Addition of Bevacizumab to Bolus Fluorouracil and Leucovorin in First-Line Metastatic Colorectal Cancer: Results of a Randomized Phase II Tr
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《临床肿瘤学》
the University of California, Los Angeles (UCLA) School of Medicine, Los Angeles
Genentech Inc, South San Francisco, CA
Virginia Oncology Associates, Newport News, VA
Florida Cancer Specialists, Ft Myers, FL
Mid Ohio Oncology Hematology Inc, Westerville, OH
Louisville Oncology, Louisville, KY
ABSTRACT
PURPOSE: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, increases survival when combined with irinotecan-based chemotherapy in first-line treatment of metastatic colorectal cancer (CRC). This randomized, phase II trial compared bevacizumab plus fluorouracil and leucovorin (FU/LV) versus placebo plus FU/LV as first-line therapy in patients considered nonoptimal candidates for first-line irinotecan.
PATIENTS AND METHODS: Patients had metastatic CRC and one of the following characteristics: age 65 years, Eastern Cooperative Oncology Group performance status 1 or 2, serum albumin 3.5 g/dL, or prior abdominal/pelvic radiotherapy. Patients were randomly assigned to FU/LV/placebo (n = 105) or FU/LV/bevacizumab (n = 104). The primary end point was overall survival. Secondary end points were progression-free survival, response rate, response duration, and quality of life. Safety was also assessed.
RESULTS: Median survival was 16.6 months for the FU/LV/bevacizumab group and 12.9 months for the FU/LV/placebo group (hazard ratio, 0.79; P = .16). Median progression-free survival was 9.2 months (FU/LV/bevacizumab) and 5.5 months (FU/LV/placebo); hazard ratio was 0.50; P = .0002. Response rates were 26.0% (FU/LV/bevacizumab) and 15.2% (FU/LV/placebo) (P = .055); duration of response was 9.2 months (FU/LV/bevacizumab) and 6.8 months (FU/LV/placebo); hazard ratio was 0.42; P = .088. Grade 3 hypertension was more common with bevacizumab treatment (16% v 3%) but was controlled with oral medication and did not cause study drug discontinuation.
CONCLUSION: Addition of bevacizumab to FU/LV as first-line therapy in CRC patients who were not considered optimal candidates for first-line irinotecan treatment provided clinically significant patient benefit, including statistically significant improvement in progression-free survival.
INTRODUCTION
The concept of targeting tumor vasculature as a therapeutic strategy in human cancer was initially based on the observation that rapid growth of transplanted tumors was often preceded by a local increase in vascular density.1 This process, termed angiogenesis, was subsequently shown to be mediated by diffusible factors released by tumor cells.2 One of the most potent of these endothelial cell-specific mitogens is vascular endothelial growth factor (VEGF), a highly conserved, homodimeric, heparin-binding glycoprotein that exists in several isoforms.3 VEGF mediates its effects by interacting with the membrane-bound tyrosine kinase receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR, flk-1), activating specific downstream survival and proliferation pathways.4 VEGF is considered essential for normal developmental vasculogenesis, and there is substantial evidence implicating VEGF as a critical factor in tumor angiogenesis.5,6 Transformed cell lines commonly express increased levels of both VEGF mRNA and protein.7 Transfection of Chinese hamster ovary cells with expression vectors encoding VEGF allows these cells to form tumors in nude mice.8 Increased VEGF expression has been described in most human tumors3 and in many instances is correlated with an adverse prognosis (increased risk of tumor recurrence and metastasis and decreased survival).9-13 Finally, an antibody against human VEGF, used either alone or in combination with chemotherapy, inhibits the growth of human tumors implanted in immunodeficient mice.14
Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA) is the recombinant humanized version of a murine antihuman VEGF monoclonal antibody A4.6.1.15 In phase I trials, bevacizumab was generally well tolerated, was not associated with a dose-limiting toxicity, and, when combined with classical cytotoxic chemotherapy agents, did not exacerbate their expected toxicities.16,17 Based on the observed prognostic role of VEGF in colorectal cancer (CRC), a randomized phase II clinical trial comparing chemotherapy alone (fluorouracil and leucovorin [FU/LV]) or in combination with bevacizumab in patients with previously untreated metastatic CRC was conducted. The results of this trial suggested that the addition of bevacizumab to chemotherapy provided a higher response rate, longer median time to disease progression, and longer median survival.18 A post hoc exploratory analysis of this trial suggested that the effect of bevacizumab was particularly significant in a subset of patients with poor prognostic features (Eastern Cooperative Oncology Group [ECOG] performance status [PS] > 0, age 65 years, and albumin 3.5 g/dL).
The study described here was reported around the same time of publication of two randomized phase III clinical trials19,20 demonstrating that the addition of irinotecan (CPT-11) to FU/LV resulted in statistically significant increases in response rate, time to disease progression, and survival, and established irinotecan-containing regimens as a new standard of care for metastatic CRC. However, retrospective analyses of these results suggested that the benefit derived from irinotecan might be limited to patients with a performance status of 0.21,22 Also, certain subgroups, including those with advanced age, impaired PS, low serum albumin, and prior pelvic radiotherapy, may experience significant toxicities when adding irinotecan to FU/LV regimens.23-27
Cognizant of these results, two subsequent randomized trials of bevacizumab were conducted in patients with previously untreated metastatic CRC. A pivotal trial utilized a regimen of irinotecan, bolus FU, and leucovorin (bolus IFL) with or without bevacizumab in a fully powered, phase III, placebo-controlled design in patients with a good ECOG PS (PS 0 or 1).28 This trial demonstrated statistically significant and clinically relevant improvements in response rate, time to disease progression, and survival. Median survival was increased by 4.7 months (15.6 v 20.3 months; P < .001). A second, supportive, placebo-controlled, randomized, phase II trial was conducted concurrently with the pivotal trial in patients deemed nonoptimal candidates for first-line irinotecan-containing regimens. This trial was designed to evaluate the safety and efficacy of bevacizumab in combination with FU/LV delivered on a weekly, high-dose schedule. The final results of this trial are reported here.
