Citations

348 Background: Neuroendocrine tumor progression is associated with decline in quality of life, both due to tumor and hormone-related symptoms. The Phase III NETTER-1 trial randomized patients with advanced, progressive midgut NETs to receive treatment with 177Lu-DOTATATE (177Lu; Lutathera) versus high-dose (60 mg) Octreotide LAR (Oct). EORTC questionnaires C30 and GINET21 were assessed during the trial in order to determine the impact of treatment on health-related quality of life (HRQoL). Methods: Patients completed EORTC QLQ-30 and QLQ-G.I.NET21 questionnaires at baseline and every 12 weeks thereafter until disease progression. Raw scores were converted to a 100-point scale and individual changes from baseline scores were assessed. Clinically relevant ( ≥ 10 point) deterioration/improvement was considered clinically significant. Results: Clinically and statistically significant improvements in QoL were observed in the 177Lu arm versus the Oct arm at certain time points in key domains of HRQoL including global health status and diarrhea. In mean, global health status improved in 28% of patients on 177Lu arm vs. 15% on Oct, and worsened in 18% of patients on 177Lu vs. 26% on Oct. Diarrhea improved in 39% of patients on 177Lu vs. 23% on Oct, and worsened in 19% of patients on 177Lu vs. 23% on Oct. There was a trend towards improvement in pain that was not statistically significant. Flushing appeared to improve compared to baseline in both arms of the study with no clear advantage to treatment with 177Lu vs. Oct. Conclusions: QoL analysis suggests benefit in important domains associated with 177Lu treatment compared to high-dose octreotide in patients with advanced midgut NETs, and confirms the treatment value of 177Lu on patient QoL, in addition to the meaningful increase in progression-free survival already reported. Clinical trial information: NCT01578239.

Abstract Purpose: Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor–positive (ER+) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. Experimental Design: Eligible patients with clinical stage II/III ER+/HER2− breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1–21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 > 10%, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7%). Results: Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs. C1D1 26%, P < 0.001). Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and PIK3CA status with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression. Conclusions: Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect. Clin Cancer Res; 23(15); 4055–65. ©2017 AACR.

224 Background: In the phase 3 RADIANT-3 trial, everolimus (EVE) demonstrated significantly improved median progression-free survival (PFS) versus placebo (PBO) (11.0 vs 4.6 months; HR=0.35, p < 0.0001) in patients (pts) with pancreatic neuroendocrine tumors (pNET) (Yao et al, NEJM, 2011). Here we present a planned exploratory analysis by prior chemotherapy (chemo) use. Methods: Pts with progressive low- or intermediate-grade pNET were prospectively stratified by prior chemo use and randomized (1:1) to EVE 10 mg/d (n = 207) or PBO (n = 203) plus best supportive care. Results: Of the 410 pts, 206 (50%) had received prior chemo and 204 (50%) were chemo naive. Baseline characteristics (age, sex, race, tumor type, histologic grade) and baseline tumor biomarker levels were similar for pts with/without prior chemo. More chemo-naive pts were newly diagnosed (time since initial diagnosis ≤ 6 mo: 50 [25%] vs. 7 [3%] pts with prior chemo). A lower proportion of chemo-naive pts received prior somatostatin therapy (45% vs. 54% prior chemo). EVE significantly prolonged median PFS regardless of prior chemo use (with prior chemo: 11.0 vs. 3.2 months; HR = 0.35, 95% CI 0.25-0.49, p < 0.001; chemo naive: 11.4 vs. 5.4 months; HR = 0.42, 95% CI 0.29-0.60; p < 0.001). Stable disease was the best overall response in 73% of EVE-treated pts irrespective of prior chemo use. The benefit from EVE irrespective of prior chemo was further demonstrated by disease stabilization or minor tumor shrinkage and in the lower incidence of progressive disease in waterfall plots. Safety of EVE was consistent regardless of prior chemo use. The most common drug-related adverse events (chemo vs chemo naive) included rash (53% vs. 52%), stomatitis (52% vs. 56%), diarrhea (41% vs. 52%), and fatigue (37% vs. 51%). Conclusions: This planned subgroup analysis demonstrated the beneficial effects of EVE in pts with pNET regardless of prior chemo use. These findings support the possible first-line use of EVE for pts with pNET.

