Strosberg, Jonathan

4099 Background: There is strong rationale to combine an m-TOR inhibitor (TEM) with a VEGF inhibitor (BEV) as a potentially active and well tolerated treatment for HCC. Both agents have shown modest single agent activity in HCC and so evaluated here in a phase II trial. Methods: A modified 2-stage Simon design planned 25 or 50 patients (pts) to test the null hypothesis that true tumor response rate is at most 10% andtrue 6-mo progression-free survival rate (PFS) (by RECIST) is at most 65%, or no better than single agent BEV (6 mo PR >2 pts or PFS 6 mo >18 out of 25.) Toxicity, TTP, PFS and survival were 2nd endpoints. Eligible pts had confirmed HCC with disease unresectable or amenable to other localised therapies, Child Pugh A liver status and no prior systemic therapy involving the VEGF or m-TOR class of agents. TEM was administered at starting dose 25 mg IV d1,8,15,22 with BEV at 10mg/kg IV d 1, 15, all q 28 days (1 cycle). Imaging was q 8 wks. Results: From 09/09 to 09/11, 27 eligible pts were enrolled with 25 evaluable for toxicity and efficacy. Med age 59 yrs, 85% male, PS 0/1: 35/65, 58% metastatic, >85% BCLC stage C. With med 6 cycles (range 1-14) delivered, most pts (88%) experienced a grade 3+ adverse event (a/e.) Common grade 3 a/es related to treatment included thrombocytopenia (40%), neutropenia (20%), leucopenia (12%), fatigue (8%), anemia, mucositis, dyspnea, diarrhea, bleeds, fistula, infections (4% each). There was one possible treatment related death. Per protocol dose reductions/discontinuation for TEM-related a/es were most common. There were 2 confirmed PRs and 16 pts progression-free by 6 mos. A third pt developed a late PR at cycle 13. Median TTP on study was 6 mos, median PFS was 7.4 mos and median survival was 8.3 mos, with 13 pts still alive. Accrual closed at end of stage 1 as neither the number of responses nor the PFS at 6 mos passed the futility stopping rule set for this combination. Conclusions: This multicenter study is the first HCC trial evaluating the BEV/TEM doublet. Despite manageable toxicity, the ORR and 6 mo PFS did not surpass assumptions based on single agent BEV in HCC. Further study of BEV/TEM combination in this advanced HCC population is not recommended.

4111 Background: The primary statistical analysis for the NETTER-1 trial showed a clinically and statistically significant PFS benefit with 177Lu-DOTATATE vs. high-dose octreotide. 177Lu-DOTATATE treatment was also correlated with a significant delay in time to deterioration in HRQoL. In addition to HRQoL questionnaires, patients were asked to record presence or absence of a range of symptoms in a daily diary. Methods: A Mixed Model Repeated Measures (MMRM) was used to analyze the change, compared to baseline, of the occurrence of abdominal Pain, diarrhea and cutaneous flushing as these symptoms were regarded as the most relevant to judge the overall disease status. For each visit (week = 0, 4, 8, etc.) the number of days with symptoms during the previous period was calculated. At baseline, the number of days with symptoms was counted over the previous 6 weeks, whereas the time frame between visits lasted 4 weeks. Results: The estimated number of days with symptoms declined significantly more in the 177Lu-dotatate arm compared to the octreotide arm. The difference in change and the confidence intervals for the symptoms abdominal pain, diarrhea and flushing of skin are, respectively: -3.11 [-4.88; -1.34], -3.11 [-5.04; -1.18] and -1.98 [-3.88; -0.08]. Conclusions: Analysis of symptom diaries confirms that 177Lu-Dotatate can palliate clinically relevant symptoms when compared to high-dose octreotide.