PATIENTS AND METHODS
Patient Eligibility
Patients with histologically confirmed, previously untreated, measurable metastatic CRC were eligible if, in the judgment of the investigator, they were not optimal candidates for first-line irinotecan-containing therapy. In addition, they were required to have at least one of the following characteristics: age 65 years, ECOG PS of 1 or 2, serum albumin 3.5 g/dL, or prior radiotherapy to abdomen or pelvis. Patients were excluded if they had undergone major surgical procedures or open biopsy, or had experienced significant traumatic injury, within 28 days before study entry; had an anticipated need for major surgery during the course of the study; were currently using or had recently used therapeutic anticoagulants (except as required for catheter patency), thrombolytic therapy, or chronic, daily treatment with aspirin (> 325 mg/d) or nonsteroidal anti-inflammatory medications; had a serious, nonhealing wound, ulcer, or bone fracture; had a history or evidence of CNS metastases; were pregnant or lactating; or had proteinuria or clinically significant impairment of renal function at baseline. All patients provided written informed consent for their participation. The study was approved by the institutional review boards of all participating centers and conducted in accordance with the US Food and Drug Administration Good Clinical Practice (GCP), and local ethical and legal requirements.
Study Design and Treatments
An interactive voice response system was used to randomly assign eligible patients to one of two treatment groups: FU/LV plus placebo, or FU/LV plus bevacizumab. A dynamic randomization algorithm was utilized to achieve balance overall and within each of the following categories: study center, baseline ECOG PS (0 v 1), site of primary disease (colon v rectum), and number of metastatic sites (1 v > 1). The FU/LV treatment, comprising LV 500 mg/m2 over 2 hours and FU 500 mg/m2 as a bolus midway through the LV infusion (Roswell Park regimen29), was administered weekly for the first 6 weeks of each 8-week cycle. Chemotherapy was continued until study completion (96 weeks) or disease progression. Bevacizumab 5 mg/kg or placebo was administered every 2 weeks. Patients in the bevacizumab arm who had a confirmed complete response or experienced unacceptable toxicity as a result of chemotherapy treatment were allowed to discontinue FU/LV and continue receiving bevacizumab alone as first-line treatment. At the time of disease progression, patients were unblinded to their treatment assignment and could receive any second-line treatment at the discretion of the investigator. Only patients who had been randomly assigned to the bevacizumab group could receive bevacizumab as a component of second-line treatment. After completing the study, patients were followed up for any subsequent treatment and survival every 4 months until death, loss to follow-up, or termination of the study.
Study Assessments
Patients underwent an assessment of tumor status at baseline and at completion of every 8-week cycle using appropriate radiographic techniques, typically spiral computed tomography scanning. Tumor response or progression was determined by both the investigator and an independent radiology facility (IRF) utilizing the Response Evaluation Criteria in Solid Tumors.30 The IRF assessment was performed without knowledge of the treatment assignment or investigator assessment. In addition, patients completed the Functional Assessment of Cancer Therapy—Colorectal (FACT-C), Version 4, a validated instrument for assessing quality of life (QOL) in CRC patients,31 at baseline and before each treatment cycle until disease progression.
Safety was assessed from reports of adverse events, laboratory test results, and vital sign measurements. Adverse events and abnormal laboratory results were categorized using the National Cancer Institute Common Toxicity Criteria version 2. Prespecified safety measures included four adverse events of special interest (hypertension, proteinuria, thrombosis, and bleeding) based on findings of previous clinical trials of bevacizumab.
Statistical Analysis
The primary outcome measure was duration of overall survival. Secondary outcome measures included progression-free survival, objective response rate (complete and partial), response duration, and change in the FACT-C QOL score. Survival duration was defined as the time from random assignment to death. For patients alive at the time of analysis, duration of survival was censored at the date of last contact. Progression-free survival was defined as the time from random assignment to the earlier of disease progression or death on study, defined as death from any cause within 30 days of the last dose of study drug or chemotherapy. For patients alive without disease progression at the time of analysis, progression-free survival was censored at their last tumor assessment or at the day of random assignment (the first day of study treatment) if no postbaseline assessment was performed. In the analysis of objective response, patients without tumor assessments were categorized as nonresponders. Disease progression and response analyses were based on the IRF assessments. Change in QOL was analyzed as time to deterioration in QOL (TDQ), defined as the length of time from random assignment to the earliest of a 3-point decrease from baseline in colon-cancer specific FACT-C subscale score (CCS), disease progression, or death on study. TDQ was also determined for the TOI-C (sum of CCS, physical and functional well-being) and total FACT-C for changes from baseline of 7 and 9 points, respectively.
To detect a hazard ratio of 0.61 for death in the FU/LV/bevacizumab group relative to the FU/LV/placebo group, approximately 133 deaths were required. A two-tailed log-rank test at the .05 level of significance with 80% power and two interim analyses were assumed in the calculations. Interim analyses were conducted by an unblinded, independent data monitoring committee. A safety interim analysis was conducted after 44 deaths, and a second safety and efficacy interim analysis was conducted after 89 deaths. The interim efficacy analysis was governed by a formal group sequential stopping rule based on an O’Brien-Fleming spending function. Kaplan-Meier methodology was applied to estimate the median survival, progression-free survival, and duration of response time for each treatment group. Hazard ratios for the bevacizumab group relative to the placebo group were determined using the stratified Cox proportional hazards model. A two-sided stratified log-rank test was used to compare the two groups. Stratified analyses included baseline ECOG PS, site of primary disease, and the number of metastatic sites. Objective response rates were compared by the 2 test. As exploratory analyses, the Cox proportional hazards model was used to estimate the effect of risk factors on modifications of treatment effect for duration of survival and progression-free survival. Efficacy analyses were performed on the intent-to-treat population, defined as all randomly assigned patients. Safety analyses included all patients who received at least one dose of study drug.
