Employee Of Sanofi Research Articles

Safety, Pharmacokinetics, and Pharmacodynamics of Oral Venglustat in Patients With Parkinson's Disease and a <i>GBA</i> Mutation: Results From Part 1 of the Randomised, Double-Blinded, Placebo-Controlled MOVES-PD Trial

Safety, Pharmacokinetics, and Pharmacodynamics of Oral Venglustat in Patients With Parkinson's Disease and a <i>GBA</i> Mutation: Results From Part 1 of the Randomised, Double-Blinded, Placebo-Controlled MOVES-PD Trial

Burden of Illness Among Medicare and Non-Medicare Populations with Acquired Thrombotic Thrombocytopenic Purpura, 2010-2018

Background and Objective Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare hematologic disorder that causes microvascular thromboses and can lead to serious and life-threatening medical complications. The aim of this study was to describe aTTP-related resource utilization, cost, complications, and overall survival (OS) among US Medicare and non-Medicare populations following aTTP episodes. Methods This retrospective study utilized administrative claims data for Medicare Fee-for-Service (FFS) beneficiaries (100% sample) and a sample of commercial, managed Medicaid [MM], Medicare Advantage [MA] plan members from the Inovalon MORE2 Registry. Patients aged 18+ with aTTP were identified using a validated algorithm (Wahl et al, 2010): ≥1 hospitalization for thrombotic microangiopathy + therapeutic plasma exchange (TPE) between 2010 and 2018. Patients with hemolytic-uremic syndrome or other conditions mimicking aTTP during same hospitalization were excluded. Outcomes included characterization of index hospitalization (including length of stay), diagnosis-related group (DRG) payment amount (2019 US$ [Medicare payments also included outlier payments]), and risk of mortality. OS was compared for Medicare FFS patients with aTTP to a 1:1 matched cohort of Medicare FFS beneficiaries without aTTP (matched on age, gender, region, index year, socioeconomic status, disability insurance benefits, and Charlson comorbidity index score). Median survival time and 1-year/2-year survival rates were estimated using Kaplan Meier methodology and hazard ratio was obtained using Cox proportional hazard model. In a subgroup analysis of aTTP patients across payer channels with at least 6 months of baseline and 1 month of follow-up data, percentage of patients with readmission for TPE (exacerbation if <30 days post-discharge; relapse if >30 days post-discharge) and rate of post-discharge clinical complications per 100 person-years was calculated. Results During the 9-year period, 2,279 patients met the study criteria for aTTP; 65.2% (N=1,486) were enrolled in Medicare FFS: 13.6% (N=312) in commercial, 15.7% (N=358) in MM, and 5.4% (N=123) in MA. Mean (SD) age (in years) varied by payers as expected: Medicare FFS: 65.9 (13.9); MA: 63.8 (13.6); commercial: 45.0 (14.3); MM: 37.5 (14.0). Mean (SD) hospitalization for index event ranged from 12.4 (9.4) to 15.8 (11.8) days; majority of patients required intensive care (Medicare FFS: 61.4% [mean (SD) ICU days: 8.3 (8.2)]; MA: 61.8%; commercial: 62.2%; MM: 60.1%). Among Medicare FFS patients, 15.7% died during initial hospitalization and 21.0% died within first 30 days of the event (mean (SD) time to death: 11.7 (7.2) days). Among matched cohorts of Medicare patients with and without aTTP (N=833 in each cohort), OS was lower for patients with aTTP (Figure 1). Specifically, 1-year survival rates among aTTP patients was 71.8% (95% CI: 68.6%-74.8%) vs. 95.6% (94.0%-96.8%) for those without aTTP. Two-year survival rates among aTTP patients was 66.6% (63.2%-69.8%) vs. 91.1% (88.8%-92.9%) for those without aTTP. Risk of mortality was 2.9 times higher for patients with aTTP vs. without aTTP (95% CI: 2.4-3.4). Mean (SD) DRG payment for index hospitalization varied by payers: Medicare FFS: $29,024 ($32,565); MA: $12,860 ($6,981); commercial: $9,996 ($5,995); MM: $10,470 ($7,370). During follow-up, 18.4%-22.4% of patients experienced aTTP-related exacerbation [Medicare FFS: 18.4%; MA: 21.9%; commercial: 22.4% and MM: 22.2%]. Annual incidence rate of relapse per 100 person-years was 5.6 [Medicare FFS: 3.6; MA: 8.7; commercial: 10.4 and MM: 14.7] and annual incidence rate of complications per 100 person-years was 16.7 [Medicare FFS: 15.5; MA: 20.5; commercial: 21.7 and MM: 19.1]. Conclusions This is the first real-world study evaluating burden of illness among aTTP patients in the US across payer types. Despite being treated with TPE, patients with aTTP have high acute mortality and are nearly three times as likely to die compared with the general Medicare population without aTTP. During the initial hospitalization, many required intensive care. Following discharge, approximately 1 in 5 was readmitted within 30 days and had higher incidence for clinical complications associated with aTTP. The study findings highlight the need for more effective therapies to reduce disease burden for this population. Disclosures Pollissard: Sanofi: Current Employment, Current equity holder in publicly-traded company. Shah:Avalere Health: Current Employment. Punekar:Sanofi: Other: Employee of Sanofi at the time of study and may hold stock/stock options in Sanofi. Petrilla:Avalere Health: Current Employment. Pham:Sanofi: Consultancy; Alexion: Other: Speaker.

P235 Glucocorticoid dose is progressively reduced in Patients with rheumatoid arthritis (RA) receiving sarilumab: results from the open label EXTEND study

Abstract Background This post hoc analysis assessed changes in oral glucocorticoid (OGC) use over time in patients receiving sarilumab 200 mg (dose reduction to 150 mg for laboratory abnormalities or per investigator’s discretion) every 2 weeks (q2w) plus conventional synthetic disease-modifying antirheumatic drugs (csDMARD) in EXTEND (NCT01146652), a long-term, open-label extension (OLE) study of sarilumab in RA. Methods Patients who had completed placebo-controlled Phase 3 studies of sarilumab +csDMARD (NCT01061736 and NCT01709578) and received sarilumab in EXTEND were included. Reported total daily OGC doses were converted to prednisone equivalent daily doses (PED). Patients were grouped by PED dose at enrollment into the OLE: 0-<5, 5-<10, and ≥10 mg/day (PED <1 mg/day imputed to 0). PED doses were analyzed over 12-week intervals to Week 216. Change from baseline for average PED was tested (Wilcoxon-Pratt-Lehman). Results In total, 891/1353 patients (65.9%) had ≥1 record of OGC use. Of these, 137 (15.4%) received baseline PED of 0-<5 mg/day, 515 (57.8%) 5-<10 mg/day, and 239 (26.8%) ≥10 mg/day. Mean (±SD) PED was 6.3 (±3.1) mg/day at baseline and decreased over time (21.3% mean reduction at 4 years: nominal p < 0.0001). By Weeks 49-60, 660/776 patients (85.1%) had stable PED, 90/776 patients (11.6%) had decreased PED, and 26/776 (3.4%) had increased PED. This difference increased during follow-up: at Weeks 205-216, 109/236 patients (46.2%) had decreased PED and 18/236 (7.6%) had increased PED. Patients with PED ≥5 mg/day were more likely than patients with PED <5 mg/day to decrease their dose. Efficacy (CDAI and DAS28-CRP) was maintained with sarilumab irrespective of OGC tapering. Conclusion Long-term RA treatment with sarilumab was associated with sustained efficacy and decreased OGC dose. The proportion of patients who reduced their OGC dose increased with time and reductions were more common among patients with baseline PED ≥5 mg/day. Disclosures R. Fleischmann: Grants/research support; AbbVie, Acea, Akros, Amgen, Astra Zeneca, Bristol-Myers Squibb, Celgene, Celltrion, Centrexion, Eli Lilly, EMD Serono, Genentech, Glaxo Smith Kline, Janssen, Merck, Nektar, Novartis, Pfizer, Regeneron, Resolve, Roche. C. Selmi: Grants/research support; AbbVie, Alfa-Sigma, Biogen, Bristol-Myers Squibb, Celgene, Eli Lilly, Glaxo Smith Kline, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Sanofi-Genzyme, and UCB. M. Gonzalez-Gay: Grants/research support; AbbVie, Celgene, Eli Lilly, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Sanofi, and Sobi. H. van Hoogstraten: Corporate appointments; Employee of Sanofi. Shareholder/stock ownership; Sanofi. O. Hagino: Corporate appointments; Employee of Sanofi. Shareholder/stock ownership; Sanofi. T. Rajput: Corporate appointments; Employee of Cytel. G. St John: Corporate appointments; Employee of Regeneron Pharmacueticals Inc. Shareholder/stock ownership; Regeneron Pharmacueticals Inc. F. Buttgereit: Grants/research support; Medac, Pfizer, Roche/Chugai, and Sanofi-Genzyme. M.C. Genovese: Grants/research support; AbbVie, Astellas, Eli Lilly, EMD Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GlaxoSmithKline, Novartis, Pfizer, RPharm, Sanofi Genzyme, and Vertex.

