Julie Hambleton

Phase II Study of Bevacizumab in Patients With Platinum-Resistant Ovarian Cancer or Peritoneal Serous Cancer

PURPOSE We evaluated the efficacy and safety of bevacizumab in patients with platinum-resistant epithelial ovarian carcinoma (EOC) or peritoneal serous carcinoma (PSC) who had experienced disease progression during, or within 3 months of discontinuing, topotecan or liposomal doxorubicin. PATIENTS AND METHODS No more than three prior treatment regimens were allowed. Patients received single-agent bevacizumab 15 mg/kg intravenously every 3 weeks. Response was assessed by computed tomography (CT) scan every 6 weeks using Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS Of 44 patients treated, 83.7% were primarily platinum resistant, 59.1% had received liposomal doxorubicin, 25% topotecan, 15.9% both agents, and 47.7% had received three prior chemotherapy regimens. A median of five (range, two to 16) bevacizumab doses were administered. Partial responses were observed in seven patients (15.9%). Median progression-free survival was 4.4 months (95% CI, 3.1 to 5.5 months), with a median survival duration of 10.7 months at study termination. Bevacizumab-associated grade 3 to 4 events included hypertension (9.1%), proteinuria (15.9%), bleeding (2.3%), and wound-healing complications (2.3%). The incidence of GI perforation (GIP; 11.4%) was higher than reported in bevacizumab trials of other tumor types. GIP occurred in 23.8% of patients receiving three prior chemotherapy regimens, compared with 0% of patients receiving two prior chemotherapy regimens (P < .01). A trend toward higher risk of GIP was observed for patients with bowel wall thickening or bowel obstruction on CT scan. Arterial thromboembolic events occurred in three patients (6.8%). Three deaths were related to bevacizumab treatment. CONCLUSION Bevacizumab has single-agent activity in patients with platinum-resistant EOC or PSC. A higher than expected incidence of GIP was noted in these heavily pretreated patients.

Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer.

PURPOSE In a phase III trial, combining bevacizumab (BV)--a recombinant, humanized, monoclonal antibody targeting vascular endothelial growth factor--with irinotecan, bolus fluorouracil (FU), and leucovorin (LV; IFL) increased survival compared with IFL alone in first-line treatment of patients with metastatic colorectal cancer (CRC). Results for the parent study of IFL/BV versus IFL/placebo are reported elsewhere. Here, we describe efficacy and safety results for the third patient cohort in this trial, who received BV combined with FU/LV, and compare them with results for concurrently enrolled patients who received IFL. METHODS Patients (N = 923) were randomly assigned to receive IFL/placebo (control), IFL/BV, or FU/LV/BV. Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA) 5 mg/kg was administered intravenously every 2 weeks. Before an interim analysis confirmed acceptable safety for IFL/BV, 313 patients were concurrently randomly assigned to these three arms; after this analysis, the FU/LV/BV arm was discontinued. RESULTS Median overall survivals were 18.3 and 15.1 months with FU/LV/BV (n = 110) and IFL/placebo (n = 100), respectively. Median progression-free survivals were 8.8 and 6.8 months, respectively. Overall response rates were 40.0% and 37.0%, and median response durations were 8.5 and 7.2 months, respectively. Adverse events consistent with those expected from FU/leucovorin- or IFL-based regimens were seen, as were modest increases in hypertension and bleeding in the bevacizumab arm, which were generally easily managed. CONCLUSION The FU/LV/BV regimen seems as effective as IFL and has an acceptable safety profile. FU/LV/BV is an active alternative treatment regimen for patients with previously untreated metastatic CRC.

Combined Analysis of Efficacy: The Addition of Bevacizumab to Fluorouracil/Leucovorin Improves Survival for Patients With Metastatic Colorectal Cancer