RESULTS
Patient Characteristics
Between August 2000 and July 2002, 209 patients were randomly assigned at 60 sites in the United States and Australia/New Zealand. For the intent-to-treat analysis of the primary end point (overall survival), there were 105 patients in the FU/LV/placebo group and 104 in the FU/LV/bevacizumab group. Table 1 presents selected demographic and baseline characteristics, which were reasonably balanced between treatment groups. Low serum albumin ( 3.5 g/dL) at baseline was less common in the bevacizumab group than in the placebo group.
Treatment
The median duration of therapy was 23 weeks in the FU/LV/placebo group and 31 weeks in the FU/LV/bevacizumab group, and the FU dose intensity (percentage of planned FU doses actually received) in the two groups was similar (92% v 84%) during the treatment course. As of November 2003, one patient in the FU/LV/placebo group and seven patients in the FU/LV/bevacizumab group remained on the assigned initial therapy. Subsequent therapies, which may have influenced survival, were used in approximately 50% of patients in both groups, though more patients in the FU/LV/placebo group were treated with the active agents irinotecan and oxaliplatin.
Efficacy
Overall survival, the primary end point, was longer in the FU/LV/bevacizumab group (median, 16.6 months) than in the FU/LV/placebo group (median, 12.9 months). The hazard ratio of death was estimated to be 0.79 (95% CI, 0.56 to 1.10; P = .16; Table 2 and Fig 1). The addition of bevacizumab to FU/LV was associated with increases in median progression-free survival (9.2 v 5.5 months; hazard ratio, 0.50; 95% CI, 0.34 to 0.73; P = .0002; Table 2 and Fig 2), response rate (26.0% v 15.2%; P = .055), and median duration of response (9.2 v 6.8 months; hazard ratio, 0.42; 95% CI, 0.15 to 1.17; P = .088). An analysis of treatment effect on overall survival and progression-free survival, by baseline characteristics, is presented in Figures 3 and 4. Patients with low serum albumin ( 3.5 g/dL) at baseline seemed to derive a significant survival benefit (hazard ratio, 0.46; 95% CI, 0.29 to 0.74; P = .001).
Bevacizumab treatment had no detrimental effect on QOL, and the TDQ results suggest a possible beneficial effect. The median TDQ as measured by the CCS score was 3.0 months in the FU/LV/placebo group and 3.1 month in the FU/LV/bevacizumab group (hazard ratio, 0.79; P = .188). Median TDQ for placebo-treated and bevacizumab-treated patients as measured by secondary TDQ measures were 2.3 and 3.2 months (TOI-C; hazard ratio, 0.71; P = .048) and 2.6 and 3.6 months (total FACT-C; hazard ratio, 0.66; P = .016).
Safety
A total of 204 patients (104 FU/LV/placebo and 100 FU/LV/bevacizumab) who received at least one dose of study drug comprised the safety population. Table 3 presents the incidence of selected adverse events during the assigned treatment. A 16% increase (71% v 87%) in total grade 3 and 4 toxicities was observed for patients receiving bevacizumab. Adverse events leading to death or study discontinuation were similar in the two groups, as were adverse events known to be associated with FU/LV (specifically, diarrhea and leukopenia). Two patients, both in the FU/LV/bevacizumab group, experienced a bowel perforation event. These events occurred at day 110 and day 338 of treatment, respectively, and both were determined to be associated with a colonic diverticulum at surgical exploration. One patient died as a result of this complication. Previous clinical trials had suggested hemorrhage, thromboembolism, proteinuria, and hypertension as possible bevacizumab-associated toxicities; however, in this study, no increases were seen in venous thrombosis, grade 3 bleeding, or clinically significant ( grade 3) proteinuria. Arterial thrombotic events (myocardial infarction, stroke, or peripheral arterial thrombotic event) occurred in 10 patients in the FU/LV/bevacizumab group, compared with five patients in the FU/LV/placebo group.
The FU/LV/placebo group had a higher 60-day all-cause mortality compared with the FU/LV/bevacizumab group (13.5% v 5.0%, respectively). Death due to disease progression in the first 60 days was similar (5.8% v 4.0%, respectively) in the two groups. In the FU/LV/placebo group, deaths within the first 60 days not due to disease progression were attributed to the following: heart failure (one patient), sepsis (three patients), diarrhea (two patients), respiratory failure (one patient), and pulmonary embolus (one patient). In the FU/LV/bevacizumab group, the single early death not due to disease progression was attributed to a myocardial infarction.
DISCUSSION
The results of this clinical trial add to a growing body of data demonstrating that bevacizumab, a humanized monoclonal antibody against VEGF, provides important clinical benefit when added to first-line chemotherapy for the treatment of metastatic CRC. When compared with FU/LV alone, the addition of bevacizumab prolonged median survival by 3.7 months, progression-free survival by 3.7 months, and response duration by 2.4 months, and increased the response rate by 11%.