P213 High baseline serum IL-6 predicts increased sarilumab treatment response for patient reported symptoms and health-related quality of life among RA patients with inadequate response to MTX

Abstract Background IL-6, a key cytokine in rheumatoid arthritis (RA) pathogenesis, is elevated in patient serum and synovial fluid. However, the impact of baseline IL-6 levels on patient-reported RA symptoms and health-related quality of life (HRQoL) following IL-6 blockade has not been explored. Sarilumab targets IL-6 receptor alpha, and sarilumab+methotrexate (MTX) significantly improved clinical and patient-reported outcomes vs MTX alone among MTX inadequate responders (IR) in MOBILITY/NCT01061736. This post-hoc analysis evaluated whether baseline IL-6 levels predict greater improvements in symptoms and HRQoL with sarilumab+MTX vs MTX. Methods 1,193 patients with moderate-to-severely active RA received MTX or MTX plus subcutaneous sarilumab at 200 mg (recommended dose) or 150 mg (recommended for management of laboratory abnormalities) every 2 weeks (q2w) and were grouped into tertiles according to baseline IL-6 levels. Patient-reported RA symptoms and HRQoL were measured at baseline and post-treatment (Weeks [W] 24 and 52). Results Baseline IL-6 tertiles among 1193 patients were 1.6-9.6 (low), 9.8-30.7 (medium), and 31.2-648.7 pg/mL (high). At baseline, patients with high IL-6 had greater disease activity, more radiographic structural damage, elevated CRP levels, and worse HRQoL (pain visual analog scale [VAS], SF36-physical component scores [PCS], and sleep VAS) vs those with low IL-6 (nominal p < 0.05) and generally reported greater improvements in symptoms and HRQoL with sarilumab+MTX vs placebo+MTX. Significant differences (nominal p < 0.005) between high and low tertiles were evident in improvement of pain VAS (W52) and SF-36 PCS (W24/W52) with sarilumab 200 mg q2w vs placebo, SF-36 mental component scores (both doses; W52) and FACIT-fatigue scores (both doses; W24/W52) vs placebo. Treatment-emergent adverse events were similar across IL-6 tertiles. Conclusion Among MTX-IR RA patients, high baseline IL-6 may predict better improvements in symptoms and HRQoL with sarilumab vs placebo, which was consistent with previous analyses across clinical/radiographic endpoints in the same study population. Disclosures V. Strand: Consultancies; AbbVie, Amgen, AstraZeneca, Biogen, BMS, Celltrion, CORRONA, Crescendo, Genentech/Roche, GSK, Janssen, Eli Lilly, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sandoz, Sanofi and U. J. Msihid: Corporate appointments; Employee of Sanofi. Shareholder/stock ownership; Sanofi. T. Kimura: Corporate appointments; Employee of Regeneron Pharmacueticals Inc. Shareholder/stock ownership; Regeneron Pharmacueticals Inc. A. Boyapati: Corporate appointments; Employee of Regeneron Pharmacueticals Inc. Shareholder/stock ownership; Regeneron Pharmacueticals Inc. G. St John: Corporate appointments; Employee of Regeneron Pharmacueticals Inc. Shareholder/stock ownership; Regeneron Pharmacueticals Inc. W. Wei: Corporate appointments; Employee of Regeneron Pharmacueticals Inc. Shareholder/stock ownership; Regeneron Pharmacueticals Inc.

Assessment of Romiplostim Immunogenicity in Adult Patients in Clinical Trials and in a Global Registry

Background: Romiplostim (Nplate®) is a thrombopoietin (TPO) receptor agonist approved for the treatment of adult chronic immune thrombocytopenia (ITP). The formation of antibodies (Abs) against romiplostim may lead to a loss of response, and a theoretical risk exists that an immune response against romiplostim might lead to the formation of Abs that bind both romiplostim and native TPO. We therefore examined Abs against romiplostim and TPO in adult patients (pts) enrolled in clinical trials and in a global postmarketing registry based on spontaneously submitted requests for Ab testing.Methods: The clinical trial population included adult pts (age ≥18 years at screening) with ITP who received ≥1 dose of romiplostim in any of 13 completed romiplostim clinical trials, including phase 1 (n=1), phase 2 (n=3), phase 1/2 (n=1), phase 3 (n=5), and open-label extension (n=3) studies. Duration of romiplostim treatment varied among the trials. The postmarketing global registry population included romiplostim-treated adult pts with ITP who had blood samples sent for Ab testing. Serum samples from the clinical trials and the registry were assessed for romiplostim and TPO binding Abs in a surface plasmon resonance (SPR)-based immunoassay, and samples positive for binding were assessed for neutralizing activity in a cell-based bioassay, as previously described (Jawa et al. Ann Hematol 2010). Pt characteristics were summarized for those who did and did not develop Abs in the clinical trials. Pts in the registry found to have romiplostim neutralizing Abs were to be followed every 3 months for up to 12 months. No formal statistical analyses were conducted.Results: A total of 1046 romiplostim-treated pts from clinical trials were available for analysis. At baseline, 958 pts had romiplostim Ab results: 35 pts (3.7%) were positive for binding Abs and 1 pt (0.1%) was positive for neutralizing Abs. Post-baseline, 961 pts had romiplostim Ab results: 80 pts (8.3%) were positive for binding Abs and 4 pts (0.4%) were positive for neutralizing Abs, independent of the baseline result.Sixty (6.2%) pts negative for anti-drug Abs at baseline developed romiplostim binding Abs during the clinical trials. Characteristics of the pts who did and did not develop romiplostim binding Abs are presented in Table 1. Development of romiplostim binding Abs was more frequent in pts with ITP duration >3 years at baseline (70.0% vs 57.4%), prior splenectomy (48.3% vs 37.5%), and a history of allergies (21.7% vs 8.4%). Pts who developed Abs also had lower baseline TPO levels (84.8 pg/mL vs 104.6 pg/mL), lower baseline platelet counts (12.5× 109/L vs 20.5 × 109/L), and a higher number of previous ITP treatments (median 3 vs 2).Four of the 60 pts with romiplostim binding Abs developed romiplostim neutralizing Abs after treatment (0.38% of 1046 pts overall; Table 2). The emergence of neutralizing Abs did not appear to be related to romiplostim dose or platelet count. The neutralizing Abs were directed against the peptide component of romiplostim and did not bind native TPO.Pts in the clinical trials were also tested for TPO Abs. At baseline, 956 pts had TPO Ab results: 31 pts (3.2%) were positive for TPO binding Abs and 1 pt (0.1%) was positive for neutralizing Abs. Post-baseline, 960 pts had TPO Ab results: 33 pts (3.4%) were positive for TPO binding Abs and no pts were positive for neutralizing Abs.Of the 184 adult pts in the registry, 9 (4.9%) were positive for binding Abs: 5 were positive for romiplostim binding, 2 for TPO binding, and 2 for romiplostim and TPO binding. No predose Ab results were available for these pts. One pt received romiplostim for 11 months at a dose of 2 µg/kg and then experienced an abrupt fall in platelet count even as romiplostim dose was increased to 10 µg/kg. The pt tested positive for romiplostim binding and neutralizing Abs. Romiplostim was discontinued, and the pt was switched to alternative therapy.Conclusions: An analysis of pts in 13 clinical trials shows that pts with indicators of more severe disease (longer duration of ITP, prior splenectomy, and a higher number of previous ITP treatments) may be at increased risk of developing romiplostim binding Abs. Development of romiplostim neutralizing Abs was uncommon in the clinical trials, and these Abs did not bind native TPO. Data from a postmarketing registry showed that the overall risk of clinically significant immunogenicity following exposure to romiplostim is low. [Display omitted] DisclosuresBarger:Amgen Inc.: Employment, Equity Ownership. Boshier:Sanofi: Other: rents a room to a Sanofi employee; Amgen Inc.: Employment, Equity Ownership. Kim:Amgen Inc.: Employment, Equity Ownership. Mytych:Amgen Inc.: Employment, Equity Ownership. Park:Amgen Inc.: Employment, Equity Ownership. Kuter:Amgen Inc.: Consultancy; Argenx: Consultancy; Rigel: Consultancy, Research Funding; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Principia: Research Funding; Protalex: Research Funding; Pfizer: Consultancy; Bioverativ: Consultancy, Research Funding; ONO: Consultancy; Syntimmune: Consultancy; BMS: Research Funding.

