Combined Analysis of Efficacy: The Addition of Bevacizumab to Fluorouracil/Leucovorin Improves Survival for Patients With Metastatic Colorec
http://www.100md.com
《临床肿瘤学》
the University of California Los Angeles, Los Angeles
Genentech Inc, South San Francisco
University of California San Francisco, San Francisco, CA
Duke University, Durham, NC
ABSTRACT
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/fluourouracil (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 .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.
INTRODUCTION
Despite recent advances achieved by combining new chemotherapeutic agents with fluorouracil and leucovorin (FU/LV), the overall survival of metastatic colorectal cancer (CRC) remains modest, and treatment-associated toxicity can be significant.1,2 Newer approaches to CRC therapy have focused on targeting cellular signaling, including the epidermal growth factor and vascular endothelial growth factor (VEGF) pathways.
Establishing a blood supply (angiogenesis) is critical to tumor growth and progression, as evidenced by local increases in vascular density that precede the rapid growth of transplanted tumors.3 There are several VEGF family members that have differential effects on angiogenesis.4 The discovery that VEGF, a homodimeric glycoprotein produced by normal and neoplastic cells, is a central mediator of angiogenesis led to exploration of VEGF effects on tumor growth. The potential of VEGF as an anticancer target was supported by the demonstration that a murine anti-VEGF monoclonal antibody was capable of inhibiting subcutaneous tumor growth in murine tumor models.5
Subsequently, a humanized variant of an anti-VEGF monoclonal antibody,6 bevacizumab (rhuMAb VEGF; Avastin; Genentech Inc, South San Francisco, CA), has been evaluated as an antiangiogenic cancer therapy in many tumor types. In patients with metastatic CRC, the addition of bevacizumab (BV) to chemotherapy has been shown to improve survival. In a large, phase III, randomized, double-blind, placebo-controlled clinical trial of patients with previously untreated metastatic CRC,7 the addition of bevacizumab to irinotecan/fluourouracil (FU)/leucovorin (LV; IFL) increased median survival from 15.6 months to 20.3 months, corresponding to a 34% reduction in the hazard of death (P .0001). Similar increases occurred in progression-free survival (6.2 v 10.6 months; hazard ratio, 0.54; P < .0001), response rate (34.8% v 44.8%; P = .0036), and duration of response (7.1 v 10.4 months; hazard ratio, 0.62; P = .0014).
Although irinotecan-based regimens such as IFL offer improved antitumor efficacy and survival relative to FU-based chemotherapy, some patients with metastatic CRC are not appropriate candidates for irinotecan, either because of its toxicity—particularly neutropenia and delayed diarrhea—or because they have characteristics suggesting they are less likely to benefit. Predictors of a poorer response to or increased toxicity with irinotecan include advanced age, low performance status, and low serum albumin level.8-15 Oxaliplatin-based regimens such as FOLFOX (oxaliplatin and infused FU/LV) offer an alternative; however, both acute and chronic neurotoxicity associated with oxaliplatin may be limiting.16 Based on these observations, various regimens have emerged as standard options in first-line therapy, including the use of FU/LV for selected patients who are not considered optimal candidates for irinotecan- or oxaliplatin-based therapies. The addition of BV to FU/LV may be an attractive alternative first-line regimen in these selected patients with metastatic CRC, despite the uncommon but serious BV-associated adverse events of GI perforation, arterial thromboembolic events, and potential wound healing issues.
Three clinical trials have evaluated the addition of BV to FU/LV chemotherapy. The first (Study 1) was a phase II study in which 104 patients were randomized to either FU/LV combined with one of two doses of BV or to FU/LV alone.17 A second, larger phase II trial (Study 2) randomized 209 patients to FU/LV/BV or to FU/LV alone.18 The third trial (Study 3) was the above-mentioned phase III, randomized, controlled study,7 which in addition to the two main treatment groups included 110 patients who received BV in combination with FU/LV. This third treatment group was enrolled only until a planned interim safety analysis established an acceptable safety profile for the IFL/BV treatment group.
