Bevacizumab In Metastatic Colorectal Cancer Research Articles

Final results and subgroup analyses of the phase 3 CAIRO3 study: Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC).

LBA388 Background: The optimal duration of chemotherapy and bevacizumab (bev) in mCRC is not well established. The CAIRO3 study investigated the efficacy of maintenance treatment with capecitabine (cap) + bev versus observation in mCRC patients (pts) not progressing during induction treatment with cap, oxaliplatin, and bev (CAPOX-B). Methods: Previously untreated mCRC pts, PS 0-1, with stable disease or better after six cycles of CAPOX-B were randomized between observation (arm A) or maintenance treatment with cap 625 mg/m2 bid daily continuously + bev 7.5 mg/kg iv q 3 weeks (arm B). Upon first progression (PFS1), pts in both arms were to be treated with CAPOX-B until 2nd progression (PFS2, primary endpoint). Secondary endpoints were overall survival (OS) and time to 2nd progression (TTP2), which was defined as the time to progression or death on any treatment following PFS1, and quality of life. Preplanned subsetanalyses were performed. Results: A total of 558 pts were randomized. Median follow-up is 48 months. Upon PFS1, CAPOX-B was reintroduced in 61% of pts in arm A and 48% in arm B. Multivariable analyses for survival, with treatment adjusted for a series of pre-specified potentially confounding factors at baseline showed significant interactions for treatment (observation vs. maintenance) with resection of the primary tumor (yes vs. no) and synchronous or metachronous metastases at baseline (p values for interaction <0.0001). Especially pts with synchronous metastases with resected primary tumor (n=180) appear to benefit from maintenance treatment; median OS 18.0 months (observation arm) vs. 25.0 months (maintenance arm) (log-rank p value: <0.0001). Conclusions: Multivariable analysis showed significant interaction of treatment with some baseline covariates which were not equally distributed among both arms. The positive effect on survival for maintenance treatment with cap + bev is most obvious in pts with synchronous disease in whom the primary tumor was resected. Further details and final results on survival will be presented at the meeting. Clinical trial information: NCT00442637.

Clinical benefits of bevacizumab in metastatic colorectal cancer depending on KRAS status.

636 Background: KRAS status is the therapeutic marker of anti-EGFR drug, and may be the prognostic marker of metastatic colorectal cancer (mCRC). However, there is no consensus whether bevacizumab (anti-VEGF drug) benefits patients with mutated KRAS in mCRC. We investigated the clinical benefits of bevacizumab treatment in mCRC depending on KRAS status, retrospectively. Methods: We investigated 49 patients who received chemotherapies with bevacizumab as first-line treatment for mCRC from May 2008 through June 2013. We evaluated response rate (RR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), tumor reduction rate and the adverse events (CTCAE v4.0 - JCOG) depending on KRAS status. Results: The median age of the patients was 66 years (range; 36 - 80). Forty-five patients received oxaliplatin-based chemotherapies with bevacizumab and four patients received irinotecan-based chemotherapies with bevacizumab. KRAS status of 30 patients was wild type and that of 19 patients was mutation type. There was no difference in patient characteristics between KRAS wild type (WT) and mutation type (MT). In all 49 patients, RR was 62.5%. DCR was 91.7%. The median PFS was 10.9 months. In RR, patients with KRAS wild type tumors had better outcome than patients with mutant type tumors (WT : MT, 69.0% : 52.6%, no statistically difference). A similar tendency was seen in DCR (WT : MT, 96.6% : 84.2%, no statistically difference). The average reduction rate in KRAS WT was 42.7% and in KRAS MT was 32.3% (p = 0.309). In the KRAS wild patients, the median PFS was longer than that in the KRAS mutant patients (WT : MT, 11.8 : 8.9 months, Log Rank p = 0.583), but there is no statistically difference between two groups. In median OS, there was no difference between two groups (WT : MT, 21.0 : 20.8 months, Log Rank p = 0.393). The incidence of severe adverse events was not statistically different between KRAS WT group and MT group. Conclusions: Regardless of KRAS status, bevacizumab provides clinical benefits for patients with mCRC.

