Citations

94 Background: Technetium (Tc99m) trofolastat (USANC) is a novel urea-based small molecule SPECT radiotracer with utility in imaging overexpression of PSMA in prostate cancer (PCa). Unlike earlier agents targeting PSMA, this ligand is rapidly internalized and retained in tumors. We conducted an open-label, multicenter phase 2 study in the US and Europe (NCT01667536). An interim analysis was performed at approximately 50% accrual. Methods: Patients (pts) with confirmed adenocarcinoma of the prostate scheduled for RP with EPLND at high risk for disease outside of the prostate gland were eligible. High risk pts were ≥cT3 or Kattan nomogram score ≥130. Within 30 days of screening, pts required a bone scan and pelvic MRI. After enrollment, pts received trofolastat followed by whole-body planar and SPECT/CT imaging 3 to 6 hrs later. Pts then underwent RP with EPLND within 21 days. SPECT/CT images were evaluated centrally by 3 readers blinded to clinical information and compared to on-site pathology assessments using a common scoring template. The primary endpoint was the ability of trofolastat to detect PCa within the gland. Secondary endpoints included detection of extent and location within the gland, pelvic lymph nodes and comparative performance against MRI. Results: 84 pts were enrolled to date from 16 centers. Interim data is available for 54 pts. A majority (≥2/3) of SPECT/CT readers correctly identified the presence or absence of primary PCa in 51/54 (94%, 85-98 95% CI) patients including 2 true-negative cases treated with neoadjuvant enzalutamide. Sensitivity and specificity were 94% (84-98 95% CI) and 100% (34-100 95% CI) respectively. Conclusions: Based on the interim data available, trofolastat has accurately detected primary prostate carcinoma within the gland with high sensitivity and specificity in high-risk pts prior to surgery. Updated results, analyses of secondary endpoints, pelvic lymph nodes, and comparative performance vs. MRI from this ongoing study will be presented. Clinical trial information: NCT01667536. [Table: see text]

326 Background: Review initial outcomes for patients enrolled on the University of Florida Proton Therapy Institute PC01 protocol for patients with unresectable pancreatic cancer. Methods: The protocol received Institutional Review Board (IRB) approval in 7/2007. The first patient was enrolled in 4/2010. The accrual target was 66 patients to test if the Serious Adverse Event (SAE) ratecould be reduced from 15% (expected) to less than 5%. Protocol therapy consisted of proton therapy to a planning target volume (PTV) dose of 59.4 Cobalt Gray Equivalent (CGE) at 1.8CGE per fraction with concomitant oral Capecitabine (1000mg PO BID 5 days/week on radiation treatment days). Only gross disease was targeted. Results: 12 patients were enrolled. 1 patient died of a gunshot wound 5 days after starting treatment so only 11 patients are reported. Median follow up from start of treatment: 13 months (range 2 to 21 months). Median age: 68 (range 51 to 86) years. Gender: Males 5, Females 6. Race/Ethnicity: 9 White, 2 Hispanic. Overall survival: 90% at 6 months and 60% at 12 months. Freedom from progression: 80% at 6 months and 53% at one year. Local control: 100% at 6 months and 86% at 12 months. Freedom from metastasis: 80% at 6 months and 67% at 12 months.No patient experienced any grade 3 or greater toxicity during treatment or the follow up period. Grade 2 toxicity was limited to a single patient experiencing grade 2 fatigue. Median weight loss over the course of treatment was 1.7 (range: loss of 5.7 to gain of 4.9) Kg. 4 patients were deemed to have had an adequate radiographic response to radiotherapy so as to justify surgical exploration. Conclusions: Proton therapy to 59.4 CGE with concomitant Capecitabine was well tolerated with no grade 2 or greater gastrointestinal toxicities. 4 of 11 patients achieved a radiographic response allowing for attempted surgical resection. The study was closed to accrual on 9/1/2013 due to recognition that slow accrual made achievement of the primary study endpoint unlikely. At the same time, the lack of any meaningful gastrointestinal toxicity suggests significant opportunities for treatment intensification when proton therapy is used in this setting. Clinical trial information: NCT00685763.