Effect of Diabetes Treatment-Related Attributes on Costs to Type 2 Diabetes Patients in a Real-World Population.

Type 2 diabetes mellitus (T2DM) results in a substantial economic burden on patients, health care systems, and society. Most literature assessing the cost of T2DM focuses on the long-term complications of the disease, the association between glucose control and cost, and patient characteristics resulting in poor and costly outcomes. However, it is likely that attributes specific to diabetes therapy can affect the use of costly resources. To estimate the effect of diabetes treatment-related attributes, such as improved efficacy, adherence, and reduced risk for hypoglycemia, on costs to T2DM patients. An observational, retrospective study was conducted using the Optum Clinformatics Database, which links medical and pharmacy claims to laboratory results. Patients aged ≥ 18 years with T2DM who had ≥ 1 antidiabetic medication claim; ≥ 1 hemoglobin A1c (A1c) test result; continuous enrollment in the health plan from April 1, 2010, to March 31, 2011; and at least 1 follow-up day were included. Nondiabetes specific total, inpatient, outpatient, emergency room, and other costs (along with antidiabetes medication costs) were defined for each patient. Generalized linear models with logarithm link were used to predict the 1-year and cumulative 3-year costs. Demographic factors and comorbidities were included as covariates in addition to the diabetes treatment-related attributes. In the entire analysis cohort, the average 3-year cost per patient was $74,862. The percentage effect on cost of diabetes treatment-related variables ranged from -18% to 429%. Drug adherence was associated with lower inpatient, outpatient, and emergency room costs and higher drug costs. Hypoglycemia was associated with higher inpatient, outpatient, emergency room, and other direct costs (except antidiabetic drug costs). Compared with A1c values ≤ 7%, patients with higher levels were associated with higher total and drug costs. Study results demonstrate the association between diabetes treatment-related attributes and costs, including inpatient, outpatient, drug, and total costs. This association raises the question: what would the effect of a new diabetes therapy, with high efficacy, high adherence, and reduced risk of hypoglycemia have on economic outcomes? Funding from Sanofi supported this study. Tong was an employee of ProUnlimited, under contract with Sanofi during the time of the study. Kitio-Dschassi was a Sanofi employee at time of the analysis. Meng, Casciano, Stern, and Gultyaev are employees of LASER Analytica, which received research funds from Sanofi to conduct this database analysis. Lee was an employee at LASER Analytica at the time of the analysis and has received grants from Sanofi. This manuscript was presented as a poster at the American Diabetes Association, 76th Scientific Sessions; New Orleans, Louisiana; June 10-14, 2016. Study concept and design were contributed by Meng, Casciano, Gultyaev, and Kitio-Dschassi. Meng and Stern collected the data, and data interpretation was performed by Casciano, Lee, Tong, and Kitio-Dschassi. The manuscript was written primarily by Lee, along with Meng and Stern, and revised by Stern, Meng, Tong, Kitio-Dschassi, and Lee.

Prevalence of Atherosclerotic Cardiovascular Disease (ASCVD) and Diabetes Populations in the United States

Lead Author’s Financial Disclosures: Dr. Gorcyca is an employee of Sanofi. Study Funding: This study was funded by Sanofi and Regeneron Pharmaceuticals Inc. Background/Synopsis: The American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the management of blood cholesterol recommend statin treatment in patients with ASCVD or diabetes. Guidelines from the National Lipid Association (NLA) recommend achievement of low-density lipoprotein cholesterol (LDL-C) thresholds in these populations. Objective/Purpose: To estimate the prevalence of ASCVD and diabetes populations overall and by disease profiles in the U.S. The secondary aim was to estimate the prevalence of subpopulations treated with lipid lowering therapy (LLT), and achieving LDL-C thresholds of ,70 mg/dL and ,100 mg/dL. Methods: The MarketScan Research Database was utilized with inclusion criteria of 2013 LDL-C measurement (index), age$18 years, and evidence of the following highrisk conditions during two years pre-index: Recent acute coronary syndrome (ACS) within 12 months, stable coronary heart disease (CHD), ischemic stroke, peripheral arterial disease (PAD), or diabetes. The resulting cohort was divided into mutually exclusive strata, which could represent disease profiles such as CHD only, ischemic stroke + diabetes, CHD + PAD + diabetes, etc. Weights by strata were estimated using an optimization algorithm that minimized the difference between the weighted totals for aggregate conditions such as CHD, ischemic stroke, PAD, diabetes and their established national prevalence based on published sources. The methodology ensured the extrapolation accounted for differential weights by disease profiles

529P - Quality of Life (Qol) on the Aflibercept/Folfiri Regimen: 4Th Interim Analysis of the Global Aflibercept Safety and Health-Related Qol Program