Primary tumor location and bevacizumab effectiveness in patients with metastatic colorectal cancer

BackgroundThere is an unmet need for predictive markers for the antiangiogenic agent bevacizumab in metastatic colorectal cancer (mCRC). We aimed to assess whether the location of the primary tumor is associated with bevacizumab effectiveness when combined with capecitabine and oxaliplatin (CAPEOX) in the first-line treatment of patients with mCRC. Patients and methodsA cohort of 667 consecutive patients with mCRC from the general community treated from 2006 to 2011 with CAPEOX and bevacizumab as standard first-line therapy was compared with a cohort of 213 patients treated with CAPEOX from 2003 to 2006, before bevacizumab was approved. Main outcome measures were progression-free survival (PFS) and overall survival (OS). Differences in outcome were tested using Kaplan–Meier curves and log-rank tests, and multivariate analyses were carried out using Cox Proportional Hazards models. ResultsPatients treated with CAPEOX and bevacizumab with primary tumors originating in the sigmoid colon and rectum had a significantly better outcome than patients with primary tumors originating from the cecum to the descending colon, both for PFS (median PFS 9.3 versus 7.2 months; hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.56–0.82) and for OS (median OS 23.5 versus 13.0 months; HR 0.47, 95% CI 0.38–0.57). This difference was confirmed in multivariate analyses after adjustment for other potentially prognostic factors. For patients treated with CAPEOX, there was no association between primary tumor location and outcome, neither in unadjusted nor adjusted analyses. ConclusionsThe addition of bevacizumab to CAPEOX in first-line treatment of patients with mCRC may primarily benefit patients with primary tumors originating in the rectum and sigmoid colon. This hypothesis needs to be validated in data from completed randomized trials. ClinicalTrials.gov identification numberNCT00212615.

A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial

BackgroundThe main objective was to study the effect on progression-free survival (PFS) of adding erlotinib to bevacizumab as maintenance treatment following chemotherapy and bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC). Patients and methodsPatients with untreated mCRC received doublet chemotherapy + bevacizumab during 18 weeks and those without tumor progression were eligible for randomization to bevacizumab + erlotinib (arm A) or bevacizumab alone (arm B), until progression or unacceptable toxic effect. ResultsOf the 249 patients enrolled, 80 started maintenance treatment in arm A and 79 in arm B. The rate of any grade 3/4 toxic effect was 53% in arm A and 13% in arm B. Median PFS was 5.7 months in arm A and 4.2 months in arm B (HR = 0.79; 95% confidence interval 0.55–1.12; P = 0.19). Overall survival (OS) from start of induction chemotherapy was 26.7 months in the randomized population, with no difference between the two arms. ConclusionsThe addition of erlotinib to bevacizumab as maintenance treatment after first-line chemotherapy in mCRC did not improve PFS significantly. On-going clinical and translational studies focus on identifying subgroups of patients that may benefit from erlotinib in the maintenance setting. Clinical Trials numberNCT00598156.

Efficacy and Safety of Bevacizumab in Metastatic Colorectal Cancer: Pooled Analysis From Seven Randomized Controlled Trials

his analysis pooled individual patient data from randomized controlled trials (RCTs) to more thoroughly examine clinical outcomes when adding bevacizumab to chemotherapy for patients with metastatic colorectal cancer (mCRC). Patient data were pooled from the first-line AVF2107, NO16966, ARTIST, AVF0780, AVF2192, and AGITG MAX RCTs and the second-line E3200 RCT. All analyses were based on the intent-to-treat population. To assess differences in time-to-event variables by treatment (chemotherapy with or without placebo vs. chemotherapy plus bevacizumab), stratified random-effects (overall) and fixed-effects (subgroup comparisons) models were used to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs). The analysis population comprised 3,763 patients (1,773 chemotherapy with or without placebo; 1,990 chemotherapy plus bevacizumab). The addition of bevacizumab to chemotherapy was associated with statistically significant increases in overall survival (OS; HR, 0.80; 95% CI, 0.71-0.90) and progression-free survival (PFS; HR, 0.57; 95% CI, 0.46-0.71). The effects on OS and PFS across subgroups defined by chemotherapy backbone (oxaliplatin-based, irinotecan-based), extent of disease (liver metastases only, extensive disease), age (<65, ≥65 years), Eastern Cooperative Oncology Group performance status (0, ≥1), and KRAS status (wild-type, mutant) were consistent with the overall analysis. Incidence rates of grade ≥3 hypertension, proteinuria, bleeding, wound-healing complications, gastrointestinal perforations, and thromboembolic events were increased with bevacizumab treatment. The use of bevacizumab with chemotherapy resulted in statistically significant increases in OS and PFS for patients with mCRC. The PFS benefit extended across the clinically relevant subgroups examined. The observed safety profile of bevacizumab was consistent with that reported in individual trials.

