Bev Group Research Articles

AT-11 * FINAL RESULTS FROM THE RANDOMIZED PHASE II TRIAL AVAREG (ML25739) WITH BEVACIZUMAB (BEV) OR FOTEMUSTINE (FTM) IN RECURRENT GBM

AIM: The treatment of recurrent glioblastoma remains an open issue and the role of BEV has been largely debated since only few data compared this agent with the standard agents. METHODS: A multicenter, open-label, randomized (2:1), non-comparative phase II study (EudraCT:2011-001363-46; AVAREG-ML25739) with BEV 10 mg/m2 iv every 2 weeks or FTM 75 mg/m2 iv day 1-8-15 followed, after a 35 days interval, by FTM 100 mg/m2 every 3 weeks, was conducted. Primary endpoint was overall survival at 6 months (OS6). RESULTS: 91 pts with recurrent GBM were enrolled among 10 Italian centers between 11/2011 and 9/2012. Median age was 57 years (range:28-78), PS was 0/1/2 in 42/35/14 pts. All pts were treated with RT/TMZ accordingly with EORTC 26981-22981/NCIC-CE3. Time from diagnosis to 1st recurrence was 331 days in the BEV arm and 460 days in the FTM arm. At time of recurrence, 21 pts (23.1%) received re-resection before the study inclusion (13/8 pts in BEV/FTM arms). Fifty-nine pts were enrolled in the BEV arm and 32 pts in the FTM arm. OS6 was 62.1% (95%CI:48.4-74.5) and 73.3% (95%CI:54.1-87.7), OS9 was 37.9% (95%CI:25.5-51.6) and 46.7% (95%CI:28.3-65.7) in the BEV and FTM arms, respectively. Median OS was 7.3 months (95%CI:5.8-9.2) in the BEV arm and 8.7 months (95%CI:6.3-15.4) in the FTM arm. PFS6 was 26.3% and 10.7%, respectively. In the BEV arm, OS6 and OS9 were 77.8% (95%CI:57.7-91.4) and 59.3% (95%CI:38.8-77.6) in pts =55 yrs, and were 48.4% (95%CI:30.1-66.9) and 19.3% (95%CI:7.4-37.5) in pts >55 yrs. HR for OS in BEV group for pts >55 yrs compared with pts =55 yrs was 2.0 (95%CI:1.0-4.1, p = 0.05). G3-4 toxicity: thrombocytopenia 0% vs 21.9%, neutropenia 1.7% vs 12.5%, intestinal perforation and cerebral ischaemia/hemorrhage 3.4% vs 0%, pulmonary thromboembolism 1.7% vs 0%, and acute myocardial infarction 1.7% vs 0%, in the Bev and FTM arms respectively. CONCLUSIONS: BEV in recurrent GBM showed survival rates superimposable with FTM.

P15 * COMPARATIVE OUTCOMES OF BEVACIZUMAB AND PCV CHEMOTHERAPY IN PATIENTS WITH RECURRENT AND PROGRESSIVE GLIOBLASTOMA: A RETROSPECTIVE STUDY

INTRODUCTION: Bevacizumab (Bev)is used in patients with recurrent high grade glioma in many countries; however, its efficacy has not been compared with a combination of procarbazine, lomustine and vincristine (PCV), a commonly used chemotherapy regimen in the UK. We present comparative outcomes in patients treated with Bev and PCV. METHOD: During January 2011 and March 2013, 40 patients receiving PCV and 35 patients receiving bev for recurrent and progressive glioblastoma (GBM)and anaplastic glioma (AA) were analysed for progression free survival (PFS,overall survival,and duration of neurological improvement. PFS is calculated from date of first cycle to the last cycles before radiological or neurological deterioration. RESULTS: PCV group had significantly younger patients with a median age 51 years compared to 56 in Bev group. Bev was used as I and II or III salvage line 49 and 51%, respectively. PCV was used I and II or III salvage line in 67 and 23% of patients, respectively. 6-month PFS was 38% (95%, CI 22-55%) with Bev and 22% (95%, CI 10-35%) with PCV (not significant). Similarly, superior but not significant increase in median PFS (4.7 vs. 3.3 months) and median overall survival (8.8 vs.5.4 months) were observed in Bev and PCV group, respectively. The number of patients experiencing neurological improvement was higher (57% vs.10%) and mean number of weeks of neurologically improvement compared to the mean number of weeks chemotherapy exposure were significantly longer in Bev group Bev:12/20weeks, PCV:2/1 weeks. CONCLUSION: Although statistically not significant, patients receiving Bev had better 6-month PFS and over survival . Also patients in Bev group experienced longer duration of neurological improvement.

518P - Folfoxiri with or Without Bevacizumab (Bev) As First-Line Treatment of Metastatic Colorectal Cancer (Mcrc): a Propensity Score-Based Analysis

