Sugrue, Mary M.

3537 Background: Bevacizumab (BV) prolongs overall survival and progression-free survival (PFS) when added to standard chemotherapy (CT) in patients with metastatic colorectal cancer (mCRC). BRiTE is a large, community-based observational registry of patients with mCRC receiving BV plus first-line CT. Safety and efficacy information in unselected patients with mCRC are collected. Chemotherapy regimen choice is at the physician’s discretion. Methods: 1968 patients receiving BV plus first-line CT were enrolled at 248 sites in 49 states between Feb 2004 and Jun 2005. Patients are followed for up to 3 years, with data reporting every 3 months (mo) including disease status as assessed by investigator using his/her method of choice. Patients were grouped twice by CT. Cox regression models, adjusted and unadjusted for treatment assignment, were used to identify baseline characteristics (BC) and differential chemotherapy effects on PFS. Results: Cohort demographics were consistent with the NCI Surveillance, Epidemiology, and End Results (SEER) database for mCRC. Median study follow-up was 10 months by Nov 4, 2005. CT regimens included FOLFOX (55.8%), FOLFIRI (14.1%), and IFL (9.7%). Based on observed progression events (n=800) or deaths (n=123), projected median PFS is 11.3 mo (95% CI: 10.4–11.7). Median PFS was comparable in patients treated with CT regimen based on irinotecan (11.3 mo), oxaliplatin (11.4 mo), or neither (10.2 mo) (CT Grouping 1); or 5FU infusion (11.5 mo), 5-FU bolus (9.7 mo), or capecitabine (11.6 mo) (CT Grouping 2). Significant BC in adjusted and unadjusted models are ECOG performance status (PS), primary disease site, and albumin, with no significant difference among CT regimens. Conclusions: This large, community-based registry included a patient population with demographics consistent with the SEER database for mCRC. Preliminary median PFS of 11.3 mo compares favorably to that reported in the pivotal trial. Median PFS appears to be comparable for all CTs when combined with BV. Higher baseline albumin, PS of 0, and primary disease site of rectum were associated with improved outcome. [Table: see text]

3536 Background: Bevacizumab (BV) prolongs overall survival and progression-free survival when added to standard chemotherapy for patients with metastatic colorectal cancer (mCRC). BRiTE is a large, community-based observational registry of patients with mCRC receiving BV plus first-line chemotherapy. Safety and efficacy information in unselected patients with mCRC are collected. Chemotherapy regimen choice is at the physician’s discretion. Methods: To facilitate and evaluate enrollment of a typical community-based mCRC population, eligibility criteria were minimized. Cohort demographics were consistent with the NCI Surveillance, Epidemiology, and End Results (SEER) database for mCRC. Patients are followed for up to 3 years, and safety data including targeted BV-associated serious adverse events (SAEs) are updated every 3 months (mo). Results are based on descriptive analyses and are not adjusted for propensity of treatment, baseline characteristics, and treatment effects. Results: 1968 patients were enrolled between Feb 2004 and Jun 2005. Median study follow-up was 10 mo by Nov 4, 2005. SAEs were reported in 12.0% of patients including gastrointestinal perforation (GIP) (1.7%), postoperative bleeding/wound healing complications (1.2%), arterial thromboembolic events (ATE) (2.1%), and grade 3–4 bleeding (1.9%). 3.2% of patients discontinued BV due to a BV-related toxicity, most commonly bleeding. For patients with the respective event(s), median time to first event was 2.1 mo for GIP, 3.5 mo for ATE and 4.0 mo for grade 3–4 bleeding. 8.9% of patients with no history of hypertension (HTN) developed HTN requiring medication and 6.2% of patients who had HTN requiring medication at baseline experienced worsening of their HTN while on study treatment. Conclusions: In this unselected population of patients with mCRC, the safety profile of BV plus various chemotherapy regimens appears consistent with that observed in the pivotal BV trial. Overall discontinuation of BV due to a BV-related toxicity was uncommon. In this large community-based observational registry, no new BV associated safety issues have been identified. [Table: see text]