These results should be viewed in the context of the study population. We specifically selected patients who were deemed by their treating physician to be suboptimal candidates for first-line irinotecan-containing therapy, either because of a low likelihood of benefit or a high likelihood of treatment-associated toxicities. Retrospective analyses of the pivotal irinotecan trials suggested that clinical benefit from this agent was largely confined to patients with a normal ECOG PS (PS 0).21,22 Advanced age, prior pelvic radiation therapy, impaired PS, and low serum albumin have all been reported to increase irinotecan-associated toxicities.23-27 Patients with these characteristics may benefit from less toxic alternative therapeutic options. We previously conducted a retrospective subset analysis from a smaller randomized phase II trial evaluating bevacizumab and FU/LV in CRC and noted that bevacizumab provided a substantial treatment effect in the subset of patients with baseline PS 1 or 2 (median survival, 6.3 v 15.2 months), in the subset aged 65 years (11.2 v 17.7 months), and in the subset with serum albumin less than 3.5 g/dL (8.1 v 14.1 months). These results encouraged us to design the current trial, specifically including a poor-prognosis study population and powering the trial to detect a large treatment effect on survival. We were largely successful in enrolling a population different from that in the concurrently conducted pivotal trial of IFL/placebo versus IFL/bevacizumab. Compared with the pivotal trial, patients in the present trial had a higher median age (72 v 61 years) and substantially more patients had a PS more than 0 (72% v 43%) and albumin 3.5 mg/dL (46% v 33%).
Despite this higher-risk study population, the regimen of FU/LV/bevacizumab seemed to be well tolerated. The well-described bevacizumab-associated adverse event of grade 3 hypertension was seen in 16% of the FU/LV/bevacizumab group versus 3% in the FU/LV/placebo group. No cases of grade 4 hypertension occurred. Proteinuria of any grade was seen in 38% of the FU/LV/bevacizumab group versus 19% of the FU/LV/placebo group; however, only a single patient in the bevacizumab group developed grade 3 proteinuria, and there were no cases of grade 4 proteinuria. No increases in grade 3 or 4 bleeding or venous thrombotic events were seen in bevacizumab-treated patients. There was an imbalance in the incidence of arterial thrombotic events: 10% in the FU/LV/bevacizumab group compared with 4.8% in the FU-/LV/placebo group. A similar imbalance was noted in the pivotal bevacizumab trial (1.0% in the IFL/placebo group and 3.3% in the IFL/bevacizumab group). The more advanced age of the population included in the present study may have contributed to a higher overall incidence of this adverse event; however, the imbalance in both studies is noteworthy. Large, observational safety trials may be required to further define the incidence and potential risk factors for these and other uncommon adverse events associated with bevacizumab therapy.
Two patients (2%) in the FU/LV/bevacizumab group developed gastrointestinal (bowel) perforation. This unusual adverse event was seen in 1.5% of bevacizumab-treated patients in the pivotal trial and has also been reported in approximately 1% of patients treated with bevacizumab in an ongoing randomized trial in second-line treatment of CRC.32 The two cases in this trial were associated with a perforated colonic diverticulum. In the previous CRC trial reports, perforation seemed to be associated with an inflammatory process involving the gastrointestinal tract, including peptic ulcer disease, peritoneal carcinomatosis, and inflammation due to recent colonic instrumentation (colonoscopy). Given the role that VEGF plays in neovascularization and wound healing, these events might not be unexpected in patients undergoing anti-VEGF treatment, and clinicians should be alert to this potential toxicity when using bevacizumab.
Two prior clinical trials have explored the use of bevacizumab in combination with FU/LV. In a small, randomized phase II trial, bevacizumab improved median survival by 4.2 months (13.8 v 18.0 months; P = .55) and progression-free survival by 2.2 months (5.2 v 7.4 months; P = .013). The pivotal bevacizumab trial that compared IFL/placebo with IFL/bevacizumab initially contained a third arm of FU/LV/bevacizumab until the safety of IFL/bevacizumab was established by an independent data monitoring committee. These patients had a median progression-free survival of 8.8 months and a median survival of 18.3 months, which compared favorably to the IFL/placebo control arm (6.8 and 15.1 months, respectively). The progression-free survival and overall survival observed in these two prior trials are remarkably consistent with the current results.
It should be noted that this trial failed to achieve the prespecified primary end point, a substantial 39% reduction in the hazard of death (hazard ratio, 0.61). There may be several possible explanations. The small sample size may have resulted in unmeasured imbalances in important baseline prognostic characteristics between the two groups. For instance, the treatment effect of bevacizumab on overall survival was particularly striking within the subgroup of patients with low serum albumin at baseline (hazard ratio, 0.46; P = .001). These patients were underrepresented in the FU/LV/bevacizumab group (42% v 49%). Another potentially important confounding factor is postprogression therapy. During the conduct of the first randomized trial evaluating FU/LV/bevacizumab18 (which provided the treatment estimates for powering the current trial), few patients received active postprogression therapy (specifically, irinotecan or oxaliplatin). However, in the current trial, 46% of the FU/LV/placebo group and 39% of the FU/LV/bevacizumab group received irinotecan, oxaliplatin, or both following initial disease progression (Table 4). Such differences in postprogression therapy have confounded the interpretation of overall survival in other randomized clinical trials in first-line metastatic CRC, most notably Intergroup trial N9741.33 The substantial difference in time to disease progression that we observed (9.2 v 5.5 months; hazard ratio, 0.50; P = .0002) is unaffected by postprogression therapy and may be a more representative assessment of the clinical benefit provided by the addition of bevacizumab to FU/LV (Fig 4).
In summary, these data demonstrate that bevacizumab, when combined with bolus FU/LV, provides substantial clinical benefit for patients with previously untreated metastatic CRC. Together with the pivotal trial results, these data strengthen the evidence that bevacizumab-based FU/LV-containing therapy should be considered a standard option for the initial treatment of metastatic CRC.