ABSTRACT Aim: In the phase 3 VELOUR trial, aflibercept (ziv-aflibercept in the United States) + FOLFIRI significantly improved overall survival vs FOLFIRI alone in metastatic colorectal cancer (mCRC) patients (pts) previously treated with an oxaliplatin-containing regimen. Results of VELOUR supported initiation of the global Aflibercept Safety and QoL Program, comprising 2 clinical studies (ASQoP [NCT01571284]; AFEQT [NCT01670721]) that capture utility values derived from QoL instruments and additional safety data from a population similar to that of VELOUR in a real-life setting. We report QoL and utility value data from the 4th interim analysis of the ASQoP/AFEQT studies. Methods: Target recruitment in ASQoP is 900 pts from 150 multiple country sites, and 200 pts from French sites for AFEQT. The EuroQoL EQ-5D™ instrument served as the utility measure and the EORTC QLQ-C30 as the generic cancer instrument. QoL populations were pts evaluable for the respective questionnaire at baseline and ≥1 assessment post-baseline and received ≥1 part of 1 dose of study treatment. Both instruments were self-administered at baseline and the beginning of every odd treatment cycle. Four preplanned interim analyses were conducted. Results: At the 4th interim analysis cutoff date, the EQ-5D population comprised 523 pts; 57.6% men, median age 62 years (range 20-89), 65.4% had Eastern Cooperative Oncology Group scores = 0. Mean baseline utility index was 0.77 (95% CI, 0.75-0.79). Utility index remained relatively stable at cycle 3 (in 449 evaluable pts) and up to cycle 17 (in 33 evaluable pts) with a mean (±SD) change from baseline of -0.02 (±0.24) and -0.08 (±0.19), respectively. Mean baseline global health status (GHS) score from EORTC QLQ-C30 was 68.44 (95% CI, 66.68-70.21) and remained in the stable range across subsequent cycles for both GHS and functional scales. Conclusions: Trends from this interim analysis suggest relatively stable utility and QoL scores in mCRC pts treated in second line with aflibercept + FOLFIRI. This has important implications in advanced cancer, as patient-reported outcomes provide an important, real-world perspective on health status and well-being. Disclosure: J. Taieb: has disclosures relating to participation in advisory boards for Sanofi and corporate-sponsored research for Sanofi;P. Garcia Alfonso: has disclosures related to participating in advisory boards for Sanofi, Roche, and Merck; Y. Moore: was an employee of Sanofi at the time the study was conducted and has stock ownership in Sanofi;S. Brette: is an employee of Lincoln, which is a consultant to Sanofi. C. Zilocchi, F. Joulain, S. Naoshy and P. Garreau-Laporte: is an employee of Sanofi and owns stock in Sanofi; E. Dochy: is an employee of Sanofi and owns stock in Sanofi; A. Sobrero: has received honoraria for advisory boards from Amgen, Roche, Sanofi, Bayer, Merck and Celgene. All other authors have declared no conflicts of interest.

246P - A Meta-Analysis of Biomarkers in Three Randomized, Phase 2 Studies of Mm-121, a Ligand-Blocking Anti-Erbb3 Antibody, in Patients with Ovarian, Lung, and Breast Cancers

ABSTRACT Aim: Heregulin (HRG)-driven ErbB3 signaling mediates resistance to standard-of-care (SOC) cancer therapy in a variety of preclinical models. MM-121, a HRG-blocking anti-ErbB3 antibody, underwent clinical evaluation to determine if patients with advanced malignancies would derive benefit from the addition of MM-121 to their standard therapy. Potential predictive biomarkers were identified from a pre-specified set of mechanistic markers. Study BM+ n/N* BM+ Prevalence PFS HR in study PFS HR in measured BM PFS HR in BM+ PFS HR in BM- Ovarian 69/150 46% 1.03 [0.74-1.42] 1.10 [0.74-1.63] 0.40 [0.21-0.76] 2.02 [1.17-3.50] Lung 36/67 54% 0.82 [0.55-1.21] 0.91 [0.51-1.61] 0.39 [0.18-0.82] 2.43 [1.07-5.55] Breast 21/57 37% 0.75 [0.48-1.15] 0.68 [0.38-1.23] 0.35 [0.13-0.94] 0.99 [0.47-2.08] *n = BM + , N = patients with measured biomarkers Methods: Randomized Phase 2 studies were conducted in: i) platinum-resistant ovarian cancer, ii) EGFR wt NSCLC, and iii) ER/PR + , HER2- mBC. Patients were randomized to SOC therapy, with or without MM-121. Safety and clinical activity data from these studies have previously been presented. Tumor tissue was acquired from each patient and five pre-specified biomarkers were measured and correlated with clinical benefit: HRG, betacellulin, EGFR, HER2, and ErbB3. Protein levels were determined by quantitative IHC (qIHC) and mRNA levels by RT-PCR and RNA in-situ hybridization (RNA-ISH). Results: Among 464 patients (220 ovarian, 115 breast, 129 lung), RNA-ISH data were available from 224 patients (157 ovarian, 67 lung), qIHC from 252 (174 ovarian, 78 lung), and RT-PCR from 175 (105 ovarian, 57 breast, 13 lung). Of the five biomarkers, the most predictive of response was HRG mRNA: patients with detectable HRG in pre-treatment biopsies or high HRG in archived tissue blocks responded poorly to SOC therapy and benefited most from MM-121. In addition, benefit was largely restricted to patients with low ErbB2. Hazard ratios for PFS were calculated, defining biomarker positive (BM+) patients: Ovarian cancer, detectable HRG and low ErbB2; Lung cancer, detectable HRG; and, Breast cancer, high HRG. PFS hazard ratios with 95% CI and prevalence of the BM+ and BM- subpopulations are provided below. Conclusions: Heregulin is a potential biomarker for poor response to SOC therapy and a potential predictor of clinical benefit from MM-121 in late-stage ovarian, lung, and breast cancers. Disclosure: G. MacBeath is an employee of Merrimack Pharmaceuticals and holds stock in the company; B. Adiwijaya is an employee of Merrimack Pharmaceuticals, the sponsor of this clinical research, and holds stock in the company; J. Liu is an unpaid advisor for Merrimack Pharmaceuticals and was a Principal Investigator for one of the clinical studies included in this analysis; L.V. Sequist is an upaid advisor for Merrimack Pharmaceuticals and was a Principal Investigator of one of the clinical studies included in this analysis; E. Pujade-Lauraine serves as an upaid advisor to Merrimack Pharmaceuticals and Sanofi. He was also a lead investigator for one of the clinical studies included in this analysis; M. Higgins is an unpaid advisor to Merrimack Pharmaceuticals and Sanofi. She was a Principal Investigator of one of the clinical studies included in this analysis; I. Tabah-Fisch is an employee of Sanofi, a sponsor of the clinical studies summarized in this abstract, and holds stock in the company; J. Pearlberg is an employee of Sanofi, a sponsor of this clinical research, and holds stock in the company; V. Moyo, W. Kubasek, R. Nering and A. Czibere: Is an employee of Merrimack Pharmaceuticals, a sponsor of the clinical research, and holds stock in the company.