Because the clinical trial experience with FU/LV/BV derives from groups of treated patients in similarly designed studies, none of which was large enough to show a statistically significant effect on overall survival, we performed a combined analysis of these three clinical trials, utilizing raw data from each, to enable evaluation of the regimen efficacy in a larger patient population. A combined analysis, based on pooled raw data from essentially similar trials, is considered more rigorous than a meta-analysis of summary statistics, which is typically performed when individual patient data from each study are not accessible or if the study designs are too different to justify pooling the raw data. Separate analyses of efficacy data from each of the three studies,17-19 utilizing the same patients included in the combined analyses reported in this article, indicated that in Studies 1 and 2, the duration of progression-free survival (PFS) with FU/LV/BV treatment was statistically significantly improved relative to the rate in the control comparator group. In Study 3, PFS was increased with the addition of BV to FU/LV, but the difference was not statistically significant. In all three studies, response rate with FU/LV/BV was increased (significantly increased in Study 1). Overall survival was longer with FU/LV/BV treatment in all three studies, but the increases were not statistically significant. Pooling of the data from the three studies allows evaluation of these three efficacy end points with greater statistical power to detect real differences between the groups of patients who were and were not treated with bevacizumab.
PATIENTS AND METHODS
End Points and Analysis Population
The primary objective of the analysis was to compare duration of survival in patients who received BV (5 mg/kg once every 2 weeks) plus FU/LV with the survival rates in a combined control group of patients who received either FU/LV or IFL alone for treatment of metastatic CRC. Secondary objectives included evaluation of progression-free survival and response rate.
The three studies contributing data to the combined analysis are schematically summarized in Figure 1. The investigative group comprised all patients randomized to FU/LV in combination with bevacizumab in the two phase II trials (Study 1 and Study 2) and in the phase III trial (Study 3). The combined control group comprised patients who were randomized to FU/LV treatment in the two phase II trials, or who were randomized to IFL/placebo treatment concurrently with those randomized to FU/LV/BV in the phase III trial.
Study Design of Three Trials
The three studies were multicenter, randomized trials conducted in patients with histologically confirmed, bidimensionally measurable, previously untreated metastatic CRC. The protocols were approved by the Institutional Review Boards of the participating centers, and the studies were conducted in accordance with the US Food and Drug Administration principles of Good Clinical Practice, as well as local ethical and legal requirements. Patients provided written informed consent for their study participation.
In all three studies, FU/LV chemotherapy (with or without the addition of bevacizumab) was administered in the weekly bolus schedule described by Petrelli et al.20 IFL was administered using the bolus schedule described by Saltz et al.1 Patients assigned to BV-containing regimens received bevacizumab by intravenous infusion once every 2 weeks.
Study 1. In the first phase II trial,17 104 patients were randomized to one of three treatment groups: a control group (FU/LV chemotherapy alone; n = 36) and two bevacizumab (5 or 10 mg/kg) plus FU/LV groups (n = 35 and n = 33, respectively). This was an open-label trial, and at the time of disease progression patients in the control group became eligible to receive bevacizumab.
Study 2. This second phase II trial18 was conducted in 209 patients who were not considered by their treating physician to be optimal candidates for first-line irinotecan-based therapy, and who were required to have at least one of the following features: advanced age ( 65 years), low serum albumin level ( 3.5 g/dL), poor Eastern Cooperative Oncology Group (ECOG) performance status21 (1 or 2), or a history of abdominal/pelvic radiotherapy. The patients were randomly assigned to receive BV plus FU/LV chemotherapy (n = 100) or FU/LV plus placebo (n = 104). Patients in the control group were not permitted to receive bevacizumab at the time of disease progression.
Study 3. In this phase III study,7 a total of 923 patients were randomized to one of three treatment groups: IFL + placebo (group 1, n = 411), IFL + BV (group 2, n = 402), or FU/LV + BV (group 3, n = 110). After 300 patients had been randomly assigned (approximately 100 patients per treatment group), enrollment to group 3 (FU/LV/BV) was suspended. For the combined analysis, only the 100 patients in the IFL/placebo group (group 1) who were enrolled concurrently with the 110 patients in the FU/LV/BV group (group 3) were included. Patients in the control group were not permitted to receive bevacizumab at the time of disease progression.
Statistical Considerations
The statistical rationale for a pooled analysis of raw data from three related trials is based on the fact that the trials used the same definitions and procedures for collecting data on baseline characteristics, primary and secondary efficacy end points, and safety assessments. The three trials used identical regimens of FU/LV, and we took the most conservative approach in assessing efficacy by including the IFL control group from Study 3.
For this combined analysis, demographic data (age, sex, and race/ethnicity) and baseline disease characteristics (site of primary disease, histologic cell type, years since diagnosis, number and location of metastatic sites, prior adjuvant therapy, and baseline ECOG performance status) for all randomized patients treated with FU/LV/BV were compared with those characteristics for the combined control group.