ABSTRACT Aim: A phase III trial by the GONO group showed that the triplet FOLFOXIRI increased RECIST response rate (RR), PFS and OS, as compared to an irinotecan-based doublet. More recently, the TRIBE trial demonstrated that first-line FOLFOXIRI plus bev improves PFS, RR and OS, compared to FOLFIRI plus bev. Also the early response rate and the deepness of response were significantly improved with the triplet plus bev. No direct comparison of FOLFOXIRI with or without bev is available, so that the impact of the addition of bev to the triplet has been never investigated. Methods: From May 2001 to April 2005 122 mCRC patients received first-line FOLFOXIRI in the phase III trial by the GONO (FOLFOXIRI group) and from July 2008 to May 2011 252 patients received first-line FOLFOXIRI plus bev in the TRIBE trial (FOLFOXIRI plus bev group). A propensity scoring method was adopted to estimate the impact of adding bev to FOLFOXIRI. All comparisons were adjusted accordingly. Results: Compared to the FOLFOXIRI group, in the FOLFOXIRI plus bev group more patients had ECOG PS 0 (p Conclusions: According to the present propensity score-based analysis, the addition of bev to first-line FOLFOXIRI provides a clear benefit in terms of PFS and improves OS with a trend toward significance, while no significant differences in terms of response are observed. Though in the absence of a randomized comparison, the present results support the addition of bev to FOLFOXIRI as first-line treatment of mCRC. Disclosure: C. Cremolini: Advisory board: Roche; F. Loupakis: Advisory board and research funding: Roche; A. Falcone: Advisory board and research funding by Roche, Merck, Amgen, Sanofi Aventis Advisory board: Bayer, Celgene. All other authors have declared no conflicts of interest.

414O - Randomized Phase Ii Trial Avareg (Ml25739) with Bevacizumab (Bev) or Fotemustine (Ftm) in Recurrent Gbm: Final Results from the Randomized Phase Ii Trial

ABSTRACT Aim: The treatment of recurrent glioblastoma (GBM) remains an open issue and the role of BEV has been largely debated since only few data compared this agent with the standard agents. Methods: A multicenter, open label, randomized (2:1), non-comparative phase II study (EudraCT 2011-001363-46; AVAREG - ML25739) with BEV 10 mg/m2 iv every 2 weeks or FTM 75 mg/m2 iv day 1-8-15 followed, after a 35 days interval, by FTM 100 mg/m2 every 3 weeks was conducted. Primary endpoint was overall survival at 6 months (OS6). Stratification factors were age ( 55 yrs) and resection for recurrent disease (yes vs no). Results: 91 patients (pts) with recurrent GBM were enrolled among 10 Italian centers between 11/2011 and 9/2012. Median age was 57 yrs (range: 28-78), ECOG PS was 0/1/2 in 42/35/14 pts. All pts received RT/TMZ accordingly with EORTC 26981-22981/NCIC CE3. Time from diagnosis to 1st recurrence was 331 days in the BEV arm and 460 days in the FTM arm. At the time of recurrence, 21 pts (23.1%) underwent re-resection before the inclusion into the study (13/8 pts in BEV/FTM arms, respectively). Fifty-nine pts were enrolled in the BEV arm and 32 pts in the FTM arm. OS6 was 62.1% (95%CI: 48.4 - 74.5) and 73.3% (95%CI: 54.1 - 87.7), OS9 was 37.9% (95%CI: 25.5–51.6) and 46.7% (95%CI 28.3–65.7) in the BEV and FTM arms, respectively. Median OS was 7.3 months (95%CI: 5.8 - 9.2) in the BEV arm and 8.7 months (95%CI: 6.3-15.4) in the FTM arm. In the BEV arm, OS6 and OS9 were 77.8% (95%CI: 57.7–91.4) and 59.3% (95%CI: 38.8 - 77.6) in pts ≤55 yrs, and were 48.4% (95%CI: 30.1 - 66.9) and 19.3% (95%CI: 7.4 - 37.5) in pts >55 yrs. HR for OS in BEV group for pts >55 yrs compared with pts ≤55 yrs was 2.0 (95%CI: 1.0-4.1, p = 0.05). G 3-4- toxicity BEV FTM Neutropenia 1 (1.7%) 4 (12.5%) Thrombocytopenia 0 7 (21.9%) Intestinal perforation 2 (3.4%) 0 Cerebral ischaemia/haemorrage 2 (3.4%) 0 Pulmonary embolism 1 (1.7%) 0 Acute myocardial infarction 1 (1.7%) 0 Conclusions: BEV in recurrent GBM showed survival rates superimposable with FTM. Disclosure: V. Zagonel: Roche – Speaker; M. Reni: Genentech - Advisory board; G. Rosti: Roche - Speaker A. Galli: Roche – employee; S. Doria: Roche – employee; All other authors have declared no conflicts of interest.

A phase II study of second-line S-1/CPT-11+bev for advanced colon cancer (NCCSG04): Subset analysis by K-ras, EGFR, UGT1A1, and previous bevacizumab.

564 Background: We planned a phase II trial to evaluate the efficacy and safety of irinotecan, S-1, and bevacizumab (IRIS/Bev) as second-line therapy for patients with metastatic colorectal cancer (mCRC). The result of this study was reported an active and generally well-tolerated 2nd-line treatment for mCRC (Takii et al. ASCO-GI 2013 #496). We analyzed subset of EGFR, K-ras, UGT1A1, and previous Bev. Methods: The study design was multicenter, single-arm, open-label phase II study. Eligible patients had to have mCRC with confirmed diagnosis of adenocarcinoma, history of oxaliplatin containing regimen as first-line therapy, an age from 20 to 80 years, ECOG performance status (PS) of 0-1. S-1 65 mg/m2 daily p.o. was given on days 1-14 and Irinotecan 75mg/m2and bevacizumab 10mg/kg i.v. were given on days 1 and 15 of a 28-day cycle. We retrospectively examined progression-free survival (PFS), overall response rate (OR), overall survival (OS), time to treatment failure (TTF) and safety by K-ras, EGFR, UGT1A1, and previous Bev status. Results: Thirty-four patients were investigated. The OR was 21.1% (7/33) and disease control rate was 84.8% (28/33). Median PFS was 8.9 months, median TTF was 8.2 months and median OS was 23.4 months. Median PFS was 9.9 months on K-ras wild group and 6.6 months on K-ras mutant group (p = 0.517). Median OS was not reached on K-ras wild group and 16.4 months on K-ras mutant group (p = 0.097). The EGFR-negative case was three cases, and it did not become a data to compare because of small number. Median PFS was 8.5 months on previous Bev group and 9.9 months on previous no-Bev group (p = 0.637). Median OS was not reached on previous Bev group and 23.1 months on previous no-Bev group (p = 0.701). Median PFS, TTF and OS was no different between UGT1A1 wild group and mutant group. On safety analysis, there were no different between the two groups, respectively. Conclusions: IRIS/Bev is an active and well-tolerated second-line treatment for patients with mCRC. Only K-ras status influendced OS. Clinical trial information: UMIN000001631.