First-line cetuximab gives longer survival than bevacizumab in metastatic colorectal cancer

First-line cetuximab gives longer survival than bevacizumab in metastatic colorectal cancer

P-0248 - Outcomes According to Kras Mutational Status in Treatment with Chemotherapy Plus Bevacizumab in Metastatic Colorectal Cancer

Background: Absence of KRAS mutations is a predictive factor of response to anti-EGFR agents in the treatment of metastatic colorectal cancer (mCRC) but it does not seem to be associated with Bevacizumab (Bv) treatment's outcomes. The aim of this study is evaluate response, progression-free survival (PFS) and overall survival (OS) according to KRAS mutational status in patients (pts) with mCRC treated with CT plus Bv.

Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC): The phase III CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG).

3502 Background: The optimal duration of chemotherapy and bevacizumab in mCRC is not well established. The CAIRO3 study investigated the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation in mCRC pts not progressing during induction treatment with capecitabine, oxaliplatin and bevacizumab (CAPOX-B). Methods: Previously untreated mCRC pts, PS 0-1, with stable disease or better after 6 cycles of CAPOX-B, not eligible for metastasectomy and eligible for future treatment with oxaliplatin, were randomized between observation (arm A) or maintenance treatment with capecitabine 625 mg/m2 bid dailycontinuouslyand bevacizumab 7.5 mg/kg iv q 3 weeks (arm B). Upon first progression (PFS1), pts in both arms were treated with CAPOX-B until second progression (PFS2, primary endpoint). For pts not able to receive CAPOX-B upon PFS1, PFS2 was considered equal to PFS1. Secondary endpoints were overall survival (OS) and time to second progression (TTP2), which was defined as the time to progression or death on any treatment following PFS1. All endpoints were calculated from the time of randomization. Results: A total of 558 pts were randomized. Median follow-up is 33 months. The median number of maintenance cycles in arm B was 9 (range 1-54). The median PFS1 in arm A vs B was 4.1 vs 7.4 months (HR 0.44, 95% CI 0.37-0.54, p&lt;0.0001). Upon PFS1, 72% of pts received CAPOX-B in arm A and 44% in arm B. The median PFS2 was 10.4 vs 10.4 months (HR 0.86, 95% CI 0.7-1.04, p=0.12). The median TTP2 in arm A vs B was 11.5 vs 15.4 months (HR 0.58, 95% CI 0.48-0.72, p&lt;0.0001), and the median OS was 17.9 vs 21.7 months (HR 0.77, 95% CI 0.62-0.96, p=0.02), respectively. Conclusions: Maintenance treatment with capecitabine plus bevacizumab after 6 cycles CAPOX-B did not significantly prolong PFS2, which may be due to the lower number of pts in arm B that received CAPOX-B following PFS1. Maintenance treatment significantly prolonged PFS1, TTP2 and OS. Our data support the use of bevacizumab plus capecitabine until progression or unacceptable toxicity. Updated results will be presented. Clinical trial information: NCT00442637.

Hispanic race and outcome of metastatic (MET) colorectal cancer (CRC): Biology or health care (HC) setting?

e17559 Background: Hispanics (H) have lower CRC related mortality compared to Whites (W). However, over the past decade H have appreciated less improvement in CRC mortality. Given that treatments (TX) for early stage CRC is unchanged we speculate that the gap is due to poorer outcome in the MET setting. Delivery of HC is identified as one of the factor for poor outcomes. We examined the relationship between HC delivery (public or private hospital) and TX as the drivers of poorer outcome in H. Methods: We identified CRC patients (pts) with at least one cycle of chemotherapy (CT) in the first line MET setting at Los Angeles County Hospital (LAC-public hospital) and Norris Cancer Center (NCC-Private hospital) between 2004-2011. Demographics; tumor and TX related factors were collected. Primary endpoint was TTP (time from first day to progression on first line CT). Descriptive statistics were used to describe the population and where appropriate chi-square, Wilcoxon, and log-rank tests were used for comparison between the groups. Results: 251 pts, 45%H, 26%W, 20% Asian (A) and 9%Black (B) were included. The median age of the population was 55 (21-82) years. 55% of pts were male.74 % of pts had de-novo MET disease. 48% of pts had left sided, 27% right sided and 25% rectal cancer. 71% of pts treated at LAC and 29% at NCC. 46% of pts at LAC and 56% at NCC received bevacizumab (BEV) as part of their TX (p= 0.26). Median TTP in H was 10.2 months (m) (95% CI: 8.1-11.8), and in W was 16.8 m (95% CI: 11.2-27.2; P&lt;0.05). Hispanics who were TX at LAC had longer TTP in comparison to H at NCC (p= 0.01). In multivariate analysis, race remained a significant predictor of TTP (p=0.001). Conclusions: H are the largest and fastest growing minority in the US, identification of factors of disparate outcome is crucial. This study revealed a significant association between race and TTP. Use of BEV for MET CRC became a standard TX in 2004 and since then TX is mostly unchanged. Our cohort received homogenous TX with regards to use of BEV. The results show that H regardless of HC setting have shorter TTP than W suggesting an inherent biological difference in the tumor or response to TX. Future biomarker studies will shed light on the cause.