PURPOSE Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA), a recombinant, humanized anti-vascular endothelial growth factor monoclonal antibody that inhibits tumor angiogenesis, has demonstrated survival benefit in patients with previously untreated metastatic colorectal cancer when combined with irinotecan/fluorouracil (FU)/leucovorin (LV; IFL). Three randomized clinical studies have evaluated bevacizumab in combination with FU/LV alone. A combined analysis of raw data from these studies was performed to better assess the efficacy of bevacizumab with FU/LV. PATIENTS AND METHODS The analysis used primary efficacy data from three independent studies, including 241 patients in a combined control group receiving either FU/LV or IFL and 249 patients receiving FU/LV/bevacizumab (5 mg/kg once every 2 weeks). The efficacy data included response rate, progression-free survival, and overall survival. RESULTS The median duration of survival was 17.9 months in the FU/LV/bevacizumab group, compared with 14.6 months in the combined control group, corresponding to a hazard ratio for death of 0.74 (P = .008). The median duration of progression-free survival was 8.8 months in the FU/LV/bevacizumab group, compared with 5.6 months in the combined control group, corresponding to a hazard ratio for disease progression of 0.63 (P < or = .0001). The addition of bevacizumab also improved the response rate (34.1% v 24.5%; P = .019). CONCLUSION The addition of bevacizumab to FU/LV provides a statistically significant and clinically relevant benefit to patients with previously untreated metastatic colorectal cancer.

Bevacizumab does not increase bleeding in patients with metastatic colorectal cancer receiving concurrent anticoagulation

3528 Background. Bevacizumab (BV, Avastin), a recombinant, humanized monoclonal antibody directed against VEGF, improves survival in combination with chemotherapy for first line treatment of metastatic colorectal cancer (CRC). The addition of BV to irinotecan/5-FU/leucovorin (IFL) resulted in a significant improvement in survival compared with IFL alone (p=0.00004; median survival increased from 15.6 to 20.3 months). Experience with BV in phase II studies, particularly in NSCLC, suggested that bleeding might be a safety signal. Therefore, patients receiving full-dose anticoagulation (FDAC) were excluded from the phase III CRC study. This analysis assesses the outcomes of patients with metastatic CRC who had a thrombotic event while receiving study treatment (BV or placebo), and remained on study while receiving FDAC. METHODS Patients with previously untreated metastatic CRC were randomized to IFL plus placebo (Arm 1) versus IFL plus BV (5 mg/kg; Arm 2). Thrombotic complications, including deep venous thrombosis, pulmonary embolus, and arterial events, and treatment were analyzed. FDAC was achieved with warfarin. RESULTS The overall rate of arterial and venous thromboembolic events was 16.2% in Arm 1 and 19.4% in Arm 2. Arterial events, such as myocardial infarction and stroke, were rare: 1% Arm 1 and 3.3% in Arm 2. Venous event rates were similar; 15.2% in Arm 1, 16.6% in Arm 2. Of those patients with a thrombotic event treated with FDAC, 30 patients (54.5%) in Arm 1 and 53 patients (82.8%) in Arm 2 continued on study drug. Grade 3/4 bleeding rates for those on FDAC and study drug are shown in Table 1. CONCLUSION Use of concomitant full-dose anticoagulation therapy with Bevacizumab in combination with chemotherapy does not appear to increase the risk of hemorrhagic complications in patients with metastatic colorectal cancer. [Figure: see text] [Table: see text].

Bleeding events in bevacizumab-treated cancer patients who received full-dose anticoagulation and remained on study

Background:Bevacizumab provides clinical benefit in multiple solid tumours, but is associated with some increase in bleeding risk. Thrombotic events necessitating therapeutic anticoagulation (TA) are common in cancer. This report describes the safety of concurrent bevacizumab and TA in three large placebo-controlled clinical studies.Methods:Study 1 (metastatic colorectal cancer (mCRC)), study 2 (mCRC), and study 3 (advanced non-small cell lung cancer) were blinded phase III studies. Eligibility criteria excluded patients on TA. Patients on protocol treatment who developed thrombotic events requiring TA were permitted to continue bevacizumab or placebo under specified conditions. Adverse events in patients who received bevacizumab and TA concurrently were assessed using the NCI–CTCAE scale.Results:While experience is limited, venous thrombotic events were the most common reason for TA initiation in the three studies. Severe bleeding event rates for patients receiving TA in the bevacizumab-treated groups were similar in frequency to the placebo groups, ranging from 0 to 8% or 0 to 67 events per 100 patient-years. No severe pulmonary bleeding was reported in any of the TA-treated populations.Conclusions:These data suggest that bevacizumab did not increase the risk of severe bleeding in cancer patients who received TA.