Authors’ Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: Robert Mass, Genentech; Brent Perrou, Genentech; Betty Nelson, Genentech; William F. Novotny, Genentech. Consultant/Advisory Role: Taral Patel, Amgen, Barlex, Genentech. Stock Ownership: Robert Mass, Genentech; Brent Perrou, Genentech; Betty Nelson, Benentech; William F. Novotny, Genentech. Honoraria: Fairooz F. Kabbinavar, Genentech; Taral Patel, Amgen, Genentech; John T. Hamm, Genentech. Research Funding: John T. Hamm, Genentech. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
NOTES
Supported by Genentech Inc.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Genentech Inc, South San Francisco, CA
Virginia Oncology Associates, Newport News, VA
Florida Cancer Specialists, Ft Myers, FL
Mid Ohio Oncology Hematology Inc, Westerville, OH
Louisville Oncology, Louisville, KY
ABSTRACT
PURPOSE: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, increases survival when combined with irinotecan-based chemotherapy in first-line treatment of metastatic colorectal cancer (CRC). This randomized, phase II trial compared bevacizumab plus fluorouracil and leucovorin (FU/LV) versus placebo plus FU/LV as first-line therapy in patients considered nonoptimal candidates for first-line irinotecan.
PATIENTS AND METHODS: Patients had metastatic CRC and one of the following characteristics: age 65 years, Eastern Cooperative Oncology Group performance status 1 or 2, serum albumin 3.5 g/dL, or prior abdominal/pelvic radiotherapy. Patients were randomly assigned to FU/LV/placebo (n = 105) or FU/LV/bevacizumab (n = 104). The primary end point was overall survival. Secondary end points were progression-free survival, response rate, response duration, and quality of life. Safety was also assessed.
RESULTS: Median survival was 16.6 months for the FU/LV/bevacizumab group and 12.9 months for the FU/LV/placebo group (hazard ratio, 0.79; P = .16). Median progression-free survival was 9.2 months (FU/LV/bevacizumab) and 5.5 months (FU/LV/placebo); hazard ratio was 0.50; P = .0002. Response rates were 26.0% (FU/LV/bevacizumab) and 15.2% (FU/LV/placebo) (P = .055); duration of response was 9.2 months (FU/LV/bevacizumab) and 6.8 months (FU/LV/placebo); hazard ratio was 0.42; P = .088. Grade 3 hypertension was more common with bevacizumab treatment (16% v 3%) but was controlled with oral medication and did not cause study drug discontinuation.
CONCLUSION: Addition of bevacizumab to FU/LV as first-line therapy in CRC patients who were not considered optimal candidates for first-line irinotecan treatment provided clinically significant patient benefit, including statistically significant improvement in progression-free survival.
INTRODUCTION
The concept of targeting tumor vasculature as a therapeutic strategy in human cancer was initially based on the observation that rapid growth of transplanted tumors was often preceded by a local increase in vascular density.1 This process, termed angiogenesis, was subsequently shown to be mediated by diffusible factors released by tumor cells.2 One of the most potent of these endothelial cell-specific mitogens is vascular endothelial growth factor (VEGF), a highly conserved, homodimeric, heparin-binding glycoprotein that exists in several isoforms.3 VEGF mediates its effects by interacting with the membrane-bound tyrosine kinase receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR, flk-1), activating specific downstream survival and proliferation pathways.4 VEGF is considered essential for normal developmental vasculogenesis, and there is substantial evidence implicating VEGF as a critical factor in tumor angiogenesis.5,6 Transformed cell lines commonly express increased levels of both VEGF mRNA and protein.7 Transfection of Chinese hamster ovary cells with expression vectors encoding VEGF allows these cells to form tumors in nude mice.8 Increased VEGF expression has been described in most human tumors3 and in many instances is correlated with an adverse prognosis (increased risk of tumor recurrence and metastasis and decreased survival).9-13 Finally, an antibody against human VEGF, used either alone or in combination with chemotherapy, inhibits the growth of human tumors implanted in immunodeficient mice.14
Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA) is the recombinant humanized version of a murine antihuman VEGF monoclonal antibody A4.6.1.15 In phase I trials, bevacizumab was generally well tolerated, was not associated with a dose-limiting toxicity, and, when combined with classical cytotoxic chemotherapy agents, did not exacerbate their expected toxicities.16,17 Based on the observed prognostic role of VEGF in colorectal cancer (CRC), a randomized phase II clinical trial comparing chemotherapy alone (fluorouracil and leucovorin [FU/LV]) or in combination with bevacizumab in patients with previously untreated metastatic CRC was conducted. The results of this trial suggested that the addition of bevacizumab to chemotherapy provided a higher response rate, longer median time to disease progression, and longer median survival.18 A post hoc exploratory analysis of this trial suggested that the effect of bevacizumab was particularly significant in a subset of patients with poor prognostic features (Eastern Cooperative Oncology Group [ECOG] performance status [PS] > 0, age 65 years, and albumin 3.5 g/dL).
The study described here was reported around the same time of publication of two randomized phase III clinical trials19,20 demonstrating that the addition of irinotecan (CPT-11) to FU/LV resulted in statistically significant increases in response rate, time to disease progression, and survival, and established irinotecan-containing regimens as a new standard of care for metastatic CRC. However, retrospective analyses of these results suggested that the benefit derived from irinotecan might be limited to patients with a performance status of 0.21,22 Also, certain subgroups, including those with advanced age, impaired PS, low serum albumin, and prior pelvic radiotherapy, may experience significant toxicities when adding irinotecan to FU/LV regimens.23-27
Cognizant of these results, two subsequent randomized trials of bevacizumab were conducted in patients with previously untreated metastatic CRC. A pivotal trial utilized a regimen of irinotecan, bolus FU, and leucovorin (bolus IFL) with or without bevacizumab in a fully powered, phase III, placebo-controlled design in patients with a good ECOG PS (PS 0 or 1).28 This trial demonstrated statistically significant and clinically relevant improvements in response rate, time to disease progression, and survival. Median survival was increased by 4.7 months (15.6 v 20.3 months; P < .001). A second, supportive, placebo-controlled, randomized, phase II trial was conducted concurrently with the pivotal trial in patients deemed nonoptimal candidates for first-line irinotecan-containing regimens. This trial was designed to evaluate the safety and efficacy of bevacizumab in combination with FU/LV delivered on a weekly, high-dose schedule. The final results of this trial are reported here.