Abstract B2: Switching to aflibercept treatment resulted in greater tumor responses than continuous bevacizumab treatment in patient-derived xenograft models of colorectal cancer.

Abstract Background: The recombinant fusion protein aflibercept (afl) binds VEGF-A, -B, and placental growth factor (PlGF). Based on an OS benefit observed in the phase 3 VELOUR trial, aflibercept in combination with FOLFIRI was approved for patients with metastatic colorectal cancer (mCRC) following a prior oxaliplatin-containing regimen. In vitro, afl inhibited VEGFR signaling more potently and blocked cell migration more effectively vs. bevacizumab (bev) which only binds VEGF-A. Recent in vivo studies comparing the anti-tumor activity of afl vs. bev were conducted in patient-derived xenograft (PDX) CRC models. The PDX models are clinically relevant as they represent common genetic backgrounds in CRC and were derived from primary tumors or from metastases. A sequential treatment regimen of aflibercept post-bev vs. continuation of bev treatment was investigated. Methods: Forty eight different CRC adenocarcinoma tumors were engrafted subcutaneously (SC) into NMRI nude mice to generate 48 distinct PDX CRC models. ELISA and Luminex measured the expression of mouse and human VEGF-A and mouse and human PlGF in untreated tumors. Tumor-bearing mice (8 mice/group) were dosed with afl, bev, or placebo 2x/wk for 3 wks and SC tumor measurements were recorded 2x or 3x/wk. In 3 PDX models, mice that were treated with bev were randomized and either switched to afl treatment or continued to receive bev. Activity was expressed as relative change in tumor volume between treatment (ΔT) and control (ΔC) at 3 wks. A ΔT/ΔC ≤0% indicated complete tumor stasis. Student's t tests evaluated statistical differences in final tumor volumes. Results: Aflbercept induced complete tumor stasis in 31/48 PDX CRC models and bev in 2/48 PDX CRC models. The PDX models were characterized into 2 phenotypes based on statistical analysis: phenotype A, where afl activity was greater than bev activity (39 /48 PDX), and phenotype B, where there was no significant difference between the 2 drugs (9/48 PDX). Three models in which bev treatment resulted in eventual tumor escape vs. continuous inhibition by afl were selected for sequential treatment of bev followed by afl. Afl treatment began after bev treatment resulted in a greater than 2-fold increase in tumor volume. Greater anti-tumor activity occurred when afl was administered after bev vs. continuous bev treatment. At the end of the study, the tumor volumes were statistically significantly different between the afl and bev groups (T test p values < 0.0001). Analysis of angiogenic factors revealed that the tumor cells were the major source of VEGF whereas PlGF was primarily produced by the tumor stroma. Conclusions: Aflibercept induced complete tumor stasis more frequently in CRC PDX models than bevacizumab. As tumor levels of hVEGF-A were far greater than mVEGF-A, the inability of bevacizumab to bind mVEGF-A is unlikely to explain the higher and more consistent activity of aflibercept. In all 3 PDX models tested, switching to aflibercept treatment after bev treatment resulted in a greater tumor response than continuous bev treatment. The greater response to aflibercept than bev after an initial treatment with bev suggests that individual patients may derive more benefit from aflibercept than bev in second line treatment after an initial bev-based regimen. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B2. Citation Format: Marielle Chiron, Rebecca G. Bagley, Jack Pollard, Christophe Henry, Parminder Mankoo, Loic Vincent, Catherine Geslin, Tatjana Kloss, Donald A. Bergstrom. Switching to aflibercept treatment resulted in greater tumor responses than continuous bevacizumab treatment in patient-derived xenograft models of colorectal cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B2.

Floxuridine Hepatic Arterial Infusion Associated Biliary Toxicity Is Increased by Concurrent Administration of Systemic Bevacizumab

Systemic bevacizumab (Bev) was added to hepatic arterial infusion (HAI) floxuridine (FUDR)-based chemotherapy in three studies in an attempt to improve outcomes. A specific review of biliary toxicity was carried out. This analysis included 203 patients from three prospective studies. The first (study A) was an adjuvant study after liver resection of colorectal metastases in which patients received HAI and systemic chemotherapy (Sys) with or without Bev. Study B comprised unresectable colorectal patients who received HAI and Sys plus Bev. Study C included patients with unresectable cholangiocarcinoma or hepatocellular carcinoma who received HAI plus systematic Bev. The outcome and toxicity of patients in studies B and C were compared with historical controls. In all three studies, the incidence of hyperbilirubinemia and biliary stent placement within 1year of treatment was increased with the addition of Bev. In the no-Bev versus Bev groups, the placement of biliary stents was as follows: study A, 0 of 38 versus 4 of 35 patients (p=0.05); study B, 0 of 49 versus 3 of 24 (p=0.06); and study C, 0 of 34 versus 3 of 22 (p=0.15). Elevation in bilirubin was noted in the no-Bev versus Bev groups: study A, 0 of 38 versus 5 of 35 patients (p=0.02); study B, 1 of 49 versus 7 of 24 (p=0.005); and study C, 2 of 34 versus 5 of 22 (p=0.10). The addition of Bev did not seem to be associated with improved progression-free or overall survival. The addition of Bev to HAI FUDR resulted in increased biliary toxicity in three separate studies. Although the sample sizes were small, there was no evidence of improved PFS or OS with the addition of Bev. Bev should not be combined with HAI FUDR.