Essential Role for Endocytosis in the Growth Factor-stimulated Activation of ERK1/2 in Endothelial Cells

Vascular endothelial growth factor (VEGF) stimulates angiogenesis by binding to VEGF receptor 2 (VEGFR2) on endothelial cells (ECs). Downstream activation of the extracellular related kinases 1/2 (ERK1/2) is important for angiogenesis to proceed. Receptor internalization has been implicated in VEGFR2 signaling, but its role in the activation of ERK1/2 is unclear. To explore this question we utilized pitstop and dynasore, two small molecule inhibitors of endocytosis. First, we confirmed that both inhibitors block the internalization of VEGFR2 in ECs. We then stimulated ECs with VEGF in the presence and absence of the inhibitors and examined VEGFR2 signaling to ERK1/2. Activation of VEGFR2 and C-Raf still occurred in the presence of the inhibitors, whereas the activation of MEK1/2 and ERK1/2 was abrogated. Therefore, although internalization is not required for activation of either VEGFR2 or C-Raf in ECs stimulated with VEGF, internalization is necessary to activate the more distal kinases in the cascade. Importantly, inhibition of internalization also prevented activation of ERK1/2 when ECs were stimulated with other pro-angiogenic growth factors, namely fibroblast growth factor 2 and hepatocyte growth factor. In contrast, the same inhibitors did not block ERK1/2 activation in fibroblasts or cancer cells stimulated with growth factors. Finally, we show that these small molecule inhibitors of endocytosis block angiogenesis in vitro and in vivo. Therefore, receptor internalization may be a generic requirement for pro-angiogenic growth factors to activate ERK1/2 signaling in human ECs, and targeting receptor trafficking may present a therapeutic opportunity to block tumor angiogenesis.

The impact of number of cycles of targeted therapy on cost evaluation in metastatic colorectal cancers.

359 Background: Increasing the number of cycles of cetuximab and bevacizumab in metastatic colorectal cancer might limit affordability and impact cost-effevctiveness. Methods: Average wholesale prices (AWPs) in U.S. dollars (US $) of cetuximab and bevacizumab were divided by reported median survival gain in days. Cost/survival of 90% of drugs was &lt;$750. A reference scale between 0% and 100% was constructed with 0% assigned to cost/overall survival (OS) &gt; $750, life threatening/fatal adverse events (AEs) and worsened quality of life (QoL). A plan was designed to correct for AEs and QoL. Results: Expressed as cost/overall survival (OS), crude and corrected scores (Table). Conclusions: Increasing number of cycles of cetuximab and bevacizumab increased the cost/survival and decreased scores. A limit on the purchase price of the entire treatment course of targeted therapy is recommended. [Table: see text]

Phase I study of ursodeoxycholic acid in combination with 5-fluorouracil, leucovorin, oxaliplatin, and bevacizumab for metastatic colorectal cancer.

