with advanced pNET. A better understanding of these risk factors can help clinicians in the treatment of their patients. Multivariate analysis of PFS. n Events n (%) Median PFS (95% CI) Hazard ratio (95% CI) P Treatment 0.33 (0.26, 0.43) <0.001 Everolimus 207 109 (52.7) 11.04 (8.41, 13.86) Placebo 203 165 (81.3) 4.60 (3.06, 5.39) WHO performance status 1.58 (0.49, 0.82) <0.001 0 272 173 (63.6) 8.15 (5.78, 8.51) ≥1 138 101 (73.2) 5.45 (4.37, 8.75) Baseline NSE 1.95 (1.49, 2.55) <0.001 Elevated 104 81 (77.9) 3.91 (2.83, 5.42) Nonelevated 293 183 (62.5) 8.08 (5.78, 8.54) Liver involvement 1.68 (1.01, 2.80) 0.048 Yes 377 257 (68.2) 5.75 (5.55, 7.98) No 32 17 (53.1) 8.94 (6.18, NA)

Everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET): Impact of somatostatin analog use on progression-free survival in the RADIANT-3 trial.

4010 Background: In the phase III RADIANT-3 trial, everolimus, an oral mTOR inhibitor, demonstrated superiority in progression-free survival (PFS) with a median of 11.0 versus 4.6 mo for placebo (HR=0.35; 95% CI, 0.27-0.45; P<0.0001) in patients with advanced pNET (ESMO 2010, Abstract LBA9). Here we present an exploratory analysis of the impact of long-acting somatostatin analog (SSA) therapy in this trial. Methods: Patients with progressive advanced low- or intermediate-grade pNET were randomized to everolimus 10 mg/d orally (n=207) or placebo (n=203); both arms received best supportive care. Long-acting SSAs were permitted before entry and as best supportive care during the study. The primary endpoint was PFS (RECIST v1.0). Patients who received SSA therapy before and during the study in each treatment arm were identified. Results: Overall, 203 (50%) patients received SSA therapy before study entry, and 163 (40%) received SSA therapy during the study. Of those patients with prior SSA therapy, 145 (71%) also received SSA therapy during the trial. Treatment arms were well balanced with respect to prior SSA treatment (50%, everolimus arm; 50%, placebo arm) and on-study SSA treatment (39%, everolimus arm; 40%, placebo arm). An improvement in median PFS was observed with everolimus compared with placebo in patients who had any SSA (11.4 mo vs 3.9 mo; HR=0.40; 95% CI, 0.29-0.56) and in those without any SSA (10.8 vs 4.6; HR=0.35; 95% CI, 0.24-0.50). The PFS benefit with everolimus was observed across all patients subgroups regardless of SSA use (Table). Conclusions: Everolimus significantly prolonged PFS compared with placebo in patients with advanced pNET in this large phase III clinical trial. This benefit was seen across all patient subgroups, including patients receiving prior and on-study SSA treatment. Hazard ratio (95% CI) Everolimus vs. placebo All patients 0.35 (0.27-0.45) Without concomitant SSA 0.34 (0.25-0.46) With concomitant SSA 0.43 (0.29-0.64) Without prior SSA 0.36 (0.25-0.51) With prior SSA 0.40 (0.28-0.56) Without prior and concomitant SSA 0.34 (0.25-0.47) With prior and concomitant SSA 0.43 (0.28-0.66)

Effect of everolimus treatment on chromogranin A, neuron-specific enolase, gastrin, and glucagon levels in patients with advanced pancreatic neuroendocrine tumors (pNET): Phase III RADIANT-3 study results.

10624 Background: Chromogranin A (CgA), neuron-specific enolase (NSE), gastrin, and glucagon are important biomarkers in pNET. The goals of this analysis were to characterize serum CgA, NSE, gastrin, and glucagon concentration changes from baseline in response to treatment with oral everolimus or placebo in patients with advanced pNET in the phase III RADIANT-3 trial (ESMO 2010, Abstract #LBA9). Methods: Patients with progressive, advanced low- or intermediate-grade pNET were randomized to everolimus 10 mg/d orally (n=207) or placebo (n=203). Serum samples were collected and analyzed for CgA, NSE, gastrin, and glucagon at baseline and, if elevated (>ULN), were repeated on day 1 of each subsequent cycle. Changes from baseline over time were analyzed using a mixed-effects model including least squares estimates and P values of treatment effect. Results: Patients with elevated baseline values had biomarkers assessed for a median number of 10 cycles in the everolimus arm and 4 cycles in the placebo arm. Everolimus vs placebo resulted in greater reductions of CgA (P<0.0001), NSE (P<0.0001), gastrin (P<0.0001), and glucagon (P<0.0001) over time. During the first cycle, the ratio in fold change from baseline for everolimus vs placebo was 0.617/1.081=0.57 (95% CI, 0.45-0.73) for CgA, 0.478/0.951=0.50 (95% CI, 0.32-0.80) for NSE, 0.581/0.833=0.70 (95% CI, 0.52-0.94) for gastrin, and 0.679/1.034=0.66 (95% CI, 0.49-0.89) for glucagon. This positive treatment effect with everolimus was maintained over subsequent treatment cycles; the ratio in fold change from baseline for everolimus vs placebo groups ranged from 0.39-0.57 for CgA, 0.23-0.51 for NSE, 0.46-0.70 for gastrin, and 0.45-0.66 for glucagon. Conclusions: In addition to the improvement in PFS seen in RADIANT-3, these results demonstrate that treatment with everolimus resulted in early, sustained decreases in serum levels of CgA, NSE, gastrin, and glucagon in patients with pNET.

Everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET): Updated results of a randomized, double-blind, placebo-controlled, multicenter phase III trial (RADIANT-3).

158 Background: There is an unmet medical need for effective treatments for patients with advanced pNET. Systemic therapies for advanced pNET are limited both by toxicity and efficacy. Everolimus, an oral mTOR inhibitor, has shown promising antitumor activity in 2 phase II studies, leading to further investigation in the largest phase III randomized controlled trial completed in pNET patients. Methods: Patients with advanced low- or intermediate-grade pNET were randomly assigned to everolimus 10 mg/d orally + best supportive care (BSC; n = 207) or placebo + BSC (n = 203). Long-acting somatostatin analogs (SSAs) were permitted as BSC during the study. The primary endpoint was progression free survival (PFS). At progression (RECIST), patients could be unblinded and those randomly assigned to placebo were offered open-label everolimus. Results: Compared with placebo, everolimus reduced the risk of progression by 65% and increased median PFS by more than 6 months, from 4.6 to 11.0 months (HR = 0.35; 95% CI: 0.27-0.45; p &lt; 0.0001), by investigator review (primary endpoint). Median PFS by central review was consistent (HR = 0.34; 95% CI: 0.26 to 0.44; p &lt; 0.001] in favor of everolimus. Eighteen-month PFS estimates were 34% for everolimus (95% CI: 26-43) vs 9% (95% CI: 4-16) for placebo. Everolimus demonstrated a significant PFS benefit across all patient subgroups according to baseline characteristics and prior SSA use. Prior SSA use was 49% in the everolimus arm and 50% in the placebo arm. Updated analyses of the impact of concomitant SSA will be reported. The most common drug-related adverse events were stomatitis, rash, diarrhea, fatigue, and infections (primarily upper respiratory); most were grade 1 or 2. Stomatitis (6.9% vs 0%), anemia (6% vs 0%), and hyperglycemia (5% vs 2%) were the most common grade 3-4 events. Conclusions: Everolimus significantly prolonged PFS compared with placebo in patients with advanced pNET in this large phase III clinical trial. This benefit was seen across all patient subgroups. Treatment resulted in a significant 6.4-month prolongation in median PFS. Everolimus had an acceptable and predictable safety profile. [Table: see text]

Everolimus versus placebo in Japanese patients with advanced pancreatic neuroendocrine tumors (pNET): Japanese subgroup analysis of RADIANT-3.

289 Background: Everolimus demonstrated a statistically and clinically significant improvement in PFS over placebo in a multi-national, randomized, placebo-controlled, phase III trial in patients with advanced low- or intermediate-grade pNET with disease progression within the prior 12 months (RADIANT-3) (Ann Oncol [2010] 21[suppl 6]: NP doi:10.1093/annonc/mdq340). Forty patients were enrolled from Japanese sites and randomized (n=23: everolimus; n=17: placebo) in that study. The purpose of this report is to investigate the efficacy and safety in the Japanese subgroup. Methods: Subgroup analysis for the Japanese patients was performed comparing the efficacy and safety between everolimus 10mg/d orally plus best supportive care (BSC) and matching placebo plus BSC. The primary efficacy endpoint was progression-free survival (PFS). The safety was evaluated based on the incidence of adverse events (AEs). Results: Treatment with everolimus resulted in a significant prolongation by 16.62 months in median PFS (19.45 months for everolimus, 2.83 months for placebo), with 81% reduction in the hazard ratio of progression/death (HR 0.19 [95% CI: 0.08, 0.48]; one-sided unstratified log-rank test: p&lt;.001). The most common AE was stomatitis (73.9% everolimus vs 23.5% placebo); mostly grade 1/2. Grade 3/4 AEs occurred in 69.5% of the everolimus arm and 29.4% of the placebo arm, and amongst the most frequent included (% in everolimus vs % in placebo): neutropenia (17.4% vs 3%); anemia (8.7% vs 0%); pneumonitis (8.7% vs 0%); leukopenia (8.7% vs 0%). The remainder of grade 3/4 AEs was less than 3%. Median duration of exposure to everolimus was 57 weeks vs 47 weeks on placebo. Treatment discontinuation for AEs was 17% in the everolimus arm vs 0% in the placebo arm. Conclusions: Everolimus demonstrated a clinically meaningful improvement in PFS over placebo in Japanese patients. Everolimus was well tolerated in Japanese patients, and no new safety concerns were noted. This result suggests that everolimus can be a standard treatment for Japanese patients with advanced pNET. [Table: see text]