94 Background: Octogenarian breast cancer (BrCa) patients accept less aggressive BrCa treatment due to decreased life expectancy, increased comorbidities, and high likelihood of death from other causes. Unfortunately little data exist stratifying octogenarian outcomes by disease risk. We sought to characterize treatment and recurrence patterns in patients >80yo. Methods: Retrospective review identified 432 women >80yo treated surgically for stage 0-3 BrCa between 11/99-8/11. We gathered clinicopathologic data and classified patients by disease risk as DCIS only, low risk (<2cm and ER positive and node negative), or high risk (>2cm or ER negative or node positive). We compared recurrence rates and estimated survival by Kaplan-Meier curves. Results: Among the 432 women, disease was found by mammogram in 86%, treated with BCT in 64%, and predominantly ER-positive (87%). We classified patients as having DCIS only (N=61), low risk (N=205), or high risk (N=166) disease. We identified the following deviations from standard treatment guidelines: 68% DCIS BCT and 38% high risk BCT patients did not have radiation therapy, 25% low risk BCT patients had surgery only, 51% low risk patients did not take adjuvant hormonal therapy, and 40% high risk patients had no adjuvant chemo/hormonal therapy. At 5 and 10 years the overall estimated survival was 63% and 31%, respectively. Overall, 19/432 (5%) patients developed recurrence (table 1). Patients needing mastectomy for high risk disease had significantly higher risk of recurrence than high or low risk BCT patients (p=0.02). Of the 19 recurrence patients, 7/19 (37%; 1 DCIS, 1 low risk, 5 high risk) occurred despite standard multimodality treatment, while12 (63%; 3 low risk, 9 high risk) had the initial tumor treated less aggressively due to patient choice (n=9) or medical co-morbidities (n=3). Conclusions: Significant deviations from treatment guidelines occur in women >80yo. Those with high risk disease should be counseled accordingly and encouraged to receive adjuvant treatment as two thirds of women >80yo will live at least 5 years. [Table: see text]

111 Background: Limited data exist on patient (pt) experience and work productivity (WP) in MBC. VIRGO is a prospective OCS following >1,200 pts with locally advanced or MBC receiving 1st-line hormonal therapy (HT) or chemotherapy (CT) in a real-world setting. We report baseline characteristics of 277 pts from the VIRGO PRO substudy and correlations between health-related quality of life (HRQoL), symptoms, activities of daily living, and WP. Methods: Symptom severity and interference (M.D. Anderson Symptom Inventory [MDASI]), functional status (Activity Level Scale [ALS] from the Rotterdam Symptom Checklist) and WP (Work Productivity and Activity Impairment Questionnaire) were assessed. Pts rated their HRQoL during the past week on a scale of 0–10. Results: See table. The five most severe symptoms at baseline were fatigue, decreased sexual interest, disturbed sleep, drowsiness, and emotional distress; these were reported with less severity in the HT cohort (24%-37% vs 42%-59%). Overall MDASI severity and interference correlated with WP measures in the CT (R=0.46 to 0.78) and HT cohorts (0.36 to 0.94). Mean of the 5 most severe symptoms also significantly correlated with WP indices (R=0.47 to 0.66). HRQoL correlated (p<0.05) with all WP measures (R=-0.46 to -0.56) in the CT cohort and with % impairment while working (R=-0.65) and % overall work impairment (R=-0.71) in the HT cohort. In univariate regression analysis, MDASI symptom interference score was the best predictor of reduced WP (R2=0.52 while working; R2=0.48 for non-work activities). Conclusions: MBC pts receiving CT and HT report significant work impairment. Results indicate moderate correlations between WP indices, HRQoL and symptom burden. [Table: see text]