569 Background: Emerging data links cancer growth with aberrant metabolism. These findings suggest that treatment directed against CRC metabolism may improve survival outcomes. Bile acids are involved in the metabolism of cholesterol and glucose. The bile acid, ursodeoxycholic acid (UDCA), protects against intestinal polyp development in animal and human studies. UDCA effects may be mediated through the nuclear receptor, farnesoid X receptor (FXR), since bile acids are the receptor’s endogenous ligands. FXR is a tumor suppressor in mouse models and a prognostic biomarker in patients with CRC. Bile acid activation of FXR in mouse models suppresses intestinal tumorigenesis. We sought to determine dose and safety of UDCA when added to standard therapy for mCRC. Methods: Patients with mCRC were accrued to an institutionally approved Phase I study. At the end of a 7-day run-in period of oral UDCA, standard doses of 5-fluorouracil, leucovorin, oxaliplatin, and bevacizumab were added. UDCA doses were escalated using a 3+3 design to determine MTD. The use of a run-in period allowed for correlative studies to identify serum biomarkers of FXR activation. Results: 11 patients were treated on three dose levels (250, 500, and 750 mg/day in divided doses). Patients were treated on protocol for a median time of 6 months with a median follow-up of 15 months. Patients were taken off protocol for progression of disease (n = 7); for declining performance status (n = 1); for toxicity (n=1); for patient refusal (n= 1). One patient remains on protocol at this time. No Grade 4 or higher toxicity was identified. Grade 3 toxicities were recorded in 5 patients; the majority was hematologic. Oral glucose tolerance tests, serum glucose and insulin levels, and serum FGF-19 were determined before and after UDCA treatment. Conclusions: UDCA, given with standard chemotherapy and biologic treatment, is safe and well tolerated in patients with mCRC. Further studies are needed to determine the efficacy of targeting FXR and cancer metabolism in mCRC. Supported by a grant from The Phase One Foundation. Clinical trial information: NCT00873275.

Phase II study to evaluate efficacy and safety of irinotecan, capecitabine, and bevacizumab in metastatic colorectal cancer (mCRC) patients.

501 Background: XELIRI regimen biweekly (combination of capecitabine and irinotecan) is an active and well tolerated treatment for mCRC. Bevacizumab provides significant clinical benefits in previously treated patients with mCRC. On this basis, the aim of this study is to evaluate the efficacy and safety of this combination. Methods: Multicentric, prospective, open-label phase II trial. Treatment scheme: irinotecan (iri) (175mg/m2 d1 q2w) + capecitabine (xel)(1,000mg/m2bid d 2-8) + bevacizumab (bev) (5mg/kg, d1 q2w). Results: 77 patients (p) were evaluated (66.2%, male) with a median age of 65.1 years (41.1-81.1). ECOG performance status was ≤1 in 96.1%. Primary tumor locations were: colon (53.2%), rectum (31.2%), and rectum/colon (15.6%). 27 p (35.1%) received adjuvant chemotherapy. Metastases were detected in liver (62.3%) and lung (54.5%). Mean time in treatment was: 7.1±4.9 months and median of cycles administered was 12(1-43). Median relative dose intensity was 89% for xel and bev and 85% for iri. Best response confirmed were: complete response (5.2%), partial response (32.5%), stable disease (46.8%). After a median of follow-up of 23.3 (0.4-39.6) months, median overall survival (OS) and progression free survival (PFS) was 24.8 and 11.8 months respectively. Analysis on Kras status was done in 71 p. There were no significant differences in OS or in PFS between WT and MUT p. 17 p (22.1%) underwent salvage surgery, 12 of whom had an R0 resection. The most frequent G3-4 toxicities were: diarrhea (18.2%), asthenia (16.9%), pulmonary embolism (13%; in eight of 10 p were asymptomatic), neutropenia (10.4%), febrile neutropenia (6.5%) and HFS (5.2%). Three treatment related deaths were reported (2 cases of multi-organ failure, and 1 case of intestinal perforation). Conclusions: Bevacizumab combined with biweekly XELIRI is an active first-line regimen for mCRC treatment with a feasible and manageable safety profile. Bevacizumab treatment efficacy was independent on Kras status. Clinical trial information: NCT00875771. [Table: see text]