443O - Pimasertib (Pim) and Sar245409 (Sar) - a Mek and Pi3K/Mtor Inhibitor Combination: a Phase Ib Trial with Expansions in Selected Genotype-Defined Solid Tumors

ABSTRACT Aim: To investigate safety and efficacy in four expansion cohorts treated with the combination of PIM and SAR. Methods: The recommended phase 2 dose (RP2D) for the combination of PIM and SAR has previously been defined in a dose escalation part of the same trial as 60 mg and 70 mg QD, respectively. Inclusion criteria included ECOG PS 0-1, and in the expansion cohorts prior MEK and/or PI3K inhibitor therapy was not allowed (NCT01390818). With an extract date of 25 March 2014, we carried out preliminary analyses for safety and efficacy using standard criteria (NCI CTCAE v4.0 and RECIST v1.1). Results: At the RP2D, 4 disease- and genotype-specific cohorts were recruited: RAS mutated non-small cell lung cancer (NSCLC, n = 24), triple-negative breast cancer (TNBC, n = 26), BRAF inhibitor resistant malignant melanoma (MEL, n = 15) and dual KRAS and PIK3CA mutated colorectal cancer (CRC, n = 18). The most frequent (≥20%) all grade treatment-emergent adverse events were: diarrhea (77.1%), fatigue (54.2%), nausea (50.6%), vomiting (47.0%), dermatitis acneiform (37.3%), maculo-papular rash (30.1%), decreased appetite (30.1%), peripheral edema (25.3%), pyrexia (25.3%), stomatitis (24.1%), dizziness (24.1%), dyspnea (21.7%), skin rash (21.7%), increased creatinine phosphokinase levels (21.7%), abdominal pain (20.5%) and pruritus (20.5%). Serous retinal detachment, which is a class effect of MEK inhibitors, was reported in 34.9% of pts and all cases were resolved without serious damage to the eyesight. Confirmed responses were observed in 2 of 18 evaluable NSCLC patients and in 1 of 13 evaluable MEL pts. Conclusions: Toxicities were manageable and improved or resolved with drug interruptions and/or dose reductions. Clinical activity was observed and an updated response evaluation will be presented at the meeting. We plan to evaluate whether there is a specific subset of pts who are more likely to benefit from the combination treatment with PIM and SAR. Disclosure: R.S. Heist: Research funding (for clinical trials) going to the institution at which I work (MGH), from the following companies: Genentech, GSK, Pfizer, Debiopharm, Infinity, Exelixis, EMD Serono, Sanofi F. Campana: Frank Campana is a Sanofi employee; C. Egile: Coumaran EGILE is a Sanofi employee; V. Jego: I am currently working for Cytel Inc, a CRO contracted by Merck KGaA. I do not have any stock ownership or advisory board or board of director membership or other substantial relationship beyond employment; L. Damstrup: I am an employer of Merck Serono, no other conflict of interest. All other authors have declared no conflicts of interest.

528P - Aflibercept + Folfiri for Treatment of Metastatic Colorectal Cancer After Oxaliplatin Failure: 4Th Interim Safety Data from the Global Aflibercept Safety and Quality-Of-Life Program (Asqop/Afeqt Studies)

ABSTRACT Aim: In VELOUR, aflibercept (ziv-aflibercept in the US) + FOLFIRI demonstrated a statistically significant improvement in overall survival vs placebo + FOLFIRI in metastatic colorectal cancer (mCRC) patients (pts) previously treated with an oxaliplatin-containing regimen. Results supported initiation of the global Aflibercept Safety and Quality-of-Life (QoL) Program composed of 2 clinical studies (ASQoP; AFEQT) to capture utility values from QoL instruments and collect safety data from a population similar to that in VELOUR in a real-life setting. We report safety data from the 4th interim analysis of these ongoing studies. Methods: ASQoP and AFEQT are single-arm, open-label trials in mCRC pts previously treated with an oxaliplatin-containing regimen. Eligible pts received aflibercept 4 mg/kg every 2 weeks on day 1 of each cycle followed by FOLFIRI. FOLFIRI starting dose and subsequent additional dose modifications are at discretion of the treating physician. Results: At data cut-off for this interim analysis, the safety population (n = 688) was compared with VELOUR. In 44% of ASQoP vs 33.5% of VELOUR, pts were ≥65 years; 10.8% of ASQoP vs 5.4% of VELOUR were ≥75 years. ASQoP pts received a median of 6 treatment cycles while VELOUR pts received a median of 9. Grade (G) 3/4 adverse events (AEs) were experienced by 72.2% of ASQoP pts vs 83.5% in VELOUR. Most were G3. G4 hypertension or diarrhea was not reported. Table shows selected G3/4 AEs. ASQoP/AFEQT VELOUR Adverse Events, % Aflibercept + FOLFIRI (n = 688) Aflibercept + FOLFIRI (n = 611) Grade 3/4 (%) Grade 3/4 (%) Proteinuria 3.6 7.9 Stomatitis and ulceration (high level term) 9.6 13.8 Diarrhea (preferred term) 14.1 19.3 Infections and infestations (system organ class) 9.6 12.3 Hypertension 23.0 19.3 Arterial thromboembolic event 0.6 1.8 Venous thromboembolic event 4.4 7.9 Fistula (gastrointestinal [GI] origin) 0.6 0.3 GI perforation 1.3 0.5 Conclusions: Interim safety analysis from ASQoP/AFEQT has identified no new safety signals. Despite a greater % of elderly pts in ASQoP/AFEQT, reported incidence of toxicity is generally similar or less than VELOUR. Differences in AE incidence in ASQoP/AFEQT vs VELOUR may be related to the VELOUR protocol requirement of full-dose FOLFIRI initiation and current overall exposure differences. Disclosure: J. Taieb: has conflicts of interest related to advisory boards for Sanofi and for corporate-sponsored research for Sanofi; Y. Moore: formerly held a leadership position at Sanofi at the time this study was conducted and has stock ownership in Sanofi; C. Zilocchi: is an employee of Sanofi and has stock ownership; S. Brette: is an employee (biostatistician) of Lincoln, which is a consultant for Sanofi. A. Sobrero: has received honoraria for participating in advisory boards for Bayer, Roche, Sanofi, Celgene, Merck, and Amgen. All other authors have declared no conflicts of interest.

787P - Association of Neutrophil-To-Lymphocyte Ratio (Nlr) with Survival (Os) in Metastatic Castration-Resistant Prostate Cancer (Mcrpc) Patients Receiving Prednisone (P) Plus Cabazitaxel (Cbz) or Mitoxantrone (Mtx) in the Tropic Trial

ABSTRACT Aim: NLR is a marker of systemic inflammation that is associated with response to abiraterone acetate in mCRPC. CBZ + P provided survival benefit over MTX + P in post-docetaxel mCRPC patients in the TROPIC trial. This retrospective analysis of the TROPIC study explores the prognostic value of NLR and its association with response to CBZ. Methods: Baseline (BL) NLR (absolute neutrophil count divided by absolute lymphocyte count) was calculated. Univariate analysis (UVA) of the association of NLR >5 with OS and response was performed, followed by inclusion in a multivariate (MVA) model (Cox regression, log-rank test) with prognostic factors previously identified in the TROPIC trial (rising PSA at BL, CBZ vs MTX, time from first hormonal treatment, BL ALP, pain, time from docetaxel chemotherapy). Results: 742 men with mCRPC had available BL NLR data. BL NLR was ≤5 in 543 and >5 in 199. No significant BL differences were found between groups. A greater risk of death in patients with NLR >5 was observed in UVA (HR 1.72, 95% CI 1.441–2.062) irrespective of treatment arm. NLR >5 remained significantly associated with OS in MVA (P = 0.0017). Prognostic factors previously identified in the TROPIC study remained significant (all P-values ≤0.0083) after the inclusion of NLR in the model. OS was significantly longer in CBZ versus MTX-treated patients with NLR ≤5 (P = 0.0002) (Table). CBZ also provided OS benefit in patients with NLR >5 (P = 0.0503). Conclusions: NLR is a valuable independent prognostic factor for OS in mCRPC. CBZ was associated with an OS benefit over MTX in both NLR ≤5 and NLR >5 subgroups. Data are consistent with previous analyses, which demonstrate CBZ superiority over MTX across subgroups. Dr Lorente is supported by a Spanish Society of Medical Oncology grant ‘Beca SEOM para la Investigacion Traslacional en el Extranjero’. OS by NLR subgroup in the TROPIC trial (intent-to-treat) Median, months (95% CI) Baseline NLR MTX (n = 371) CBZ (n = 371) HR (95% CI) CBZ vs. MTX P-value * NLR ≤5 (n = 543) 14.0 (12.7–15.6) 16.9 (15.2–18.5) 0.687 (0.564–0.837) 0.0002 NLR >5 (n = 199) 9.17 (7.33–11.3) 11.2 (9.23–13.6) 0.741 (0.548–1.002) 0.0503 Overall (N = 742) 12.8 (11.6–13.7) 15.2 (14.1–16.7) 0.703 (0.596–0.829) * Log rank test. Disclosure: O. Sartor: has a consultant/advisory relationship with Sanofi; A. Bahl: has a consultant/advisory relationship with Sanofi, and has received honoraria and research funding from Sanofi; Z. Su: is a Medical Director at Sanofi, and has stock/other ownership interests at Sanofi; J. Devin: is an employee of Sanofi; J. de Bono: has received research funding from the Institute of Cancer Research. All other authors have declared no conflicts of interest.