4005 Background: Patients (pts) with progressive advanced well-differentiated neuroendocrine tumors arising outside of the pancreas have limited systemic treatment options. Pazopanib (PZ) is an oral multi-kinase inhibitor with activity against VEGFR-2,-3, PDGFR-α, and β, and c-KIT, with initial data suggesting efficacy in CARC. Methods: This was a multicenter, randomized, double-blind, phase II study of PZ (800 mg/day) versus placebo (PL) in progressive CARC. Key eligibility: low-intermediate grade CARC, radiologic progressive disease (PD) < 12 months (mo), and adequate end-organ function. Prior somatostatin analog (SSA) mandated for midgut tumors. Concurrent SSA allowed if previous PD on SSA documented. Primary endpoint was progression-free survival (PFS), defined as time from randomization to PD by central review or death. Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. The trial had 85% power to detect a difference in median PFS of 14 v 9 mo (hazard ratio [HR] 0.64) at one-sided alpha = 0.1. A stratified log-rank test based on the intend-to-treat (ITT) principle was used. Unblinding and crossover were allowed if PD confirmed by central review. Results: 171 (97 PZ, 74 PL) pts were randomized between 6/2013-10/2015: median age 63; 56% female; 66% small bowel primary; 87% concurrent SSA. Median follow-up of 31 mo; 112 (56 PZ, 56 PL) PFS events observed. 6 pts (4 PZ, 2 PL) remain on initial treatment. Median PFS was 11.6 and 8.5 mo in PZ and PL, respectively (HR = 0.53, 1-sided 90% upper confidence limit [UCL] 0.69, p = 0.0005) which crossed the pre-specified protocol efficacy boundary. 49 PL pts received PZ after PD. Median OS was 41 and 42 mo in PZ and PL, respectively (HR = 1.13, 1-sided 90% UCL 1.51, p = 0.70). RR data will be presented. Notable grade 3+ adverse events were (PZ v. PL %) hypertension (35 v. 8), fatigue (11 v. 4), ALT (10 v. 0), AST (10 v. 0), and diarrhea (7 v. 4). Conclusions: PZ compared to PL was associated with significant improvement in PFS in patients with progressive CARC. The results confirm that VEGF signaling pathway is a valid target for therapy in CARC. Support: U10CA180821, U10CA180882 https://acknowledgments.alliancefound.org . Clinical trial information: NCT01841736.

322 Background: The role of perioperative systemic therapy (PST) is unclear in the management of localized pancreatic neuroendocrine tumor (pNET). We aim to evaluate the benefit of PST compared to surgical resection alone in localized pNET. Methods: We identified patients with stage I–III pNET who underwent curative-intent surgical resection in National Cancer Database from 2006 to 2014. Patients who underwent PST and surgical resection were matched with patients who received surgery alone by propensity score at 1:1 ratio with nearest neighbor method. Factors predicting the use of PST were identified from logistic regression. Survival was estimated with Kaplan-Meier method and compared with Cox proportional hazards regression. Results: 4919 patients were included in this study with median age of 60 years. 1397 (28%) patients had pNET at the head of pancreas. 2708 (55%) patients had pNET at pancreas body and tail. 334 (6.8%) patients received PST. Factors associated with significant more use of PST compared to surgery alone were age < 65 years, low income, community medical facilities, grade 3/4 tumor, tumor at the head of pancreas, T3-4 tumor and N1 tumor. 310 patients in PST group were matched with 310 patients in surgery alone group, with no significant difference for all covariates after match. For those in PST group, 64 (21%) patients received neoadjuvant systemic therapy, 173 (56%) patients received adjuvant systemic therapy, 7 (2.3%) patients received both, and 66 (21%) patients received PST without clear sequence. In the matched cohort, PST group had significantly shorter overall survival (OS) compared to surgery alone group (median OS 91.1 months versus not reached, p = 0.04). This finding was confirmed by multivariable Cox proportional hazards regression in unmatched cohort with HR 1.5 (95% CI 1.2 – 1.9, p = 0.002). Subgroup analysis in patients with grade 3/4 tumor demonstrated PST group has a trend of shorter OS compared to surgery alone group (median OS 34.1 versus 54.4 months, p = 0.1). Conclusions: PST compared to surgery alone is associated with worse OS in patients with localized pNET. This finding suggests that we may use PST in localized pNET with caution in the absence of solid clinical trial data.