Bevacizumab for Metastatic Colorectal Cancer

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of bevacizumab (Roche Products) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of patients with metastatic colorectal cancer (mCRC), as part of the Institute's Single Technology Appraisal (STA) process. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG). This paper provides a description of the company submission, the ERG review and NICE's subsequent decisions. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology provided within the manufacturer's submission to NICE. The ERG also independently searched for relevant evidence and modified the manufacturer's decision analytic model to examine the impact of altering some of the key assumptions. The main clinical effectiveness data were derived from a phase III, multicentre, multinational, two-arm, randomized, open-label study with the primary objective of confirming the non-inferiority of oxaliplatin plus capecitabine (XELOX) compared with oxaliplatin plus 5-fluorouracil and folinic acid (FOLFOX-4) in adult patients with histologically confirmed mCRC who had not previously been treated. The ERG considered that the NO16966 trial was of reasonable methodological quality and demonstrated a significant improvement in both progression-free and overall survival when bevacizumab is added to either XELOX or FOLFOX-4. The ERG considered that the size of the actual treatment effect of bevacizumab was uncertain due to trial design limitations, imbalance of a known prognostic factor, relatively short treatment duration compared with that allowed within the trial protocol, and interpretation of the statistical analyses. The manufacturer's submission included a de novo economic evaluation using a cost-effectiveness model built in Microsoft® Excel. The ERG believed that the modelling structure employed was appropriate but highlighted several areas of uncertainty that had the potential to have a significant impact on the resulting incremental cost-effectiveness ratios (ICERs). The areas of uncertainty identified by the ERG included whether chemotherapy would be administered continuously or intermittently, patient access scheme (PAS) costs and uptake, survival that was dependent on the statistical analyses used, and the likely duration of continued treatment with bevacizumab after cessation of oxaliplatin and the efficacy associated with continuation. The STA described here highlighted the challenges in appraising interventions with a complex PAS. Based on the analyses that include a discount to the list price of oxaliplatin, the ERG concluded that the ICERs for the addition of bevacizumab to XELOX or FOLFOX were both over £50 000. The NICE Appraisal Committee concluded that bevacizumab in combination with oxaliplatin and either 5-fluorouracil plus folinic acid or capecitabine (i.e. FOLFOX or XELOX) was not recommended for the treatment of mCRC.

Association between VEGF Splice Isoforms and Progression-Free Survival in Metastatic Colorectal Cancer Patients Treated with Bevacizumab

Bevacizumab improves survival for patients with metastatic colorectal cancer with chemotherapy, but no proven predictive markers exist. The VEGF-A splice form, VEGF(165)b, anti-angiogenic in animal models, binds bevacizumab. We tested the hypothesis that prolonged progression-free survival (PFS) would occur only in patients with low relative VEGF(165)b levels treated with bevacizumab. Blinded tumor samples from the phase III trial of FOLFOX4 ± bevacizumab were assessed for VEGF(165)b and VEGF(total) by immunohistochemistry and scored relative to normal tissue. A predictive index (PI) was derived from the ratio of VEGF(165)b:VEGF(total) for 44 samples from patients treated with FOLFOX + bevacizumab (arm A) and 53 samples from patients treated with FOLFOX4 (arm B), and PFS, and overall survival (OS) analyzed on the basis of PI relative to median ratio. Unadjusted analysis of PFS showed significantly better outcome for individuals with VEGF(165)b:VEGF(total) ratio scores below median treated with FOLFOX4 + bevacizumab compared with FOLFOX4 alone (median, 8.0 vs. 5.2 months; P < 0.02), but no effect of bevacizumab on PFS in patients with VEGF(165)b:VEGF(total) ratio >median (5.9 vs. 6.3 months). These findings held after adjustment for other clinical and demographic features. OS was increased in arm A (median, 13.6 months) compared with arm B (10.6 months) in the low VEGF(165)b group, but this did not reach statistical significance. There was no difference in the high VEGF(165)b:VEGF(total) group between FOLFOX + bevacizumab (10.8 months) and FOLFOX alone (11.3 months). Low VEGF(165)b:VEGF(total) ratio may be a predictive marker for bevacizumab in metastatic colorectal cancer, and individuals with high relative levels may not benefit.

555P - Efficacy and Safety of Bevacizumab in Metastatic Colorectal Cancer (MCRC): First-Line Analysis of Pooled Data From Randomized Controlled Trials (RCTS)