PATIENTS AND METHODS
Patient Eligibility
Patients with histologically confirmed, previously untreated, measurable metastatic CRC were eligible if, in the judgment of the investigator, they were not optimal candidates for first-line irinotecan-containing therapy. In addition, they were required to have at least one of the following characteristics: age 65 years, ECOG PS of 1 or 2, serum albumin 3.5 g/dL, or prior radiotherapy to abdomen or pelvis. Patients were excluded if they had undergone major surgical procedures or open biopsy, or had experienced significant traumatic injury, within 28 days before study entry; had an anticipated need for major surgery during the course of the study; were currently using or had recently used therapeutic anticoagulants (except as required for catheter patency), thrombolytic therapy, or chronic, daily treatment with aspirin (> 325 mg/d) or nonsteroidal anti-inflammatory medications; had a serious, nonhealing wound, ulcer, or bone fracture; had a history or evidence of CNS metastases; were pregnant or lactating; or had proteinuria or clinically significant impairment of renal function at baseline. All patients provided written informed consent for their participation. The study was approved by the institutional review boards of all participating centers and conducted in accordance with the US Food and Drug Administration Good Clinical Practice (GCP), and local ethical and legal requirements.
Study Design and Treatments
An interactive voice response system was used to randomly assign eligible patients to one of two treatment groups: FU/LV plus placebo, or FU/LV plus bevacizumab. A dynamic randomization algorithm was utilized to achieve balance overall and within each of the following categories: study center, baseline ECOG PS (0 v 1), site of primary disease (colon v rectum), and number of metastatic sites (1 v > 1). The FU/LV treatment, comprising LV 500 mg/m2 over 2 hours and FU 500 mg/m2 as a bolus midway through the LV infusion (Roswell Park regimen29), was administered weekly for the first 6 weeks of each 8-week cycle. Chemotherapy was continued until study completion (96 weeks) or disease progression. Bevacizumab 5 mg/kg or placebo was administered every 2 weeks. Patients in the bevacizumab arm who had a confirmed complete response or experienced unacceptable toxicity as a result of chemotherapy treatment were allowed to discontinue FU/LV and continue receiving bevacizumab alone as first-line treatment. At the time of disease progression, patients were unblinded to their treatment assignment and could receive any second-line treatment at the discretion of the investigator. Only patients who had been randomly assigned to the bevacizumab group could receive bevacizumab as a component of second-line treatment. After completing the study, patients were followed up for any subsequent treatment and survival every 4 months until death, loss to follow-up, or termination of the study.
Study Assessments
Patients underwent an assessment of tumor status at baseline and at completion of every 8-week cycle using appropriate radiographic techniques, typically spiral computed tomography scanning. Tumor response or progression was determined by both the investigator and an independent radiology facility (IRF) utilizing the Response Evaluation Criteria in Solid Tumors.30 The IRF assessment was performed without knowledge of the treatment assignment or investigator assessment. In addition, patients completed the Functional Assessment of Cancer Therapy—Colorectal (FACT-C), Version 4, a validated instrument for assessing quality of life (QOL) in CRC patients,31 at baseline and before each treatment cycle until disease progression.
Safety was assessed from reports of adverse events, laboratory test results, and vital sign measurements. Adverse events and abnormal laboratory results were categorized using the National Cancer Institute Common Toxicity Criteria version 2. Prespecified safety measures included four adverse events of special interest (hypertension, proteinuria, thrombosis, and bleeding) based on findings of previous clinical trials of bevacizumab.
Statistical Analysis
The primary outcome measure was duration of overall survival. Secondary outcome measures included progression-free survival, objective response rate (complete and partial), response duration, and change in the FACT-C QOL score. Survival duration was defined as the time from random assignment to death. For patients alive at the time of analysis, duration of survival was censored at the date of last contact. Progression-free survival was defined as the time from random assignment to the earlier of disease progression or death on study, defined as death from any cause within 30 days of the last dose of study drug or chemotherapy. For patients alive without disease progression at the time of analysis, progression-free survival was censored at their last tumor assessment or at the day of random assignment (the first day of study treatment) if no postbaseline assessment was performed. In the analysis of objective response, patients without tumor assessments were categorized as nonresponders. Disease progression and response analyses were based on the IRF assessments. Change in QOL was analyzed as time to deterioration in QOL (TDQ), defined as the length of time from random assignment to the earliest of a 3-point decrease from baseline in colon-cancer specific FACT-C subscale score (CCS), disease progression, or death on study. TDQ was also determined for the TOI-C (sum of CCS, physical and functional well-being) and total FACT-C for changes from baseline of 7 and 9 points, respectively.
To detect a hazard ratio of 0.61 for death in the FU/LV/bevacizumab group relative to the FU/LV/placebo group, approximately 133 deaths were required. A two-tailed log-rank test at the .05 level of significance with 80% power and two interim analyses were assumed in the calculations. Interim analyses were conducted by an unblinded, independent data monitoring committee. A safety interim analysis was conducted after 44 deaths, and a second safety and efficacy interim analysis was conducted after 89 deaths. The interim efficacy analysis was governed by a formal group sequential stopping rule based on an O’Brien-Fleming spending function. Kaplan-Meier methodology was applied to estimate the median survival, progression-free survival, and duration of response time for each treatment group. Hazard ratios for the bevacizumab group relative to the placebo group were determined using the stratified Cox proportional hazards model. A two-sided stratified log-rank test was used to compare the two groups. Stratified analyses included baseline ECOG PS, site of primary disease, and the number of metastatic sites. Objective response rates were compared by the 2 test. As exploratory analyses, the Cox proportional hazards model was used to estimate the effect of risk factors on modifications of treatment effect for duration of survival and progression-free survival. Efficacy analyses were performed on the intent-to-treat population, defined as all randomly assigned patients. Safety analyses included all patients who received at least one dose of study drug.