Regions of interest and parameters for the quantitative analysis of contrast-enhanced ultrasound to evaluate the anti-angiogenic effects of bevacizumab

The aim of the present study was to identify effective regions of interest (ROIs) and parameters for the quantitative analysis of contrast-enhanced ultrasound (CEUS) to evaluate the anti-angiogenic effects of bevacizumab. Thirty mice were subcutaneously injected with CT26 cells and randomly divided into a bevacizumab‑treated (Bev) group and a control group (normal saline-treated). CEUS and quantitative analysis were performed on days7, 11, 14 and 21 following tumor establishment. ROItotal, which included the whole tumor, and ROIsmall, which included the most enhanced part of the tumor, were selected and outlined. Parameters including time to peak (TTP), maximum intensity (Imax) and area under the curve (AUC; in addition to rates of AUC1, AUC2, AUCfast and AUCslow) were recorded. The tumors were resected on day21 for microvessel density (MVD) counting. Our results showed that the MVD in the Bev group was significantly lower compared with that in the control group (4.09 vs. 6.41; P=0.001). Additional parameters of ROIsmall were identified to be significantly different between the two groups, compared with those of ROItotal. No significant differences in TTP and Imax were observed between the two groups at the four time‑points examined (P>0.05). For the AUC parameters in ROIsmall, AUC and the rates of AUC2, AUCfast and AUCslow were lower in the Bev group compared with those in the control group on days7and11 (P<0.05). These findings indicate that ROIsmall and AUC parameters in the quantitative analysis of CEUS may be useful for the evaluation of changes in tumor angiogenesis following bevacizumab treatment.

Pathologic response, KRAS status, and bevacizumab: The Bermuda triangle for outcome prediction after hepatic colorectal cancer metastases (HCRM) resection.

e14716 Background: Clinicopathologic factors are insufficient to stratify prognosis after HCRM resection. The identification of prognostic biomarkers is an unmet clinical need. Even if the prognostic role of KRAS mutations in the metastatic setting is controversial, recent data hypothesized a correlation to worse outcome after HCRM resections. This analysis evaluated the correlation between KRAS mutation, pathological response and outcome. Methods: Fifty-eight pts with HCRM were resected at National Cancer Institute of Milan from 2007 to 2012 following bevacizumab (Bev) (n=30) or cetuximab (Cmab) (n=28) based neoadjuvant regimens. Tumor regression grade (TRG) was classified from TRG 1 for pathological complete response (pCR), to TRG5 for no response; TRG 1-3 for response; TRG 4-5 for scarce/no response. KRAS exons 2 to 4 were sequenced by direct PCR. Results: KRAS missing in 3 pts (1 Bev/2 Cmab), mutated in 23 (42%) vs wild-type in 32 (58%), mutated in 18 (62%) of Bev group vs 5 (19%) of Cmab. Mean TRG: 2.9 (2.2-4) in Bev vs 3.8 (3-5) in Cmab group (p=0.04 at Kruskal-Wallis test). Pathological response higher for Bev vs Cmab (70% vs 39%; p=0.037 at Chi-square test). Bev also increased pCRs (20% vs 0%, p=0.024 at Fisher’s test). Pathological response higher for KRAS mutant vs wild-type (70% vs 41%; p=0.003 at Chi-square test). At log-rank test, DFS significantly shorter for KRAS mutated vs wild-type (7.6 vs 14.6 months; p=0.05), and for TRG4-5 vs TRG1-3 (8.1 vs 15.3 months; p=0.02), while no difference observed according to treatment. OS data are not mature. Multivariable Cox model for DFS shown in the Table. Conclusions: After Bev-based neoadjuvant treatment, patients with KRAS mutated HCRM and without good pathological response may have the worst outcome after curative resection. [Table: see text]

Efficacy of bevacizumab-containing chemotherapy for non-squamous non-small cell lung cancer with bone metastases

Skeletal-related events (SREs) negatively affect the quality of life of patients with cancer. Vascular endothelial growth factor receptor (VEGFR)-targeted therapy is effective against bone metastasis in animal models, but the clinical efficacy of anti-VEGFR inhibitors against bone metastases remains unclear. Therefore, we aimed to investigate the efficacy of chemotherapy with bevacizumab, an anti-VEGF antibody, against bone metastases. We retrospectively reviewed consecutive patients with non-squamous non-small cell lung cancer who received first-line platinum-based chemotherapy with zoledronic acid at Shizuoka Cancer Center between 2007 and 2011. Of 25 patients, 13 received bevacizumab-based chemotherapy (BEV group) and 12 received chemotherapy without bevacizumab (non-BEV group). The overall response (54 vs. 8 %, p = 0.01) and disease control (100 vs. 50 %, p = 0.01) rates were higher in the BEV group than in the non-BEV group. The bone-specific response (23 vs. 0 %, p = 0.038) and disease control (100 vs. 67 %, p = 0.01) rates were also higher in the BEV group. The median time to progression (TTP) for bone metastases was higher in the BEV group (13.7 vs. 4.3 months, p = 0.06), whereas that for overall disease was similar between the groups (5.7 vs. 2.6 months, p = 0.17). The proportions of patients with SREs were 23 and 50 % in the BEV and non-BEV groups, respectively (p = 0.16). Bevacizumab might potentiate the antitumor activity of chemotherapy against systemic disease and bone metastases, prolonging bone-specific TTP and reducing the incidence of SRE.