CRA1008 Background: S0221 is a SWOG-coordinated phase III adjuvant chemotherapy intergroup trial in node-positive and high-risk node-negative operable breast cancer which hypothesized that 1) the weekly AC+G regimen is superior to ddAC x 6 and 2) 12 weeks of weekly paclitaxel (wP) is superior to q 2 week paclitaxel x 6 (ddP). Methods: Between December 2003 and November 2010, 2,716 patients were randomized in a 2 x 2 factorial design to 1) AC+G vs ddAC and 2) P 80 mg/m2/week x 12 vs P 175 mg/m2 q 2 weeks x 6. If there was no significant interaction between the factors, the trial was powered to find a disease-free survival hazard ratio (HR) ≤ 0.82 for weekly vs q 2 week for each factor. At the first interim analysis, the AC randomization was halted for futility, and S0221 was closed to accrual 10 November 2010. S0221 reopened 15 December 2010, after which time all patients received 4 cycles of ddAC and randomization to P weekly x 12 and ddP x 6 continued. Accrual halted at a total of 3,294 in January 2012. Results: By September 7, 2012, 487 events and 340 deaths had occurred, prompting the third planned interim analysis. The Data Safety and Monitoring Committee recommended reporting the results since the futility boundary was crossed. A Cox model adjusting for the AC arms had a HR = 1.08 (95% CI 0.90-1.28; p=0.42), with the 99.5% CI excluding the original alternative hypothesis that the HR=0.82. There was no significant interaction of the two factors. Estimated 5-year progression-free survivals were 82% for weekly P and 81% for ddP. Toxicity data were available for 1,385 patients treated with ddP and 1,367 treated with weekly P. Grade 5 toxicity occurred in 4 patients on ddP and 2 on weekly P. Percent grade 3-4 toxicity per arm are shown in the Table. Conclusions: Either ddPx6 or weekly P x 12 are acceptable schedules of P administration. The differences in leukopenia likely reflect ascertainment bias against weekly P. If this is accepted, weekly P x 12 produces less overall toxicity than 6 cycles of ddP. Support: NCI grants CA32102, CA38926, CA21115, CA21076, CA77597, CA25224, CA77202, CCSRI15469, and Amgen, Inc. Clinical trial information: NCT00070564. [Table: see text]

194 Background: Currently, there are limited therapeutic options for patients with advanced midgut neuroendocrine tumors progressing on first-line somatostatin analog therapy. Methods: NETTER-1 is the first Phase III multicentric, randomized, controlled trial evaluating 177Lu-DOTA0-Tyr3-Octreotate (Lutathera) in patients with inoperable, progressive, somatostatin receptor positive midgut NETs. 230 patients with Grade 1-2 metastatic midgut NETs were randomized to receive Lutathera 7.4 GBq every 8 weeks (x4 administrations) versus Octreotide LAR 60 mg every 4-weeks. The primary endpoint was PFS per RECIST 1.1 criteria, with objective tumor assessment performed by an independent reading center every 12 weeks. Secondary objectives included objective response rate, overall survival, toxicity, and health-related quality of life. Results: Enrolment was completed in February 2015, with a target of 230 patients randomized (1:1) in 36 European and 15 sites in the United States. At the time of statistical analysis, the number of centrally confirmed disease progressions or deaths was 23 in the Lutathera group and 67 in the Octreotide LAR 60 mg group. The median PFS was not reached for Lutathera and was 8.4 months with 60 mg Octreotide LAR [95% CI: 5.8-11.0 months], p < 0.0001, with a hazard ratio of 0.21 [95% CI: 0.13-0.34]. Within the current evaluable patient dataset for tumor responses (n = 201), the number of CR+PR was 19 (18.8%) in the Lutathera group and 3 (3.0%) in the Octreotide LAR 60 mg group (p < 0.0004). Although the OS data were not mature enough for a definitive analysis, the number of deaths was 13 in the Lutathera group and 22 in the Octreotide LAR 60 mg group (p < 0.019 at interim analysis) which suggests an improvement in overall survival. Conclusions: The Phase III NETTER-1 trial provides evidence for a clinically meaningful and statistically significant increase in PFS and ORR, and also suggests a survival benefit in patients with advanced midgut NETs treated with Lutathera. Clinical trial information: NCT01578239.