ABSTRACT Background Bevacizumab (BV) with chemotherapy (CT) is a standard treatment for mCRC. This analysis pooled individual patient data from the clinical databases of six RCTs (phase 2 or 3) of BV to further define clinical outcomes with first-line treatment, including within subgroups. Methods Patient data were pooled from first-line (AVF2107, NO16966, ARTIST, AVF2192, AVF0780, AGITG MAX) mCRC trials of BV. All analyses were based on the intent-to-treat population. Overall and progression-free survival estimates (OS, PFS) were calculated by Kaplan-Meier methods. To assess differences in time to response variables by treatment arm (CT vs BV + CT), stratified random (overall) and fixed (subgroup comparisons) models were used to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs), with each study included as a stratum. Overall: BV + CT vs CT HR (95% CI) P value OS 0.81 (0.70 - 0.93) .0034 PFS 0.58 (0.46 - 0.73) Subgroup comparisons: BV + CT vs CT HR (95% CI) for OS HR (95% CI) for PFS Monotherapy (n = 751) 0.86 (0.72–1.02) 0.56 (0.48–0.67) Doublet therapy (n = 2427) 0.84 (0.77–0.92) 0.73 (0.67–0.80) Patients with liver metastases only (n = 1095) 0.87 (0.76–1.00) 0.67 (0.59–0.77) Patients with extensive disease (n = 1049) 0.79 (0.69–0.90) 0.67 (0.59–0.77) KRAS wildtype patients (n = 364) 0.70 (0.54–0.91) 0.57 (0.45–0.72) KRAS mutant patients (n = 166) 0.85 (0.60–1.22) 0.54 (0.38–0.76) Results Of the 3178 pooled first-line patients (CT [n = 1481]; BV + CT [n = 1697]), 58.5% were male, 40.1% were ≥65 years, and 44.9% had an ECOG performance status ≥1. OS and PFS were statistically significantly increased in BV-treated patients vs control patients. The BV-associated adverse event profile from this pooled analysis identified no new safety signals. Conclusions The addition of bevacizumab to first-line CT resulted in statistically significant improvements in OS and PFS for mCRC patients in the overall analysis, with PFS benefit extending across subgroups defined by CT intensity, site of metastatic disease, and KRAS status. Disclosure F.F. Kabbinavar: Dr Kabbinavar has received honoraria from Genentech/Roche. H.I. Hurwitz: Dr Hurwitz has served in a consultant/advisory role for Genentech, Roche, Sanofi, Amgen, and BMS. He has received honoraria from Roche. Dr Hurwitz has received research funding from Roche, Genentech, BMS, Sanofi, and Pfizer. N.C. Tebbutt: Dr Tebbutt has received research funding from industry. B.J. Giantonio: Dr Giantonio has received honoraria from Genentech/Roche. L. Mitchell: Dr. Mitchell is an employee of F. Hoffmann-La Roche Ltd. D. Waterkamp: Dr Waterkamp is an employee of F. Hoffmann-La Roche Ltd. J. Tabernero: Dr Tabernero has served in a consultant/advisory role for Genentech/Roche. All other authors have declared no conflicts of interest.

653 - Japanese Cohort Study of First Line Chemotherapy (CT) for Metastatic Colorectal Cancer (MCRC) Containing Fluoropyrimidine, Oxaliplatin and Bevacizumab: Emerald Study, First Report

ABSTRACT Background An observational cohort study plays a crucial role to understand the current status of clinical practice and can be utilized as database for multi-purpose outcome research. Such database is available in Europe and the United States based on several cohort studies especially in mCRC, while there is no database available including treatments for mCRC patients in Japan. Methods According to the Japanese Ethical Guideline for Epidemiologic Study, we planned and conducted a large cohort study in Japan. Data from more than 1000 patients were planned to be collected between October 2010 and September 2011 with 2-year follow-up period. Enrollment criteria included documented mCRC and first line CT containing fluoropyrimidine, oxaliplatin and bevacizumab, started treatment in or after January 2010, tumor response image assessment available, safety assessment available and able to offer information outside of originally enrolled studies. The primary objectives are to evaluate overall survival, liver resection rate, R0 liver resection rate; the secondary objectives are to evaluate response rate, progression-free survival, sub-group analysis by treatment regimens and by KRAS gene status, and safety. Results From October 2010 to September 2011, 1270 patients were recruited from 132 centers in Japan. The background of patients were as the following; male/female, 766/504; median age of 65 (range, 21-89); ECOG PS 0/1/2/3, 1045/203/17/5; FOLFOX/ CapeOX/ others with bevacizumab, 563/667/40, KRAS gene status at baseline was wild/mutant/unknown, 286/223/761; CEA median of 13.8 (range, 0.0–90055.0 ng/ml) and comorbidity no/yes, 798/472. Conclusion We have started the large Japanese cohort study which investigates first line CT containing fluoropyrimidine, oxaliplatin and bevacizumab for metastatic colorectal cancer. We performed a preplanned interim analysis. We present the first report of 6-month efficacy and safety data on 500 patients at the ESMO 2012 Congress. The final results will be available in 2013. This study is sponsored by the Public Health Research Center Foundation CSPOR in Japan. Disclosure All authors have declared no conflicts of interest.