RESULTS
Patient Characteristics
Between August 2000 and July 2002, 209 patients were randomly assigned at 60 sites in the United States and Australia/New Zealand. For the intent-to-treat analysis of the primary end point (overall survival), there were 105 patients in the FU/LV/placebo group and 104 in the FU/LV/bevacizumab group. Table 1 presents selected demographic and baseline characteristics, which were reasonably balanced between treatment groups. Low serum albumin ( 3.5 g/dL) at baseline was less common in the bevacizumab group than in the placebo group.
Treatment
The median duration of therapy was 23 weeks in the FU/LV/placebo group and 31 weeks in the FU/LV/bevacizumab group, and the FU dose intensity (percentage of planned FU doses actually received) in the two groups was similar (92% v 84%) during the treatment course. As of November 2003, one patient in the FU/LV/placebo group and seven patients in the FU/LV/bevacizumab group remained on the assigned initial therapy. Subsequent therapies, which may have influenced survival, were used in approximately 50% of patients in both groups, though more patients in the FU/LV/placebo group were treated with the active agents irinotecan and oxaliplatin.
Efficacy
Overall survival, the primary end point, was longer in the FU/LV/bevacizumab group (median, 16.6 months) than in the FU/LV/placebo group (median, 12.9 months). The hazard ratio of death was estimated to be 0.79 (95% CI, 0.56 to 1.10; P = .16; Table 2 and Fig 1). The addition of bevacizumab to FU/LV was associated with increases in median progression-free survival (9.2 v 5.5 months; hazard ratio, 0.50; 95% CI, 0.34 to 0.73; P = .0002; Table 2 and Fig 2), response rate (26.0% v 15.2%; P = .055), and median duration of response (9.2 v 6.8 months; hazard ratio, 0.42; 95% CI, 0.15 to 1.17; P = .088). An analysis of treatment effect on overall survival and progression-free survival, by baseline characteristics, is presented in Figures 3 and 4. Patients with low serum albumin ( 3.5 g/dL) at baseline seemed to derive a significant survival benefit (hazard ratio, 0.46; 95% CI, 0.29 to 0.74; P = .001).
Bevacizumab treatment had no detrimental effect on QOL, and the TDQ results suggest a possible beneficial effect. The median TDQ as measured by the CCS score was 3.0 months in the FU/LV/placebo group and 3.1 month in the FU/LV/bevacizumab group (hazard ratio, 0.79; P = .188). Median TDQ for placebo-treated and bevacizumab-treated patients as measured by secondary TDQ measures were 2.3 and 3.2 months (TOI-C; hazard ratio, 0.71; P = .048) and 2.6 and 3.6 months (total FACT-C; hazard ratio, 0.66; P = .016).
Safety
A total of 204 patients (104 FU/LV/placebo and 100 FU/LV/bevacizumab) who received at least one dose of study drug comprised the safety population. Table 3 presents the incidence of selected adverse events during the assigned treatment. A 16% increase (71% v 87%) in total grade 3 and 4 toxicities was observed for patients receiving bevacizumab. Adverse events leading to death or study discontinuation were similar in the two groups, as were adverse events known to be associated with FU/LV (specifically, diarrhea and leukopenia). Two patients, both in the FU/LV/bevacizumab group, experienced a bowel perforation event. These events occurred at day 110 and day 338 of treatment, respectively, and both were determined to be associated with a colonic diverticulum at surgical exploration. One patient died as a result of this complication. Previous clinical trials had suggested hemorrhage, thromboembolism, proteinuria, and hypertension as possible bevacizumab-associated toxicities; however, in this study, no increases were seen in venous thrombosis, grade 3 bleeding, or clinically significant ( grade 3) proteinuria. Arterial thrombotic events (myocardial infarction, stroke, or peripheral arterial thrombotic event) occurred in 10 patients in the FU/LV/bevacizumab group, compared with five patients in the FU/LV/placebo group.
The FU/LV/placebo group had a higher 60-day all-cause mortality compared with the FU/LV/bevacizumab group (13.5% v 5.0%, respectively). Death due to disease progression in the first 60 days was similar (5.8% v 4.0%, respectively) in the two groups. In the FU/LV/placebo group, deaths within the first 60 days not due to disease progression were attributed to the following: heart failure (one patient), sepsis (three patients), diarrhea (two patients), respiratory failure (one patient), and pulmonary embolus (one patient). In the FU/LV/bevacizumab group, the single early death not due to disease progression was attributed to a myocardial infarction.
DISCUSSION
The results of this clinical trial add to a growing body of data demonstrating that bevacizumab, a humanized monoclonal antibody against VEGF, provides important clinical benefit when added to first-line chemotherapy for the treatment of metastatic CRC. When compared with FU/LV alone, the addition of bevacizumab prolonged median survival by 3.7 months, progression-free survival by 3.7 months, and response duration by 2.4 months, and increased the response rate by 11%.
These results should be viewed in the context of the study population. We specifically selected patients who were deemed by their treating physician to be suboptimal candidates for first-line irinotecan-containing therapy, either because of a low likelihood of benefit or a high likelihood of treatment-associated toxicities. Retrospective analyses of the pivotal irinotecan trials suggested that clinical benefit from this agent was largely confined to patients with a normal ECOG PS (PS 0).21,22 Advanced age, prior pelvic radiation therapy, impaired PS, and low serum albumin have all been reported to increase irinotecan-associated toxicities.23-27 Patients with these characteristics may benefit from less toxic alternative therapeutic options. We previously conducted a retrospective subset analysis from a smaller randomized phase II trial evaluating bevacizumab and FU/LV in CRC and noted that bevacizumab provided a substantial treatment effect in the subset of patients with baseline PS 1 or 2 (median survival, 6.3 v 15.2 months), in the subset aged 65 years (11.2 v 17.7 months), and in the subset with serum albumin less than 3.5 g/dL (8.1 v 14.1 months). These results encouraged us to design the current trial, specifically including a poor-prognosis study population and powering the trial to detect a large treatment effect on survival. We were largely successful in enrolling a population different from that in the concurrently conducted pivotal trial of IFL/placebo versus IFL/bevacizumab. Compared with the pivotal trial, patients in the present trial had a higher median age (72 v 61 years) and substantially more patients had a PS more than 0 (72% v 43%) and albumin 3.5 mg/dL (46% v 33%).