3535 Background: Bevacizumab (BV) prolongs overall survival and progression-free survival when added to standard chemotherapy in patients (pts) with metastatic colorectal cancer (mCRC). BRiTE is a large, community-based observational registry of pts with mCRC receiving BV plus first-line chemotherapy (CT). Incidence rate, temporal pattern, and potential risk factors associated with gastrointestinal perforation (GIP) were explored. Methods: Baseline patient characteristics (BC), including prospectively identified potential risk factors for GIP, were collected at study entry. Safety data were collected every 3 months (mo). Logistic regression models, adjusted and unadjusted for treatment assignment, were used to identify BC potentially associated with GIP. Results: 1968 pts were enrolled between Feb 2004 and Jun 2005. Median study follow-up was 10 mo as of Nov 4, 2005. GIPs were observed in 34 pts (1.7%). For pts with GIP, median time to first event was 2.1 mo; the majority of events were non-fatal and occurred within the first 3 mo after starting BV. BC including GI medical history (chronic aspirin or NSAID use, peptic ulcer disease, diverticulosis) were similar in pts with or without GIP and with earlier or later GIP onset (≤ or >3 mo from start of BV). Although adjusted models did not show any significant BC, GIP rates were numerically higher in pts with primary tumor intact (2.6%) vs. resected (1.6%). Furthermore, univariate analyses revealed a significant difference between intact (2.3%) and resected (0.8%) primary tumor for earlier GIP (≤3 mo from start of BV). The majority of pts with GIP had at least one of the following: acute diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, tumor at GIP site, abdominal carcinomatosis, prior abdominal or pelvic radiation therapy. Conclusions: Preliminary analyses indicate the incidence of GIP in this large, community-based observational registry is similar to that previously reported in phase III mCRC trials with BV. No associations between specific BCs and an increased risk of GIP were identified. Patients with primary tumor intact were more likely to incur a GIP within the first 3 mo of starting BV and CT. [Table: see text]

4136 Introduction: BV prolongs overall survival (OS) and progression-free survival (PFS) when added to 1st- or 2nd -line chemotherapy (CT) in mCRC. Though serious toxicities specific to BV are uncommon, a retrospective pooled analysis of 5 randomized trials showed an association of arterial thromboembolic events (ATEs) with BV use (3.8% vs 1.7% with CT alone), with age ≥65 and prior history (Hx) of ATE identified as associated risk factors (Skillings, JCO 2005). The BRiTE mCRC registry evaluated BV-associated serious adverse events (SAEs), including ATEs presenting as SAEs (sATE), in a general practice setting. Methods: Pts and methods have been described (Hedrick ASCO 2006). Hx of sATE, timing of prior sATE relative to starting BV, and anti-platelet agent (anti-plt) use were summarized. Definition of sATE included myocardial infarction (MI), cerebral vascular accident (CVA), transient ischemic attack (TIA), and peripheral arterial disease. Incidence rate of sATE was expressed as events per pt-yr of follow-up. Fisher’s exact test and multiple logistic regression was used to assess the univariate and multivariate associations. Results: Median follow- up was 17.5 mo. Of 1953 evaluable pts, 45.9% (n=896) were ≥65, 18.0% (n=352) had Hx of sATE, and 11.2% (n=219) received anti-plt. A total of 38 sATE [CVA (n=14), MI (n=11), sudden cardiac death (n=1), TIA (n=7), and other (n=5)] were reported in 34 (1.7%) pts. Median time to sATE was 3.6 mo. The calculated sATE rate was 2.2/100 pt-yr overall and 4.7/100 pt-yr in pts with prior sATE. Table 1 summarizes the results of univariate and multivariate analyses. Conclusions: In this series of BV-treated pts, the incidence of sATE associated with BV use was comparable with the rate of analogous events reported in previous controlled trials of BV in mCRC. In this series, prior history of sATE and ECOG PS were found to be associated with sATE risk in multivariate analyses. [Table: see text] [Table: see text]