368 Background: SGN-75 is an antibody-drug conjugate composed of a humanized anti-CD70 mAb conjugated to the microtubule-disrupting agent MMAF via a plasma-stable linker. Upon binding to CD70, SGN-75 internalizes and releases cys‑mcMMAF which binds tubulin and induces G2/M arrest and apoptosis. Methods: A phase 1, dose-escalation, multicenter study was initiated to investigate the safety, tolerability, PK, and antitumor activity of SGN-75 monotherapy in pts with CD70-positive metastatic RCC or relapsed/refractory NHL (ClinicalTrials.gov #NCT01015911). SGN-75 was administered IV in cohort-specific doses using 2 schedules [every 3 weeks (q3wk) or weekly (days 1, 8, 15 q28 days)] at doses of 0.3-4.5 mg/kg. Pts were eligible to receive treatment until PD. Results: A total of 58 pts (39 RCC/19 NHL) with a median age of 60.5 yrs (range 30-82) were treated. The MTD was 3 mg/kg q3wk; 2 pts had DLTs at 4.5 mg/kg q3wk (NHL pt had neutropenia and RCC pt had proteinuria). Weekly dosing (N=11) was terminated at the 0.6 mg/kg dose level after 2 pts with NHL developed idiopathic thrombocytopenic purpura. At the MTD, adverse events (AEs) in ≥30% of RCC pts (N=21) were fatigue (52%), dry eye (48%), nausea (38%), constipation (33%), and corneal epithelium defect (33%). AEs ≥ Grade 3 in >10% of RCC pts treated at the MTD were corneal epithelium defect (19%) and thrombocytopenia (14%). PK analysis suggested that SGN-75 exposure was approximately dose-proportional with a mean terminal half-life of 6-11 days. Among the 32 pts with RCC treated in the q3wk schedule, all had prior nephrectomy and a median of 3 prior therapies (range 1-6). All pts had clear cell RCC, with the exception of 2 pts who had papillary RCC. Most pts had high CD70 expression by central IHC analysis (2 or 3+, 80-100% of cells). The best clinical responses of RCC pts treated q3wk were 2 PR, 12 SD, 12 PD, and 6 were not evaluable. Durations of response for the 2 responding pts were 23 and 41 weeks. The median duration of disease control (PR and SD) was 46.4 weeks [95% CI (12, 46)]. Conclusions: SGN-75 monotherapy was generally well tolerated in pts with metastatic RCC. Evidence of antitumor activity was observed in heavily pretreated RCC pts and further studies of SGN-75 in RCC are warranted. Clinical trial information: NCT01015911.

287 Background: Our preliminary immunohistochemical studies of bladder cancer patients have shown that the inflammatory/immune responses associated with bladder cancer appear to be Th2-polarized as judged by the preponderance of tumor infiltrating GATA-3+ (Th2) vs. T-bet+ (Th1) T cells, as well as by evidence of tumor-associated eosinophil infiltration and activation. The standard-of-care treatment for Tis bladder cancer is intravesical administration of BCG, a Th1-polarizing immunomodulator. The aim of the present study was to assess the Th2/Th1 ratio correlation with response to BCG therapy in patients with Tis bladder cancer. Methods: Two groups of patients were studied. Group A included 20 patients that responded to BCG, and Group B included 20 patients that did not respond to therapy. Response to BCG was determined as presence/absence of disease at 6 months post-BCG therapy. The initial diagnostic biopsies of these patients were subjected to immunohistochemical analysis using commercially available antibodies specific for Th2 (GATA-3+) and Th1 (T-bet+) lymphocytes, and our unique monoclonal antibody specific for eosinophil peroxidase (EPX-mAb). Ten random high powered (400X) fields at the maximum focus of mononuclear infiltration were examined and the number of GATA 3+ and T-bet+ tumor infiltrating T cells were counted to define the G/T ratio for each patient sample. Eosinophils and their degranulation activity were counted in the same fields. Results: Patients with response to BCG therapy had a G/T ratio of ≥ 3 and patients with non-response to BCG therapy had a G/T ratio of ≤ 1.5. Correlation of these scores with subsequent patient outcomes following BCG immune therapy demonstrated that patient responsiveness (i.e., tumor elimination at 6 months) trended with the higher G/T ratio patients. In addition, initial biopsies of BCG responsive patients display a higher number of eosinophils and degranulation relative to BCG non-responsive patients. Conclusions: Evaluations of initial biopsies revealed a strong correlation between Th1 and Th2 immune response with BCG therapy outcomes. The development of specific and novel tools to identify/measure Th2 immune responses in Tis bladder cancer provides a unique opportunity to predict outcomes at the time of diagnosis.