Despite this higher-risk study population, the regimen of FU/LV/bevacizumab seemed to be well tolerated. The well-described bevacizumab-associated adverse event of grade 3 hypertension was seen in 16% of the FU/LV/bevacizumab group versus 3% in the FU/LV/placebo group. No cases of grade 4 hypertension occurred. Proteinuria of any grade was seen in 38% of the FU/LV/bevacizumab group versus 19% of the FU/LV/placebo group; however, only a single patient in the bevacizumab group developed grade 3 proteinuria, and there were no cases of grade 4 proteinuria. No increases in grade 3 or 4 bleeding or venous thrombotic events were seen in bevacizumab-treated patients. There was an imbalance in the incidence of arterial thrombotic events: 10% in the FU/LV/bevacizumab group compared with 4.8% in the FU-/LV/placebo group. A similar imbalance was noted in the pivotal bevacizumab trial (1.0% in the IFL/placebo group and 3.3% in the IFL/bevacizumab group). The more advanced age of the population included in the present study may have contributed to a higher overall incidence of this adverse event; however, the imbalance in both studies is noteworthy. Large, observational safety trials may be required to further define the incidence and potential risk factors for these and other uncommon adverse events associated with bevacizumab therapy.
Two patients (2%) in the FU/LV/bevacizumab group developed gastrointestinal (bowel) perforation. This unusual adverse event was seen in 1.5% of bevacizumab-treated patients in the pivotal trial and has also been reported in approximately 1% of patients treated with bevacizumab in an ongoing randomized trial in second-line treatment of CRC.32 The two cases in this trial were associated with a perforated colonic diverticulum. In the previous CRC trial reports, perforation seemed to be associated with an inflammatory process involving the gastrointestinal tract, including peptic ulcer disease, peritoneal carcinomatosis, and inflammation due to recent colonic instrumentation (colonoscopy). Given the role that VEGF plays in neovascularization and wound healing, these events might not be unexpected in patients undergoing anti-VEGF treatment, and clinicians should be alert to this potential toxicity when using bevacizumab.
Two prior clinical trials have explored the use of bevacizumab in combination with FU/LV. In a small, randomized phase II trial, bevacizumab improved median survival by 4.2 months (13.8 v 18.0 months; P = .55) and progression-free survival by 2.2 months (5.2 v 7.4 months; P = .013). The pivotal bevacizumab trial that compared IFL/placebo with IFL/bevacizumab initially contained a third arm of FU/LV/bevacizumab until the safety of IFL/bevacizumab was established by an independent data monitoring committee. These patients had a median progression-free survival of 8.8 months and a median survival of 18.3 months, which compared favorably to the IFL/placebo control arm (6.8 and 15.1 months, respectively). The progression-free survival and overall survival observed in these two prior trials are remarkably consistent with the current results.
It should be noted that this trial failed to achieve the prespecified primary end point, a substantial 39% reduction in the hazard of death (hazard ratio, 0.61). There may be several possible explanations. The small sample size may have resulted in unmeasured imbalances in important baseline prognostic characteristics between the two groups. For instance, the treatment effect of bevacizumab on overall survival was particularly striking within the subgroup of patients with low serum albumin at baseline (hazard ratio, 0.46; P = .001). These patients were underrepresented in the FU/LV/bevacizumab group (42% v 49%). Another potentially important confounding factor is postprogression therapy. During the conduct of the first randomized trial evaluating FU/LV/bevacizumab18 (which provided the treatment estimates for powering the current trial), few patients received active postprogression therapy (specifically, irinotecan or oxaliplatin). However, in the current trial, 46% of the FU/LV/placebo group and 39% of the FU/LV/bevacizumab group received irinotecan, oxaliplatin, or both following initial disease progression (Table 4). Such differences in postprogression therapy have confounded the interpretation of overall survival in other randomized clinical trials in first-line metastatic CRC, most notably Intergroup trial N9741.33 The substantial difference in time to disease progression that we observed (9.2 v 5.5 months; hazard ratio, 0.50; P = .0002) is unaffected by postprogression therapy and may be a more representative assessment of the clinical benefit provided by the addition of bevacizumab to FU/LV (Fig 4).
In summary, these data demonstrate that bevacizumab, when combined with bolus FU/LV, provides substantial clinical benefit for patients with previously untreated metastatic CRC. Together with the pivotal trial results, these data strengthen the evidence that bevacizumab-based FU/LV-containing therapy should be considered a standard option for the initial treatment of metastatic CRC.
Authors’ Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: Robert Mass, Genentech; Brent Perrou, Genentech; Betty Nelson, Genentech; William F. Novotny, Genentech. Consultant/Advisory Role: Taral Patel, Amgen, Barlex, Genentech. Stock Ownership: Robert Mass, Genentech; Brent Perrou, Genentech; Betty Nelson, Benentech; William F. Novotny, Genentech. Honoraria: Fairooz F. Kabbinavar, Genentech; Taral Patel, Amgen, Genentech; John T. Hamm, Genentech. Research Funding: John T. Hamm, Genentech. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
NOTES
Supported by Genentech Inc.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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