795P - A Prognostic Model for Predicting Radiographic Progression- Free Survival (Rpfs) in Metastatic Castrate-Resistant Prostate Cancer Men Treated with Second-Line Chemotherapy

ABSTRACT Aim: This work sought to develop and validate a prognostic model to predict rPFS in men who had progressed following first-line chemotherapy, and were selected to receive second-line chemotherapy. Methods: Data from a phase III trial in mCRPC men who had developed progressive disease following first-line chemotherapy (TROPIC trial) were used. The TROPIC was randomly split into training (n = 507) and testing (n = 248) sets. RPFS was defined as the time from randomization to first bone progression, objective progression (RECIST1.1), or death, whichever occurred first. Adaptive LASSO selected eight prognostic factors of rPFS. A prognostic score was computed from the regression coefficients and the model was assessed on the testing set for its predictive accuracy using the time-dependent area under the curve (tAUC). Results: The eight prognostic variables in the final model included: ECOG performance status, race, time since last docetaxel use, presence of lung metastases, presence of liver metastases, duration of hormonal use, hemoglobin, and treatment with cabazitaxel. In the training and testing sets, the tAUC for this model were 0.72 (95% CI = 0.66-0.79) and 0.67 (95% CI = 0.60-0.76) respectively. Conclusions: A prognostic model of rPFS in the post-docetaxel second-line chemotherapy mCRPC setting was developed and validated. This model incorporates established prognostic factors and can be used to select patients to participate in clinical trials on the basis of their prognosis. External validation is needed. Disclosure: S. Halabi: Reserach support from sanofi; A.J. Armstrong: Research support and consultant for sanofi; L. Shen: Sanofi employee; S. Oudard: Consultant and investigator for sanofi; O. Sartor: Consultant for sanofi, Bayer, Astellas, Janssen; J.S. de Bono: Consultant and Investigator for Sanofi. All other authors have declared no conflicts of interest.

981P - Epidemiology Projection Trends for Ovarian Cancer (OC) Patients by Platinum Response Status in Europe and U.S.

ABSTRACT Background Ovarian cancer is the eighth most commonly diagnosed cancer among women worldwide with an estimated 225,500 new cases and 140,000 deaths per year. There is a lack of published data on the distribution of patients across lines of therapy based on their platinum response status i.e. platinum resistant/refractory or platinum-sensitive. Table: 981P Year Line of therapy * Number of patients France Germany Italy Spain UK EU 5 US 2010 1L ** 4046 7546 4479 2649 5386 24106 16301 2L Platinum Sensitive 1448 2711 1604 947 1937 8647 4546 2L Platinum Refractory 1196 2238 1324 782 1599 7139 2557 3L 1233 2316 1366 806 1656 7377 4430 ^ 4L 407 767 451 266 549 2440 NA 2020 1L ** 4552 8015 4928 3067 5774 26336 19258 2L Platinum Sensitive 1631 2874 1767 1098 2069 9439 5354 2L Platinum Refractory 1346 2373 1458 906 1708 7791 3011 3L 1389 2451 1506 935 1763 8044 5218 ^ 4L 459 810 498 308 582 2657 NA NA = not available Source: CancerMPact® Kantar Health (www.cancermpact.com) Accessed Mar 2011 for EU, Jan 2012 for US * patient may receive multiple lines of therapy in given year; ** stage II, III, IV combined; ^ for US, includes 3L + 4L; Methods Epidemiological data was obtained for US and EU using CancerMPact® database. This database includes line of therapy estimations using the US National Oncology Data Alliance numbers combined with a survey of a representative sample of physicians in the U.S. and Europe. Using historical data, we analyzed projection estimates up to 2020 across US and EU5 countries by line of therapy and platinum response status. Results Projection estimates from 2010 to 2020 by line of therapy varied by country. Among EU countries, the highest number of treated patients was in Germany, followed by United Kingdom (UK) and Italy. By 2020, the percentages of patients that are platinum sensitive and platinum refractory are expected to increase by about 17% in the US and 9% in the EU. Regional variation was observed across Europe with percentage increase in France being 12%, Germany 6%, Italy 10%, Spain 16% and UK 7%. The table below refers to the number of ovarian cancer patients by line of therapy. Conclusions Despite ongoing therapeutic efforts, only 44%of patients in US and 65% in EU who receive 1L go on to 2L. This argues for continued efforts to be made for the development of more efficacious treatments for ovarian cancer. Real world data and disease based registries can help in validating emerging trends in therapy through providing up to date global projection estimates across line of therapy. Disclosure J. Mehta: Employee of Sanofi R. Olivares: Employee of Sanofi O. Moulard: Employee of Sanofi P. Trask: Employee of Sanofi and owns stock A. Hamed: Employee of Sanofi.

632 - Epidemiology Projection Trends for Metastatic Colorectal Cancer (MCRC) Patients Receiving Second Line (2L) Therapy in EU and US

ABSTRACT Background Worldwide, CRC is the third most common cancer in men (663,000 cases, 10% of the total) and second in women (571,000 cases, 9.4% of the total) (IARC 2008). Due to demographic expansion and an ageing population, the annual number of newly diagnosed and treated CRC cases is expected to increase in Western countries. Hence, epidemiology projection estimates by line of therapy are needed to support clinical, economic and resource planning. Methods Epidemiological data was obtained using the CancerMPact® database (accessed Oct 2011), which includes line of therapy estimations through the US National Oncology Data Alliance and survey of a representative physician sample. Data was grouped by stage at diagnosis and stage IV refers to metastatic patients. Results From 2010-2020, the distribution of mCRC patients receiving 2L differs by country in EU. The highest number of treated patients is in Germany, followed by Italy and UK. Among all treated mCRC patients, about 42% of patients in EU and 45% of patients in US will go on to 2L. By 2020, the percentage of patients receiving 1L and 2L will increase by about 15% across US and EU. Over a 10 year period, the number of treated patients for each line of therapy will increase by 19%, 11%, 15%, 20%, and 14% for France, Germany, Italy, Spain and UK, respectively. The table below refers to the number of metastatic patients by line of therapy. Conclusions Despite improvement in survival rates, approximately half of patients in US and EU who receive 1L go on to 2L. In addition to survey data, real world data and disease based registries can help validate these projection estimates. The projected increase in mCRC patients by 10-20% across the EU has implications for disease management and health resource planning in oncology. Table: 632 Year Line Number of patients France Germany Italy Spain UK EU 5 US 2010 1L 13705 25590 18171 9590 16646 83702 40484 2L 8212 15378 10904 5746 9988 50228 27217 3L 3117 5846 4125 2177 3792 19057 14602 4L+ 695 1296 868 474 840 4173 5429 Total stage IV * 19344 36313 25408 13432 23372 117869 60703 2020 1L 16273 28410 20956 11533 19060 96232 47447 2L 9755 17048 12592 6916 11434 57745 31672 3L 3704 6476 4767 2622 4341 21910 16999 4L+ 825 1439 1002 571 961 4798 6324 Total stage IV * 22947 39931 29361 16194 26733 135166 69391 * a patient may receive multiple lines of therapy in a given year Source: CancerMPact® Kantar Health ( www.cancermpact.com ) Disclosure O. Moulard: I am an employee of Sanofi. J. Mehta: I am an employee of Sanofi. S. Naoshy: I am an employee of Sanofi. R. Olivares: I am an employee of Sanofi. S.U. Iqbal: I am an employee of Sanofi. All other authors have declared no conflicts of interest.