702 Background: Median overall survival (OS) in mCRC has significantly improved over the past 20 yrs, but the observed range of OS in pts remains wide; a large percentage of pts have OS <1 yr or >4 yrs. ARIES was a prospective OCS conducted from 2006–2012 that evaluated outcomes in pts receiving BV + chemotherapy (CT) for mCRC in general clinical practice. The objective of this analysis is to examine clinical characteristics of pts with long vs short OS. Methods: This analysis included 1,417/1,550 first-line (1L) BV-treated mCRC pts who died or had complete follow-up on study. Long OS was defined as OS within the upper quartile of the analysis population (range 42–67 mos); short OS was defined as OS within the lower quartile (range 0.3–12 mos). Progression-free survival (PFS) was estimated using Kaplan-Meier methods. Pt and disease characteristics and treatment patterns were described using summary statistics. Results: Pt and disease characteristics are shown in the Table. Median PFS was 22.3 mos (95% CI, 19.9–23.3) vs. 4.9 mos (95% CI, 4.6–5.4), in the long-OS vs. short-OS groups. More pts with long OS received any second-line (2L) therapy (71% vs. 46%), and were exposed to 5-fluorouracil, oxaliplatin, and irinotecan throughout the course of their disease (53% vs. 32%) compared with pts with short OS. KRAS/BRAF mutation status was not collected. Conclusions: Pts with long OS had better baseline performance status, primary tumors more likely to have been resected, and were more likely to have received 2L CT. Additional analyses of detailed treatment patterns and safety are ongoing. Clinical trial information: NCT00388206. [Table: see text]

541 Background: A long wait-time for colectomy for colon cancer should theoretically affect survival but, to date, the association between delay to colectomy and survival remains unresolved. Methods: We studied 4,692 patients who underwent colectomy for colon cancer between 1990 and 2012. Wait-time was defined as the number of days between diagnosis and colectomy. Cox regression models were used to estimate all-cause mortality across wait-time categories. Multivariable analyses were controlled for clinicopathologic variables and Charlson comorbidity index. Results: The number of patients in the wait-time group of 1-28 days was 3,950 (84.2%), 29-84 days was 681 (22.7%), and >84 days was 61 (1.3%). A wait-time of 29-84 days was not associated with an increased risk of death (HR=1.13; p=0.056) when compared to a wait-time of 1-28 days. Though a wait-time >84 days represented a small group, it was associated with an increased risk of death (HR=1.60; p=0.013). For patients with stage I and II disease, wait-times of 29-84 days (HR =1.44; p=0.0001) and >84 days (adjusted HR=2.24; p=0.0007) were associated with an increased risk of mortality. Conclusions: A wait-time for colon cancer surgery of up to 12 weeks is likely safe for most patients. However, those suspected to have early-stage colon cancer may benefit from less of delay. These data provide a framework to address concerns over prolonged wait-times and can direct efforts for timely surgical intervention in patients with colon cancer. [Table: see text]