High pathologic response rate of hepatic colorectal cancer metastases (HCRM) following neoadjuvant bevacizumab (Bev)-based treatment (tx).

529 Background: Pathologic response of HCRM to neoadjuvant tx is associated to better outcome. In retrospective analyses Bev-based tx improved tumor regression grade (TRG), while cetuximab (Cmab) increased RECIST response and R0 resections in prospective studies. The aim of this analysis was to assess the effect of Bev vs Cmab-based tx in terms of HCRM pathological response and outcome. Methods: Fifty-eight pts with HCRM were resected at National cancer Institute of Milan from 2007 to 2012 following Bev (n=30) or Cmab (n=28) based neoadjuvant tx. Pathological response was classified from TRG 1 for pathological complete response (pCR), to TRG5 for no response; TRG 1-3, for histological response; TRG 4-5 for scarce/no response (Rubbia-Brandt L, Ann Oncol 2007). Results: KRAS missing in 9 pts (3 Bev/6 Cmab), mutated in 18 pts (60%) in Bev vs 4 (14%) in Cmab group.Median number of resected metastases: 4.6 vs 3.9; mean TRG: 2.9 (2.2-4) in Bev vs 3.8 (3-5) in Cmab group (p=0.04 at Kruskal-Wallis test). Pathological response rate was higher for Bev vs Cmab (70% vs 39%; p=0.037 at Chi-square test). Bev also increased pCRs (20% vs 0%, p=0.024 at Fisher’s test). With generalized estimating equation for all resected nodules, mean TRG was lower in Bev vs Cmab group: 2.6 (2-4) vs 3.7 (3-4), p&lt;0.001. At univariate analysis, no PFS and OS difference was observed according to tx. Multivariable Cox models shown below: Conclusions: Bev-based tx obtained an excellent pathological response rate, despite the high proportion of KRAS mutated tumors, and further prospective confirmation of these data is planned. [Table: see text]

155P - Effect of Bevacizumab on Tumour 5-Fluorouracil Concentration and Microcirculatory Parameters Obtained by Dynamic Contrast-Enhanced MRI in a Hepatocellular Carcinoma Xenograft Model

ABSTRACT Introduction Vascular endothelial growth factor (VEGF) is expressed by tumours to promote angiogenesis. Clinical trials of anti-VEGF therapy combined with chemotherapy demonstrate improvement in survival. We investigate the effect of bevacizumab (bev), a humanized monoclonal antibody that inhibits VEGF-A, on tumour 5-fluorouracil (5FU) concentration in a hepatocellular carcinoma (HCC) xenograft model, together with changes in tumour microcirculatory parameters obtained by dynamic contrast-enhanced (DCE) MRI. Methods 48 immunodeficient mice implanted with subcutaneous HCC xenografts were first injected with bev (1mg/kg or 10mg/kg) or omalizumab (control). 1 day later, they received 5FU and were sacrificed. Tumour and plasma 5FU concentration was measured by liquid chromatography-mass spectrometry. A subset of 17 mice underwent DCE MRI with gadolinium contrast at baseline and one day after bev/omalizumab injection. Scans employed a three-dimensional spoiled gradient recalled sequence with tracer concentration estimated using variable flip-angle technique. Data analysis employed a conventional two-compartment tracer kinetic model. Results Tumour 5FU concentration (µg/g) was significantly lower 1 day after bev (10mg/kg) compared to control (8.4 vs 21.6, p = 0.027). However, there was no significant difference in plasma 5FU concentration between the bev and control groups. Following bev (10mg/kg), DCE MRI measurements of tumour intravascular blood volume reduced by 38.3% (p = 0.01); there was no significant change in DCE-MRI parameters in the control group. Following bev (1mg/kg), tumour permeability-surface area product (ml/100ml/min) correlated with tumour 5FU concentration (r2 = 0.84, p = 0.01). Conclusion Bev causes vascular shutdown consistent with its anti-angiogenic mode of action. Reduced tumour 5FU concentration suggests that the reported synergism between anti-VEGF and chemotherapy may not be attributable to improved drug delivery at this early time point. DCE-MRI may play a role as a biomarker for tumour drug concentration following anti-VEGF therapy. Disclosure All authors have declared no conflicts of interest.