260 Background: Recent placebo-controlled phase III trials of the mTOR inhibitor everolimus and the VEGF/ PDGF receptor inhibitor sunitinib in PNET noted improved progression-free survival (PFS). However, objective response rates (RR) with these agents are <10%. Preclinical studies suggest enhanced anti-tumor effects with combined mTOR and VEGF targeted therapy. Methods: We conducted a phase II trial of the mTOR inhibitor TEM (25 mg IV q week) and the VEGF-A monoclonal antibody BEV (10 mg/kg IV q 2 weeks) in patients (pts) with well or moderately differentiated PNET and progressive disease by RECIST within 7 months of study entry. Co-primary endpoints were RR and 6-month PFS. Planned enrollment is 50 patients, with interim analysis after the first 25 evaluable pts. Pts had no prior mTOR or VEGF targeted agents, ECOG PS 0-1, and adequate hematologic and organ function. Continued octreotide was allowed, but not required. Prior interferon, embolization, and ≤ 2 chemotherapy regimens were allowed. Results: Confirmed PR was documented in 11 of the first 25 (44%) evaluable patients. 20 of 25 (80%) patients were progression-free at 6 months. Both endpoints exceeded pre-defined criteria to continue enrollment. For 35 evaluable patients, the most common grade 3-4 adverse events attributed to therapy were leukopenia (12%), hypertension (12%), hyperglycemia (12%), mucositis (9%), and fatigue (9%). Conclusions: The combination of TEM/BEV has substantial activity in a multi-center phase II trial with RR of 44%, well in excess of single targeted agents in PNET. 6-month PFS was a notable 80% in a population of patients with RECIST criteria progression within 7 months of study entry. Accrual is ongoing. Supported by NCI N01 Contracts: 662205, 62203, 62208, 62209, 62206, 62204, 62207, 62201.

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 < 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 < 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]

Purpose Everolimus improved median progression-free survival by 6.4 months in patients with advanced pancreatic neuroendocrine tumors (NET) compared with placebo in the RADIANT-3 study. Here, we present the final overall survival (OS) data and data on the impact of biomarkers on OS from the RADIANT-3 study. Methods Patients with advanced, progressive, low- or intermediate-grade pancreatic NET were randomly assigned to everolimus 10 mg/day (n = 207) or placebo (n = 203). Crossover from placebo to open-label everolimus was allowed on disease progression. Ongoing patients were unblinded after final progression-free survival analysis and could transition to open-label everolimus at the investigator’s discretion (extension phase). OS analysis was performed using a stratified log-rank test in the intent-to-treat population. The baseline levels of chromogranin A, neuron-specific enolase, and multiple soluble angiogenic biomarkers were determined and their impact on OS was explored. Results Of 410 patients who were enrolled between July 2007 and March 2014, 225 received open-label everolimus, including 172 patients (85%) randomly assigned initially to the placebo arm. Median OS was 44.0 months (95% CI, 35.6 to 51.8 months) for those randomly assigned to everolimus and 37.7 months (95% CI, 29.1 to 45.8 months) for those randomly assigned to placebo (hazard ratio, 0.94; 95% CI, 0.73 to 1.20; P = .30). Elevated baseline chromogranin A, neuron-specific enolase, placental growth factor, and soluble vascular endothelial growth factor receptor 1 levels were poor prognostic factors for OS. The most common adverse events included stomatitis, rash, and diarrhea. Conclusion Everolimus was associated with a median OS of 44 months in patients with advanced, progressive pancreatic NET, the longest OS reported in a phase III study for this population. Everolimus was associated with a survival benefit of 6.3 months, although this finding was not statistically significant. Crossover of patients likely confounded the OS results.