501 Background: Predictive biomarkers of response to targeted therapy are lacking in renal cell carcinoma (RCC). We evaluated a cohort of RCC patients referred for molecular profiling to identify potentially actionable recurrent molecular aberrations. Methods: 166 consecutive renal cases referred to Caris Life Sciences over 2 yrs were evaluated with central pathology review. Cases were subtyped into clear cell (ccRCC), n=100, papillary (PRCC), n=20, sarcomatoid, n=10, translocation, n=6, medullary, n=4 or unclassified, n=26. 63% of cases were metastatic. Testing included a combination of sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]), and/or gene amplification (CISH or FISH). Results: ccRCC had a 52% loss of PTEN, while PRCC had a 21% loss (p value=0.02). 100% of ccRCC with sarcomatoid features (4) showed aberrant expression of PD-L1 and were infiltrated with PD-1+ tumor infiltrating lymphocytes; 100% of 10 non-ccRCC sarcomatoids also had aberrant expression of PD-L1. Loss of PBRM1 expression was observed in 60% of ccRCC. Loss of histone 3 lysine 36 trimethylation (H3K36me3), which is associated with SETD2 mutations, was observed in 30% of ccRCC. TOP2A was overexpressed in ccRCC at 30% and in non-ccRCC at 50%. 100% of ccRCC and PRCC overexpressed EGFR; a single unclassified renal cell carcinoma did not overexpress EGFR. 50% of cases had cMET overexpression, amplification, or mutation. HER2 was not amplified or overexpressed in any RCC; a single rare HER2 mutation (R816H) was found in a collecting duct carcinoma. VHL mutations were identified in 50% of ccRCC tumors. We observed lower rates of TP53 (14%), ATM (6%), and PIK3CA(4% ccRCC, 7% PRCC) mutations compared to other cancers. Conclusions: Multiplatform molecular profiling of renal cell carcinoma identifies potential predictive biomarkers in ccRCC. The documented activity of everolimus in ccRCC (RECORD-1 trial) may be attributable to PIK3CA pathway alterations. RCC with sarcomatoid features may respond to PD1/PD-L1 targeted immunotherapies. The impact of molecular profiling in ccRCC to predict responses to currently available targeted therapy has important implications for trial design and patient selection.

LBA7005 Background: The phase III HELIOS study evaluated the first-in-class, oral covalent BTK inhibitor ibrutinib in combination with BR (BR+ibr) vs BR plus placebo (BR+plb) in patients (pts) with previously treated CLL/SLL. The preplanned interim analysis reported here showed that the primary end point was met, upon which the IDMC recommended unblinding the study. Methods: Pts received BR ( ≤ 6 cycles) and were randomized 1:1 to ibr (420 mg daily) or plb. Purine analog refractoriness was a stratification factor. Pts with del17p ( > 20% of cells) were excluded. Primary end point was independent review committee (IRC)-assessed progression-free survival (PFS). Secondary end points included overall survival (OS) and overall response rate (ORR) per IRC. Results: 578 pts were randomized (289 per arm); median age 64 yrs; 38% Rai Stage III/IV; median 2 prior therapies. 6 cycles of BR were completed in 83% and 78% of pts in the ibr and plb arms, respectively. At a median follow-up of 17.2 months, IRC-assessed PFS was significantly longer with BR+ibr vs BR+plb (median not reached vs 13.3 months; HR: 0.203, 95% CI: 0.150-0.276, P< 0.0001); PFS results were consistent across high-risk subgroups. ORR and CR/CRi rates were 82.7% vs 67.8% (P< 0.0001) and 10.4% vs 2.8%. Median OS was not reached. 90 pts (31%) in the BR+plb arm with confirmed PD crossed over to receive ibr, as permitted per the protocol. Incidence of most AEs was similar between arms. The most common all-grade AEs with BR+ibr and BR+plb were neutropenia (58.2% vs 54.7%) and nausea (36.9% vs 35.2%); most common grade 3/4 AEs were neutropenia (53.7% vs 50.5%) and thrombocytopenia (15.0% each arm). Rates of grade 3/4 atrial fibrillation were 2.8% and 0.7%, and major hemorrhage were 2.1% and 1.7%. Fatigue (FACIT-Fatigue) was improved with BR+ibr vs BR+plb. Conclusions: The addition of ibr to BR reduced the risk of progression or death by 80% compared with BR+plb. ORR was also significantly improved. Safety of BR+ibr was consistent with the known profiles for BR and ibr. The data further support ibr as an important treatment option for pts with previously treated CLL/SLL. Clinical trial information: EudraCT No. 2012-000600-15; UTN No. U1111-1135-3745.