Comparison of bevacizumab versus pemetrexed in combination with platinum-based doublets in first-line treatment of advanced non-small cell lung cancer.

e18078 Background: First-line treatment of advanced nonsquamous non-small cell lung cancer (NSCLC) with platinum-based doublets, including pemetrexed (P) or bevacizumab (B), has achieved more than 12 months of survival. At the moment, there are no phase III head-to-head comparisons of these combinations. Methods: We retrospectively analyzed, from 05/2007 to 02/2011, in a single institution, all pts with stage IIIB or IV nonsquamous NSCLC treated with B or P combined with platinum compounds in first-line treatment to determine differences in OS, PFS, ORR and toxicity. We performed multivariate analysis to identify prognostic factors for survival. Results: Of the 82 pts included, 40 pts (48,8%) received carboplatin/paclitaxel or cisplatin/gemcitabine combined with B (BEV group), while 42 pts (51,2%) received cisplatin or carboplatin combined with P (PEM group). BEV had significantly fewer pts with age &gt; 70 years (p=0,01) and CNS metastases (p&lt;0,001) than PEM. Maintenance therapy was administered in 65,0% and 52,4% of pts in BEV and PEM groups, respectively (p=0,17). Significantly more pts in BEV received second-line treatment (72,5% vs. 52,4%; p=0,04) than in PEM, prevailing P as drug of choice (79,3%). ORR (60,0% vs. 35,7%; p=0,04) and median survival (26,4 vs. 16,4 months; p=0,009) were significantly superior for BEV. Median PFS were not different between BEV and PEM (10,5 vs. 7,7 months; p=0,06). In multivariate analysis, ECOG 2 (p=0,005), bone (p=0,01) and adrenal metastases (p=0,005) were independent prognostic factors for worst survival, while treatment with BEV did not reach statistical significance (p=0,07). Grade 3-4 neutropenia (27,5% vs. 9,5%; p=0,03) and neuropathy (17,5% vs. 0%;p=0,005) were more frequent in BEV. Conclusions: First-line treatment of advanced nonsquamous NSCLC patients with platinum-based doublets combined with B resulted in better ORR and higher rate of toxic effects as compared with P-based regimens. ECOG 2, bone and adrenal metastases were independent prognostic factors for poor survival. Although there was a survival benefit at univariate analysis, use of B combination was not an independent prognostic fator.

Effect of bevacizumab on sinusoidal injury in patients receiving oxaliplatin-based chemotherapy and liver damage after massive hepatectomy in rats.

276 Background: The aim of this study was to clarify impact of bevacizumab (Bev) on both hepatic sinusoidal injury after oxaliplatin (L-OHP)-based chemotherapy for metastatic colorectal cancer, and on liver regeneration after massive hepatectomy (Hx). Methods: &lt;Study 1: Clinical&gt; Fourteen patients who underwent Hx after receiving L-OHP-based chemotherapy for liver metastases from colorectal cancer were divided into two groups (Bev group (n=8) and No-Bev group (n=7)). Histology of non-cancerous liver tissue, blood chemistry such as hyaluronic acid (HA), spleen size, and postoperative complications were compared between the two groups. &lt;Study 2: Experimental&gt; Male Wister rats that underwent 90%-Hx were divided into two groups (Control group (n=7) and Bev group (n=7), in which Bev was injected intraperitoneally (5mg/kg) 7days before Hx). The following parameters were compared; blood chemistry, liver weight to body weight (Lw/Bw) ratio, and cytokines in liver tissues by RT-PCR, and survival rate. Results: &lt;Study 1&gt; Incidence of sinusoidal dilatation in Bev group was lower than that in No-Bev group (25% vs. 67%). Serum HA before Hx in Bev group (28 ng/ml).was lower than that in No-Bev group (155ng/ml). Spleen size in Bev group (174 ml) tended to be smaller than that in No-Bev group (252 ml). No significant postoperative complication was observed in Bev group, while 4 out of 7 patients had complications in No-Bev group. &lt;Study 2&gt; Liver damage such as ALT in Bev group (1471 IU/L) was smaller than that in Control group (2287 IU/L). Regeneration rate (Lw/Bw ratio) in Bev group was greater than that in Control group (0.80 vs. 0.67). Expression levels of IL-1β, MMP2 and MMP9 in Bev group tended to be lower than those in Control group. Survival rate at 72 hours after Hx in Bev group (83%) tended to be better than that in Control group (50%). Conclusions: Bev could reduce sinusoidal injury in patients with L-OHP-based chemotherapy, furthermore, Bev reduced liver injury and promoted liver regeneration after massive hepatectomy in rats. Those data strongly suggest Bev has beneficial effects for patients receiving L-OHP-based chemotherapy who undergo massive Hx.

Predictive value of contrast enhancement on computed tomography for the responses to oxaliplatin-based chemotherapy with bevacizumab for hepatic metastases from colorectal cancer.

e14105 Background: The addition of bevacizumab (Bev) to chemotherapy is associated with improved survival by anti-angiogenic mechanism in colorectal cancer (CRC). Therefore, the antitumor effect of Bev may correlate with the degree of the contrast-enhancement (CE) of targets reflecting tumor microvessels on the computed tomography (CT). The purpose of this study was to determine whether responses to chemotherapy with bevacizumab correlated with the degree of CE of hepatic metastatic lesions of colorectal cancer (CRC). Methods: Thirty one patients with hepatic metastases from CRC who underwent at least three course of mFOLFOX6 or XELOX therapy as the first-line chemotherapy between September 2006 and April 2010 were analyzed retrospectively. The patients were divided into two groups with or without Bev (17 in the Bev group and 14 in the non-Bev group). CT scans were performed during the late arterial phase following intravenous injection with a nonionic contrast medium at a dose of 600 mgI/kg, using a multi detector CT. Using an imaging control system, the diameter and mean CT values of metastatic lesions before chemotherapy were determined in each patient. The degree of CE was evaluated by the ratio of the CT value of hepatic metastases in the late arterial phase by in the noncontrast phase (i.e., CE ratio), whereby the patients were divided into the high or low CE group by the median CE ratio. Results: There was significant correlation between the CE ratio and the tumor shrinkage rate in the Bev group (R2 =0.3817, p=0.0082), whereas no such relationship was noted in the non-Bev group. In the high CE group (n=16), the tumor shrinkage rate increased to 35.9% in the Bev group from 8.6% in the non-Bev group (p=0.0716). In the low CE group, however, no significant difference was noted. Conclusions: The present study demonstrated the correlation between the CE ration and the tumor shrinkage in patients treated with Bev. The results suggest that the CE ratio on CT scanning in hepatic metastatic lesion can be a predictive value for the response to chemotherapy with Bev, although generalization of the CE ratio and the prospective study should be need.