652 - Primary Resistance to First-Line Bevacizumab in Metastatic Colorectal Cancer: Implications on Prognosis

ABSTRACT A role of Bevacizumab after first-line failure is currently in study. We focused our analysis on patients who progressed directly under first-line Bevacizumab and assessed if lack of effect could be managed with second line chemotherapy. We conducted a retrospective analysis on metastatic colorectal cancer patients treated in the 2008-2011 period with first-line Bevacizumab. Stratification criteria were sex, age, performance status, metastatic sites, metachronous vs synchronous metastases, chemotherapy backbone, K-ras status. Chest-abdomen CT scan was performed every 3 months. Response was scored according to RECIST criteria. Progression free survival and overall survival were defined as usual. 146 patients were eligible for analysis. 60 (41%) partial responses, 54 (37%) stable disease and 32 (22%) progressions were seen. Median overall survival was 18.5 months and median progression free survival was 8.2 months. No significant differences were seen in regards to stratification criteria for different response groups. Progression free survival for patients who achieved a partial response, a stable disease or progression were respectively 10.6 vs 8.5 vs 3.0 months (p Disclosure All authors have declared no conflicts of interest.

Treatment with bevacizumab and FOLFOXIRI in patients with advanced colorectal cancer: presentation of two novel trials (CHARTA and PERIMAX) and review of the literature.

BackgroundMore than half of patients with colorectal cancer will develop metastatic disease either evident at the time of initial diagnosis or during their course of disease. Besides multidisciplinary management further treatment intensification is warranted to improve the still limited prognosis.Methods/designIn these two multi-centre, randomized phase II trials, conducted in Germany, 380 patients with R0-resectable colorectal liver metastases (PERIMAX) and with unresectable, metastatic colorectal cancer (CHARTA) will be recruited. Patients previously untreated for metastatic disease with either synchronous or metachronous metastases are randomly assigned in a 1:1 ratio to resection of colorectal liver metastases followed by postoperative FOLFOX for 6 months or perioperative FOLFOXIRI and bevacizumab for 3 months pre- and postoperative and resection (PERIMAX), or to induction chemotherapy with FOLFOX and bevacizumab +/− irinotecan for a maximum of 6 months followed by maintenance treatment with fluoropyrimidine and bevacizumab. The primary objective of these trials is to evaluate the feasibility and efficacy of FOLFOXIRI and bevacizumab in metastatic colorectal cancer. Primary endpoint is failure free survival rate at 18 months in the PERIMAX trial and progression free survival rate at 9 months in CHARTA. Secondary objectives include efficacy, safety and tolerability.DiscussionThe CHARTA and PERIMAX trials are designed to evaluate the benefits and limitations of a highly active four-drug regimen in distinct treatment situations of metastatic CRC. Eligible patients are classified into resectable liver metastases to be randomized to perioperative treatment with FOLFOXIRI and bevacizumab or postoperative FOLFOX in the PERIMAX, or unresectable metastatic CRC to be randomized between FOLFOX and bevacizumab with or without irinotecan, stratified for clinical groups according to disease and patients’ characteristics in the CHARTA trial.Trial registrationClinical trial identifier CHARTA: NCT01321957, PERIMAX: NCT01540435

Evaluating coagulation disorders in the use of bevacizumab for metastatic colorectal cancer by thrombelastography

The aim of this study was to evaluate coagulation disorders in patients with metastatic colorectal cancer treated with bevacizumab by using rotation thrombelastogram (ROTEM(®)) and correlate ROTEM(®) parameters with routine coagulation tests. A total of 18 colorectal cancer patients who received bevacizumab combined with chemotherapy were included. There was no statistically significant difference between results of platelet count, prothrombin time (PT) and activated partial thromboplastin time (APTT), fibrinogen, and D-Dimer obtained at baseline and on day 1 of chemotherapy cycles 4, 8, and 12. CFT value was significantly increased on day 1 of cycle 12 compared with baseline value by both INTEM and EXTEM assays while CT and MCF showed no significant difference. Correlation analysis revealed significant correlation between laboratory parameters and ROTEM(®) parameters. Platelet count showed a positive correlation with MCF in INTEM (r = 0.627) and EXTEM (r = 0.699) assays while showed a negative correlation with CFT in EXTEM (r = -603). There was a significant negative correlation between fibrinogen levels and CFT in INTEM (r = -0.617) and EXTEM (r = -0.512). Our data demonstrated the value of TEG over conventional coagulation tests in evaluating antiangiogenesis agents-induced coagulation disorders.