4036 Background: While BV prolongs OS when used with standard 1st- or 2nd-line chemotherapy (CT) in mCRC, no data exist on the effects of BBP. A previous report from BRiTE showed favorable median OS (27.1 mo, 95% CI 24.8-NE), with 1st line PFS (median 10.1 mo, 95% CI:9.7–10.4) comparable to historical mCRC trials, suggesting significant impact of post-progression survival on OS. This exploratory analysis evaluates the association of various pre- and post-treatment variables with OS in BRiTE. Methods: Pt population and methods have been described previously (Kozloff, ASCO 2006). All pts in BRiTE received BV as part of 1st-line therapy. The use of BBP and choice of CT were at investigator’s discretion. Kaplan-Meier methods were used to estimate PFS and OS. Cox’s proportional hazard model was used to assess the independent effects of pre- and post-treatment pt- related factors on OS, including age, ECOG PS, albumin, alkaline phosphatase, site of primary tumor, 1st-line CT regimen, 1st-line PFS, exposure to all 3 active CT agents, receipt of any 2nd-line CT, exposure to cetuximab, and BBP. Though there was variability observed in patterns of BBP, including continuous and discontinuous use, for the purpose of this analysis, BBP was defined as any exposure to BV after 1st progression (PD). Results: A total of 1,953 pts were treated in BRiTE. At median follow-up of 17.5 mo, there were 1,369 1st PD and 839 deaths. Among pts with 1st PD, 65.2% received any 2nd-line CT, 34.8% received cetuximab, and 53.8% received BBP. In a multivariate analysis, BBP and exposure to any 2nd-line CT were independently associated with increased OS (both p<0.0001). Age ≥65, PS ≥1, low albumin, elevated alkaline phosphatase, colon primary, and use of IFL were associated with inferior OS. Conclusions: BBP appears to be associated with longer OS in BRiTE. This finding supports the evaluation of BBP in prospective randomized clinical trials. Other factors that may have impacted this finding, including physician-related variables, will be investigated in future analyses. [Table: see text]

Abstract Background. The Bevacizumab Regimens’ Investigation of Treatment Effects (BRiTE) study is a prospective, observational cohort study designed to elucidate safety and effectiveness outcomes associated with bevacizumab combined with chemotherapy as used in clinical practice for first-line treatment of metastatic colorectal cancer (mCRC). Patients and Methods. Baseline characteristics, prespecified bevacizumab-related adverse events, and effectiveness data were collected from 1,953 mCRC patients who were receiving first-line treatment including bevacizumab at 248 U.S. sites. Results. At database lock, the median follow-up was 20.1 months. At baseline, 46% of patients were aged ≥65 years and 49% had an Eastern Cooperative Oncology Group performance status score ≥1. Fluorouracil, leucovorin, and oxaliplatin was the most common first-line chemotherapy regimen (56%). Overall rates of bevacizumab-related adverse events in the BRiTE study, such as gastrointestinal perforation (1.9%), arterial thromboembolic events (2%), grade 3–4 bleeding (2.2%), and de novo hypertension requiring medication (22%), were consistent with those reported in randomized clinical trials (RCTs) of bevacizumab in first-line mCRC treatment. The median progression-free survival (PFS) and overall survival (OS) times were 9.9 (95% confidence interval [CI], 9.5–10.3) months and 22.9 (95% CI, 21.9–24.4) months, respectively. Conclusion. The median PFS and OS durations and safety profile of bevacizumab in the BRiTE study were similar to those in RCTs of bevacizumab plus chemotherapy in first-line mCRC patients. The observations from the BRiTE study complement and expand upon RCT data, providing clinical information in a large cohort of bevacizumab-treated patients and subgroups such as the elderly.

Purpose Bevacizumab provides a survival benefit in first- and second-line metastatic colorectal cancer (mCRC). In a large, observational, bevacizumab treatment study (Bevacizumab Regimens: Investigation of Treatment Effects and Safety [BRiTE]) in patients who had mCRC, a longer-than-expected overall survival (OS) of 25.1 months was reported. The association between various pre- and post-treatment factors (including the use of bevacizumab beyond first progression [BBP]) and survival was examined. Patients and Methods The 1,445 of 1,953 previously untreated patients with mCRC who were enrolled in BRiTE and who experienced disease progression (PD) were classified into three groups: no post-PD treatment (n = 253), post-PD treatment without bevacizumab (no BBP; n = 531), and BBP (n = 642). Relevant baseline and on-study variables, including BBP, were analyzed with a Cox model with respect to their independent effect on survival beyond first PD. Results Median OS was 25.1 months (95% CI, 23.4 to 27.5 months), and median progression-free survival was 10.0 months in the overall BRiTE population. Baseline and postbaseline factors were well balanced between the BBP and no-BBP groups. Median OS rates were 12.6, 19.9, and 31.8 months in the no post-PD treatment, no-BBP, and BBP groups, respectively. In multivariate analyses, compared with no BBP, BBP was strongly and independently associated with improved survival (HR, 0.48; P < .001). Hypertension that required medication was the only bevacizumab-related safety event that occurred more frequently in the BBP group (24.6% v 19.2%). Conclusion These results from a large, prospective, observational study suggest that continued vascular endothelial growth factor inhibition with bevacizumab beyond initial PD could play an important role improving the overall success of therapy for patients who have mCRC.