The impact of bevacizumab on liver regeneration following hepatectomy in rats.

228 Background: In our clinical data, we had the interesting findings that the pathologic sinusoidal obstruction syndrome and serum hyaluronic acid after neoadjuvant oxaliplatin-associated chemotherapy for liver metastatic colorectal cancer with bevacitumab (Bev) was ameliorated compared to those without Bev. The purpose of this study was to investigate the influence of bevacizumab administration on regenerating liver in rat 70% and 90% hepatectomy (Hx) model as a surrogate model of human massive hepatectomy for liver metastatic colorectal cancer. Methods: Male Wister rats weighing 180-230g were divided into the following four groups: 70%Hx, 70%Hx + Bev, 90%Hx and 90%Hx+Bev group. The rats were pretreated with intraperitoneal administration of bevacizumab (5mg/kg) 7 days before hepatectomy. The remnant liver and blood samples were taken one day after hepatectomy, and the following parameters were evaluated: blood analysis (AST, ALT, LDH, T- Bil, and hyaluronic acid), liver weight to body weight (Lw/Bw) ratio, and postoperative survival rate for three days. Results: In the 70%Hx model, there was no significant difference between the 70%Hx group and 70%Hx + Bev group in blood analysis one day after hepatectomy; AST (1928 vs. 923 IU/L), ALT (1282 vs. 670 IU/L), T-Bil (0.17 vs. 0.19 mg/dl), LDH (3822 vs. 2967 U/L) and hyaluronic acid (995.7 vs. 1026.6 ng/ml) and in Lw/Bw ratio (1.78 vs. 1.84). In 90%Hx model, AST and ALT of blood analysis in 90%Hx+Bev group significantly decreased compared to those in 90%Hx group; AST (3428 vs. 4995 IU/L, P&lt;0.05), ALT (1471 vs. 2287 IU/L, P&lt;0.05), T-Bil (1.94 vs. 2.57 mg/dl), LDH (3229 vs. 5351 U/L) and hyaluronic acid (3865.7 vs. 7862.2 ng/ml). The Lw/Bw ratio in 90%Hx+Bev group significantly increased compared to that in 90%Hx group (0.80 vs. 0.67, P&lt;0.05). The postoperative survival rate in 90%Hx+Bev group showed tendency to improve compared to that in 90%Hx group (75% vs. 50%, P=0.19). Conclusions: The administration of bevacizumab seven days before hepatectomy did not significantly affect the liver functions and liver regeneration rate. These findings suggest that hepatectomy might be safe and feasible after the use of bevacizumab. No significant financial relationships to disclose.

A randomized phase II trial of adjuvant hepatic arterial infusion and systemic chemotherapy with or without bevacizumab in patients with resected hepatic metastases from colorectal cancer.

3557 Background: To determine whether intravenous bevacizumab (Bev) added to adjuvant systemic chemotherapy and hepatic arterial infusion (HAI) after liver resection increases recurrence free survival (RFS). Secondary endpoints are evaluation of overall survival and toxicity. Methods: Patients with resected liver metastases were randomized to HAI plus systemic therapy with or without Bev after stratification by clinical risk score and previous chemotherapy. RFS of ≥ 80% at 1 year in the Bev group would be considered worthy of future study. The initial dose of HAI FUDR 0.12 mg/kg plus dexamethasone was infused over the first 2 weeks of a 5-week cycle. Systemic chemotherapy was delivered on days 15 and 29 with oxaliplatin (oxal) at 85 mg/m2, 5FU 48-hour continuous infusion dose at 2,000 mg/m2 and bolus LV at 400 mg/m2 (if patient received prior oxal, irinotecan at 150 mg/m2 was used). Survival curves were estimated using the Kaplan-Meier method and compared by the log-rank test. Results: After randomization of 73 patients, study was terminated early due to signs of increased toxicity and lack of improvement in efficacy in the Bev arm. The study's two arms had similar patient characteristics (Table). With a median follow-up of 26 months, the 1-year RFS is 65% (Bev arm) and 83% (non-Bev) (log-rank test p-value=0.15); 4 year RFS is 31% and 45%, respectively. The 4-year survival is 87% (Bev arm) and 91% (non Bev) (log-rank test p-value=0.7). Biliary toxicity was increased in Bev arm, including biliary stenting in 4/35 (Bev arm), and 0/38 (non Bev) (p=0.05). Conclusions: The addition of bevacizumab toadjuvant HAI and systemic therapy after liver resection does not increase RFS or survival and appears to cause increased biliary toxicity. Patient characteristics HAI + SYS (n=38) HAI + SYS + Bev(n=35) P value(reported if significant at 0.05 level) Synchronous 66% 63% 3 or more lesions 68% 49% Prior liver surgery/RFA 5% 17% RFA at time of pump placement 16% 14% CRS ≥ 3 50% 46% Post-op CEA > 5 21% 20% Largest diameter ≥ 5 18% 17% Prior oxal 79% 69% Kras mutated 28% 21% Toxicity Diarrhea 8% 17% Alk phos ≥ 2-fold increase 16% 31% Bili > 3 0% 14% 0.02 Stents 0% 11% 0.05 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech

Intravitreal Bevacizumab With or Without Photodynamic Therapy for the Treatment of Polypoidal Choroidal Vasculopathy

Purpose: To compare the efficacy of photodynamic therapy (PDT) using verteporfin combined with intravitreal bevacizumab and bevacizumab monotherapy in polypoidal choroidal vasculopathy (PCV). Methods: Twenty-six eyes, diagnosed with PCV were reviewed retrospectively. They were divided into two groups: combined treatment (COMB) and bevacizumab monotherapy (BEV). Visual acuity, fluorescein angiography (FA) and indocyanine green angiography (ICG) results were reviewed to compare changes in the polypoidal vessels and the branching vascular networks. Results: Among 26 eyes of 26 patients, there were 12 eyes in the COMB group and 14 eyes in the BEV group. Follow-up periods were about 42 weeks and 48 weeks for the respective groups. In the COMB group, visual acuity improved from log MAR 0.92 to 0.56, whereas visual acuity in the BEV group changed only minimally from log MAR 0.98 to 0.97. In the COMB group, the polypoidal vessel resolved in six eyes. In the BEV group, the polypoidal vessel resolved in one eye. In the COMB group, the vascular network resolved in one eye, improved in ten eyes, and did not change in one eye. In the BEV group, the vascular network did not change in any of the 14 eyes. Conclusions: Combined treatment with PDT and intravitreal bevacizumab resulted in a more prolonged effect, induced the resolution of polypoidal vessels more effectively than did bevacizumab monotherapy, and is expected to reduce recurrence and retreatment.

3055 POSTER Cetuximab plus irinotecan in patients (pts) with metastatic colorectal cancer (mCRC) progressing on or after prior irinotecan therapy: final results of the LABEL study

Small bowel adenocarcinomas (SBAs) are rarely seen tumors. Data regarding the use of chemotherapy together with bevacizumab in patients with advanced SBA are lacking. The aim of this study was the evaluation of treatment with bevacizumab in advanced SBA.Twenty-eight patients from 5 centers with a diagnosis of advanced SBA who received first-line treatments with modified FOLFOX6 (mFOLFOX6; oxaliplatin, leucovorin, and 5-fluorouracil) and FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan) chemotherapy regimens were involved in the study. All patients were divided into 2 groups; those who received bevacizumab together with these chemotherapy regimens (Chemo+Bev group) and those who did not receive bevacizumab (Chemo group).The median progression-free survival (PFS) and overall survival (OS) times of all population were 8.7 months and 16.9 months, respectively. The overall response rate was 43.7% in the Chemo group and 58.3% in the Chemo+Bev group. The median PFSs in the Chemo and Chemo+Bev groups were found to be 7.7 months and 9.6 months, respectively, and the median OSs were 14.8 months and 18.5 months, respectively. There was not a significant difference between the groups in terms of overall response rate, PFS, and OS.Although there was no significant difference in any of the outcomes, use of bevacizumab together with chemotherapy is a more effective treatment approach compared with chemotherapy alone, and it does not cause an excess of significant toxicity.

Verteporfin Therapy and Intravitreal Bevacizumab Combined and Alone in Choroidal Neovascularization due to Age-Related Macular Degeneration

To evaluate the efficacy and safety of photodynamic therapy (PDT) with verteporfin combined with intravitreal bevacizumab in choroidal neovascularization (CNV) owing to age-related macular degeneration (AMD) in comparison with individual monotherapies used as controls. Randomized controlled pilot clinical trial. Males or females, aged > or =50 years, with minimally classic or occult CNV owing to AMD in at least 1 eye that had never been treated previously. One hundred sixty-five eyes in 165 subjects (53 males, 112 females) aged between 60 and 87 years (mean [standard deviation]: 75.7 [6.0] years) were randomly assigned to receive either a single PDT session with verteporfin (PDT group; n = 55), or a single administration of intravitreal bevacizumab (1.25 mg; BEV group; n = 55), or their combination (COMB group; n = 55). In the COMB group, bevacizumab was administered within 1 hour of PDT. Subjects were followed up at 1 and 3 months after treatment. Ophthalmic evaluations including optical coherence tomography, fluorescein angiography, and visual acuity (VA) and central foveal thickness (CFT) measurements were performed at each visit. Changes from baseline in best-corrected VA and CFT measured at 1- and 3-month follow-up visits. One hundred fifty-six subjects (54 BEV, 50 PDT, and 52 COMB) completed the study. At the 3-month follow-up, significant improvements in best-corrected VA were observed in the BEV and COMB groups (0.079 and 0.223 logarithm of the minimum angle of resolution [logMAR], respectively; P<0.0001 for both). In the PDT group, a slight worsening was noted. Significant reductions of CFT were observed in the 3 groups (-34.0 microm [BEV], -59.6 microm [COMB], and -50.5 microm [PDT]; P<0.0001 for all). At the 1-month follow-up, 46 subjects (16 BEV, 29 COMB, and 1 PDT) had an improvement >0.2 logMAR in best-corrected VA; at 3-month follow-up, this improvement persisted in 23 subjects (1 BEV, 22 COMB, and 0 PDT). Significant improvements in best-corrected VA after 1 month and their maintenance over a 3-month period were observed after verteporfin PDT combined with intravitreal bevacizumab. These results should be confirmed in larger and long-term prospective randomized trials.