Between October 1998 and September 2001, 116 patients were enrolled, of whom 108 had progressive disease during the course of the study. The median follow-up time from study entry was 27 months. Forty patients were randomly assigned to placebo, 37 to low-dose bevacizumab, and 39 to high-dose bevacizumab. All planned doses of the study drug were given unless grade 3 toxic effects occurred, in which case doses were withheld as specified by the study protocol. Only one patient (who was assigned to low-dose bevacizumab) was lost to follow-up after therapy. The three groups had similar demographic and clinical characteristics and laboratory results (). All patients received at least one dose of the assigned drug, and 114 of the 116 patients underwent at least one planned follow-up evaluation (evidence concerning disease progression was available for the remaining 2 patients).
Characteristics of Patients before Treatment.*
There were no life-threatening toxic effects (grade 4, major organ) or deaths possibly related to bevacizumab (). Hypertension and asymptomatic proteinuria were associated with bevacizumab therapy (). Of 13 patients with grade 2 or 3 hypertension, 7 (54 percent) had grade 2 or 3 proteinuria; of 63 patients with grade 0 or 1 hypertension, 10 (16 percent) had grade 2 or 3 proteinuria (P=0.007 by Fisher’s exact test). None of these patients, or any other patient, had renal insufficiency. Hypertension and proteinuria uniformly decreased after the cessation of therapy, but death from renal cancer, the slow rate of correction of hypertension and proteinuria, and the commencement of other therapies prevented the documentation of complete resolution of these toxic effects in all but one patient.
Toxic Effects of Treatment.*
There were no episodes of grade 4 hypertension during randomized therapy, but in one patient who was initially assigned to placebo, hypertension with coma developed after the patient crossed over to low-dose bevacizumab plus thalidomide. These complications resolved completely after therapy was stopped. Typically, hypertension during the study was treated by the patients’ private physicians with standard regimens for essential hypertension. Among all bevacizumab-treated patients who required therapy for newly diagnosed hypertension (for whom the dates of onset could be most accurately determined), the median interval from the first dose of bevacizumab to the onset of hypertension was 131 days (range, 7 to 316). Grade 1 or 2 hemoptysis developed in four patients (one receiving high-dose bevacizumab, one receiving low-dose bevacizumab, and two receiving placebo), and one patient receiving placebo had a pulmonary embolus.
At the second interim evaluation (which analyzed the data on 110 patients), the NCI data safety and monitoring board recommended closure of accrual on the basis of the difference between the placebo and high-dose bevacizumab groups in the time to progression of disease. According to intention-to-treat analysis, progression-free survival in the group receiving 10 mg of bevacizumab per kilogram (with a median time to progression of 4.8 months) was significantly longer than that in the placebo group (with a median time to progression of 2.5 months, P<0.001 by the log-rank test) (). The difference between the time to progression of disease in the group receiving 3 mg of bevacizumab per kilogram (median time, 3.0 months) and that in the placebo group was of borderline significance (P=0.041 by the log-rank test) ().
Kaplan–Meier Analysis of Survival Free of Tumor Progression for Patients Receiving High-Dose Bevacizumab (Panel A) or Low-Dose Bevacizumab (Panel B), as Compared with Placebo
The planned analysis of progression from the five-week assessment yielded the same results. The percentages of patients assigned to high-dose bevacizumab, low-dose bevacizumab, and placebo who had no tumor progression were 64 percent, 39 percent, and 20 percent, respectively, four months after randomization and 30 percent, 14 percent, and 5 percent eight months after randomization. A Cox proportional-hazards model yielded hazard ratios for the time to progression of disease of 2.55 among patients given high-dose bevacizumab (P<0.001) and 1.26 among those given low-dose bevacizumab (P=0.053), as compared with those given placebo.
Only four patients had objective responses (all of which were partial responses), and all of these had received high-dose bevacizumab; thus, the response rate for high-dose bevacizumab was 10 percent (95 percent confidence interval, 2.9 to 24.2 percent). One patient had a partial response for the maximal treatment period of two years. This patient then stopped therapy, had a relapse six months later, and is currently having a second partial response after retreatment under a compassionate exemption (). Another patient treated for two years had a sustained minor response, had a relapse after stopping therapy, and had another minor response after being retreated.
Serial Radiographs of a Patient Treated with High-Dose Bevacizumab
Measurements of plasma vascular endothelial growth factor were available for 113 patients. Of these, 76 had a base-line level below the lower limit of detection (40 pg per milliliter). There were no significant associations between a detectable pretreatment level of vascular endothelial growth factor and the clinical response or the time to progression in either bevacizumab group (all P values were greater than 0.20). However, the limited sensitivity of the assay does not permit the definitive conclusion that there is no correlation between the base-line plasma level of vascular endothelial growth factor and the clinical response or the time to progression. After antibody therapy was started, the plasma levels of vascular endothelial growth factor rose steadily (the assay measures both free and antibody-bound vascular endothelial growth factor). After 5 weeks and 13 weeks of therapy, all bevacizumab-treated patients had detectable plasma levels of vascular endothelial growth factor. The median levels were 196 and 246 pg per milliliter, respectively, for patients receiving high-dose bevacizumab and 155 and 170 pg per milliliter for patients receiving low-dose bevacizumab. The percentages of patients assigned to placebo who had undetectable plasma levels of vascular endothelial growth factor at base line, 5 weeks, and 13 weeks were 66 percent, 67 percent, and 75 percent, respectively. Patients receiving low-dose bevacizumab had mean (±SE) peak and trough serum levels of bevacizumab of 101±9 and 39±3 μg per milliliter, respectively; patients receiving high-dose bevacizumab had mean peak and trough levels of 392±24 and 157±13 μg per milliliter, respectively. In both groups, the trough levels were above that needed to abolish detectable free vascular endothelial growth factor in the plasma of patients in previous phase 1 studies.14
At the most recent analysis, in February 2003, 19 of 116 patients (16 percent) were alive, and there were no significant differences in survival between the treatment groups (all P values were greater than 0.20) (). The complete radiographic records of 113 patients (3 were no longer complete at the time of audit) were blindly audited by a team of extramural radiologists under the supervision of the Cancer Therapy and Evaluation Program of the NCI. The prolongation of time to progression of disease was confirmed radiologically.
Overall Survival of Patients Receiving Placebo, Low-Dose Bevaci-zumab, or High-Dose Bevacizumab