1369P - Risk of Major Bleeding in Cancer Patients Receiving Chemotherapy

ABSTRACT Cancer patients receiving chemotherapy are at increased risk of venous thromboembolism (VTE). The presence of cancer and anticoagulant use are risk factors for bleeding, yet data on bleeding risk are limited in these patients. This analysis evaluated the risk of major bleeding in cancer patients receiving chemotherapy using a US claims database. This retrospective cohort study used the MarketScan® databases, a nationwide database containing data from about 100 payers and covering > 30 million patients annually. Adult cancer patients receiving chemotherapy within 6 months of cancer diagnosis between January 2004 and December 2010 were included. Cancers of interest were: lung, colon/rectum, pancreas, bladder, stomach, and ovary. The index date was the first date of chemotherapy. Patients were followed until the earliest of: 1) first diagnosis of major bleeding; 2) termination of enrolment in the health plan; 3) end of study. The primary outcome was the first occurrence of major bleeding, based on selected ICD-9-CM/CPT codes, following chemotherapy initiation. Of 74,575 patients identified, exclusion of those with prior history of bleeding at baseline (∼5%) resulted in 70,822 patients included in the analysis. Mean age was 62 years, 37% were ≥ 65 years, and 52% were male. Average time of follow up and chemotherapy were 14.3 and 8.6 months, respectively; 6% had a history of VTE within 6 months prior to the index date. Major bleeding occurred in 5.8% of patients and the incidence rate for all cancers combined was 4.9 per 100 person-year (PY) and 10.5, 9.3, 6.2, 4.3, 3.6, and 3.3/100 PY for pancreatic, stomach, lung, bladder, colon/rectum, and ovarian cancer, respectively. Approximately 14% of patients (N = 10,456) developed VTE after chemotherapy initiation (> half in the first 3 months of chemotherapy treatment). Of these, 7.8% experienced major bleeding with incidence rates ranging from 5.9-17.7/100 PY after VTE. Major bleeding incidence in cancer patients receiving chemotherapy varies by cancer type with the highest rates in patients with upper gastrointestinal cancer. Compared to the overall cohort, major bleeding risk was higher in cancer patients who developed VTE. Disclosure J.H. Zong: Employee of Sanofi. L. Eckert: Employee of Sanofi. L. Zhang: Employee of Sanofi. W.S. Dai: Employee of Sanofi. A.T. Cohen: Consult: Astellas, AZ, Bayer, BI, BMS, Daiichi, GSK, JJ ResFund: AZ, Bayer, BI, BMS, Daiichi, GSK, JJ BoardSpeakerAdvis comm: Bayer, BI, BMS, Daiichi, GSK, J&J, Mitsubishi, Pfizer, Sanofi. All other authors have declared no conflicts of interest.

948 - Analysis of the USA Postmarketing Safety Profile of Cabazitaxel in the Treatment of Metastatic Castrate-Resistant Prostate Cancer (MCRPC) Previously Treated with a Docetaxel-Containing Treatment Regimen

ABSTRACT Background Cabazitaxel (Jevtana®) in combination with prednisone was licensed in the United States (USA) in June 2010 for the treatment of mCRPC in patients (pts) previously treated with a docetaxel-containing treatment regimen. We estimate that over 13,000 patients have since been treated in the US. This research analyzes the post-marketing safety profile of cabazitaxel based on spontaneously reported pharmacovigilance (PV) Adverse Events (AEs) in the USA. As such reports depend on voluntary reporting, only a qualitative comparison to the safety profile observed in the clinical trial setting is possible. Methods Safety information spontaneously reported to Sanofi US PV from June 17, 2010 - March 31, 2012 was reviewed. The most frequently reported AEs are presented, using MedDRA preferred terms and compared with the safety profile observed in clinical trials. Results A total of 692 spontaneously reported AEs were received for 373 US men in the time period indicated, 312 (45%) serious (SAEs) and 380 (55%) non-serious. The pts were 45 to 88 years old (mean ± SD: 68.6 ± 12) and virtually all with mCRPC. The most frequently reported hematologic AEs were neutropenia [n = 27; 16 SAEs], febrile neutropenia [n = 18; 17 SAEs], anemia [n = 9; 4 SAEs] and thrombocytopenia [n = 7; 3 SAEs]. The most frequently reported non-hematologic AEs included diarrhea [n = 32; 8 SAEs], fatigue [n = 28; 1 SAEs], hematuria [n = 15; 5 SAEs], nausea [n = 14; 1 SAEs], vomiting [n = 9; 2 SAEs] and pyrexia [n = 3; 0 SAEs]. Concomitant therapies and co-morbidities were associated with most of the cases. Disease progression was reported as an event in 68 pts with 38 pts reporting increased PSA levels. A total of 57 deaths were reported: 9 due to disease progression; 3 pulmonary embolism; 2 chronic obstructive pulmonary disease; 2 febrile neutropenia; 2 sepsis; 2 septic shock; 12 other causes; and, 25 cause not specified. Conclusion Although subject to the limitations of the post-marketing voluntary adverse event reporting system, the emerging safety profile of Jevtana is consistent with that observed in the clinical trial setting. Disclosure L. Nicacio: I am an employee of Sanofi and own Sanofi stock. P. Raina: I am an employee of Sanofi and own Sanofi stock. R. Sands: I am an employee of Sanofi and own Sanofi stock. S. Neibart: I am an employee of Sanofi and own Sanofi stock.

633 - Aflibercept/Folfiri (AF) VS Placebo/Folfiri (PF) In Metastatic Colorectal Cancer (MCRC): Post-Hoc Analysis of Survival Excluding Adjuvant (ADJ)-Only Patients in the Velour Trial

ABSTRACT Background A small proportion of poor prognosis CRC patients (pts) treated with ADJ therapy relapse within 6 months of treatment, and progress to mCRC (Sargent JCO 2007;25:4569). The VELOUR phase III trial evaluated the novel fusion protein aflibercept (VEGF Trap) plus FOLFIRI in mCRC pts previously treated with oxaliplatin. In this study 10% of pts directly progressed from ADJ setting to first-line. Median and mean overall survival (OS) was determined for VELOUR pts excluding those that progressed directly from the ADJ setting. Method Baseline characteristics and efficacy were determined for the ITT pts excluding ADJ-only pts. Since some pts were alive at the time of final analysis, mean OS was estimated by extrapolating the trial Kaplan-Meier curve using a survival function. The goodness-of-fit of parametric distributions was evaluated by AIC, BIC criteria. Survival functions were fit to each treatment (TXT) arm separately or by combining the two arms and using TXT as a covariate to control for variation. Results Of 1226 pts enrolled in VELOUR, 60 (9.8%) AF pts and 64 (10.4%) pF pts received oxaliplatin in ADJ setting only. Excluding these pts, baseline characteristics remained similar between the 2 arms. Median age was 61 years, 60% of pts were male, 30% of pts were randomized in the prior bevacizumab stratum and very few pts had ECOG PS 2 (2.1%) as per IVRS. 43.6% of pts had 1 or less metastatic site at baseline and 25.4% had liver metastasis only. Median OS was significantly improved with AF vs pF (13.8 vs 11.9 months; adjusted HR = 0.80 [95% CI: 0.69 to 0.92]). For mean OS, the loglogistic function provided the best fit of the VELOUR data for the ITT population excluding ADJ-only pts both with and without TXT as covariate. Conclusion Excluding ADJ-only pts, the VELOUR trial increased median OS (1.9 vs 1.4) and mean OS (5.1 vs 4.7) with AF compared to pF, thus reinforcing the therapeutic benefit of AF in clinically relevant patient populations. Table: 633 Median OS (months) Restricted Mean OS (months) over 15 years AF (N = 552) pF (N = 550) Δ Δ ITT Loglogistic AF pF Δ Δ ITT 13.8 11.9 1.9 1.4 TXT group independently 22.7 17.6 5.1 4.7 TXT group as covariate 21.5 18.5 3.0 2.5 Disclosure F. Joulain: I am an employee of Sanofi. U. Iqbal: I am an employee of Sanofi. F. Diamand: I am an employee of Sanofi. E. Van Cutsem: I have received research funding from Sanofi. J. Tabernero: I have an advisory relationship with Sanofi, Roche, and Regeneron. C. Allegra: I have an advisory relationship with Sanofi.

497P - Dose-Escalation Phase I Study of Cabazitaxel (CBZ) + Gemcitabine (GEM) in Patients (PTS) with Metastatic or Unresectable Advanced Solid Malignancy

ABSTRACT Rationale Gem + taxane combinations have shown activity in some advanced cancers. Cbz (a novel taxane) + prednisone (P) improved overall survival vs mitoxantrone + P in pts with metastatic castration-resistant prostate cancer previously treated with docetaxel (de Bono 2010). Methods A Phase I study (NCT01001221) was conducted to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz + Gem (parts 1a and 1b) and to evaluate antitumour activity at the MTD (part 2). Pts with histologically or cytologically confirmed metastatic or unresectable solid tumours without existing standard treatment were eligible. Cohorts of 3–6 pts were treated with Cbz (15–20 mg/m2 1-h infusion) followed by Gem (700–1000 mg/m2) on d1 and Gem alone on d8 (part 1a). The administration sequence on d1 was then reversed (part 1b), based on preliminary PK data. Results Of the 12 pts in part 1a, 5 pts were treated at Cbz 20 mg/m2 + Gem 1000 mg/m2 dose level (DL 20/1000), 5 pts at DL 15/900 and 2 pts at DL 15/700. In part 1b, all 6 pts were treated at the lowest DL (700/15) allowed. At all DLs, ≥ 2 pts experienced a DLT, regardless of administration sequence. DLTs were febrile neutropenia (FN) (4 pts), Grade (Gr) 4 neutropenia (2 pts), Gr 4 thrombocytopenia (2 pts) and Gr 3 AST increase (1 pt). No MTD was established and part 2 was not performed. All pts experienced at least 1 treatment-emergent AE (TEAE); the most frequent all grade non-haematological TEAEs were fatigue 66.7%, decreased appetite 50.0%, diarrhoea 44.4%, nausea 38.9% and weight decrease 33.3%. Gr 3–4 haematological toxicities included neutropenia 66.7%, thrombocytopenia 33.3% and FN 22.2%. Nine pts continued study treatment and received 6–22 cycles; 3 pts had a partial response (melanoma, prostate small cell and appendiceal tumours), while 8 pts experienced stable disease. PK analysis did not reveal a drug–drug interaction between Cbz and Gem. Conclusion The MTD of Cbz + Gem could not be established due to DLTs. Antitumour activity was observed and drug administration sequence did not affect the toxicity profile. Further investigation of alternative dosing regimens is warranted in an effort to establish a tolerable combination. Disclosure P.M. LoRusso: Has received research funding from Sanofi. J. Yin: Is a Sanofi employee and owns Sanofi stocks and shares. S. Doroumian: Is a Sanofi employee (pharmacokineticist) and owns Sanofi stocks and shares. X. Zhi: Is a Sanofi employee (statistician) and owns Sanofi stocks and shares. A.J. Olszanski: Research funding - Sanofi supplies support for the conduct of the study. All other authors have declared no conflicts of interest.

1250P - Disrupt: A Randomized Phase 2 Trial of Ombrabulin (AVE8062) Combined with a Taxane-Platinum Regimen in the First-Line Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC)

ABSTRACT Introduction Ombrabulin is a vascular disrupting agent and analogue of combretastatin A4 that damages established tumor vasculature, which causes tumor necrosis and regression. DISRUPT (NCT01263886) evaluated whether adding ombrabulin to a taxane-platinum doublet in the first-line setting improves outcomes in patients with metastatic NSCLC. Methods Patients (≥18 yrs of age, ECOG PS 0–1, stage IV) were randomized 1:1 to either ombrabulin 35 mg/m2 or placebo (Pbo) on day 1 followed by a taxane-platinum regimen on day 2 (docetaxel 75 mg/m2 + cisplatin 75 mg/m2 or paclitaxel 200 mg/m2 + carboplatin AUC 6), every 3 weeks. Randomization was stratified by histology (squamous/nonsquamous) and taxane-platinum regimen. Treatment was continued up to 6 cycles, or until unacceptable toxicity, disease progression, or consent withdrawal. The primary endpoint was progression-free survival (PFS) (stratified log-rank analysis; one-sided significance level 0.2). The study had 92% power to detect a 33% risk reduction in the hazard rate for progression (HR 0.67). Secondary endpoints included overall survival (OS), response rate (RR), and safety. Results From February 2011 to January 2012, a total of 176 patients were randomized (n = 88 in each group). Groups were balanced in terms of baseline characteristics. Overall, the median age was 62 yrs (range, 32 – 84), 76% were male, 66% were nonsquamous and 34% squamous, 52% received paclitaxel-carboplatin and 48% docetaxel-cisplatin. PFS was analyzed after 124 events (61 ombrabulin; 63 Pbo); median follow-up was 8 months. PFS was not significantly improved in the ombrabulin group versus Pbo (median 5.7 vs 5.5 months, respectively; HR 0.95; 60%CI 0.81–1.11; one-sided p = 0.39). Overall RR were similar (ombrabulin 32%; Pbo 31%). Median OS was 11.0 months in both arms. Safety profiles were comparable; rates of grade 3-4 adverse events were 57% for ombrabulin and 52% for Pbo. Conclusions This randomized phase 2 trial of ombrabulin combined with a platinum-taxane regimen did not meet the primary endpoint of improving PFS compared with Pbo in the first-line treatment of metastatic NSCLC. Study sponsored by Sanofi. Disclosure J. von Pawel: Member of Sanofi Steering Committee. V. Gorbounova: Member of advisory board: Novartis and Pfizer Honoraria for lectures: Hoffman La Roche. M. Reck: Ad board membership: Lilly, Hoffmann-La Roche, Daiichi-Sankyo, Pfizer, AstraZeneca, BMS Honoraria for lectures: Lilly, Hoffmann-La Roche, Daiichi-Sankyo, AstraZeneca. A. Allard: Sanofi employee. M. Chadjaa: Sanofi employee and stock holder. A. Rey: Sanofi employee and stock held. J. Bennouna: Advisory board: Sanofi-Aventis. F. Grossi On Behalf of The Disrupt Investigators: Membership on advisory board: Sanofi. All other authors have declared no conflicts of interest.