Efficacy analyses were based on the intent-to-treat population. The primary efficacy end point, duration of survival, was defined as the time from randomization to death from any cause. Formal hypothesis testing using the stratified log-rank test was performed to determine whether survival was prolonged in the FU/LV/BV group compared with the combined control. The only stratification variable employed was the categoric variable "study." The purpose of the stratification was to adjust for differences in the patient populations across the three studies.
The Kaplan-Meier method was used to estimate the median survival time for each treatment group. A stratified log-rank test with = .05 (two-sided) was used to compare survival between treatment groups. Estimation of hazard ratio employed a stratified (by study) Cox model with an indicator variable for FU/LV/BV treatment.
Progression-free survival (time from randomization to disease progression or death as a result of any cause during first-line therapy) was compared between treatment groups using stratified log-rank tests, with = .05 (two-sided). Median time-to-disease progression during first-line therapy was estimated for each treatment group using Kaplan-Meier methods, and hazard ratio was estimated using a stratified Cox model. The null and alternative hypotheses regarding time-to-disease progression were considered in terms of the adjusted hazard ratio. An adjusted hazard ratio less than 1 (from stratified Cox model) would indicate that the duration of survival is prolonged for patients in the FU/LV/BV group compared with the survival rate in the combined control group.
Objective response during first-line therapy was defined as a complete response or partial response (per the Response Evaluation Criteria in Solid Tumors22) determined by investigators' assessment in Study 3 and by independent review for Studies 1 and 2. Objective response rates were compared between treatment arms using the 2 test. An estimate of objective response rate and its 95% CI was determined; the 95% CI was constructed using the normal approximation to the binomial distribution.
RESULTS
Patient Demographics
Table 1 lists by treatment group the distributions of patients in the efficacy analysis populations, overall and for each of the three trials. Demographics and other selected baseline characteristics of all randomized patients (Table 2) were well balanced between the treatment groups.
Efficacy
Survival duration. There were 165 and 151 deaths in the combined control group and in the FU/LV/BV group, respectively (Table 3). Stratified analysis showed a significant increase in median survival duration in the FU/LV/BV group (17.9 v 14.6 months). The stratified hazard ratio for death for patients treated with FU/LV/BV relative to those treated with FU/LV or IFL was 0.742 (95% CI, 0.59 to 0.93). Kaplan-Meier curves for duration of survival are shown in Figure 2.
Progression-free survival. A significant benefit in progression-free survival was observed in patients who received FU/LV/BV compared with those who received FU/LV or IFL (8.77 v 5.55 months; Table 4). The stratified hazard ratio was 0.63 (95% CI, 0.5 to 0.78). Kaplan-Meier curves for duration of progression-free survival are shown in Figure 3.
Response rate. A significant increase in the objective response rate (complete response + partial response) was noted in patients who received FU/LV/BV compared with those in the combined control group (34.1% v 24.5%; P = .019; see Table 4).
Safety
The safety analyses from the three individual studies have been reported previously.17-19 The safety analysis for the combined raw data is listed in Table 5. Interpreting differences between the two groups is complicated by the inclusion of irinotecan in the combined control group. Overall, no new bevacizumab safety events were noted.
DISCUSSION
This combined analysis of pooled individual patient data from three similarly designed clinical trials demonstrates that the addition of bevacizumab to FU/LV provides an important clinical benefit for the first-line treatment of metastatic CRC. This benefit includes significant improvements in response rate, progression-free survival, and most importantly, overall survival. The addition of bevacizumab to FU/LV improved survival by 3.3 months, from 14.6 to 17.9 months (hazard ratio, 0.74; P = .008), progression-free survival by 3.2 months, from 5.6 months to 8.8 months (hazard ratio, 0.63; P < .001), and response rate by nearly 10%, from 24.5% to 34.1%. One should note that the individual studies were underpowered to demonstrate overall survival benefit on their own, and proof of survival benefit with FU/LV and BV has yet to be shown in a single clinical trial. However, the inclusion of patients receiving IFL in the combined control group, though statistically conservative, may have resulted in an underestimate of the true magnitude of the benefit provided by the addition of BV to FU/LV.
The analyses reported here used the combined data adjusted for population differences across the three studies. Analysis of pooled primary data from similar trials allows a more rigorous assessment of treatment efficacy than can be achieved by the meta-analysis approach, which combines summary statistics from trials that may have markedly different study designs. As with other published meta-analyses,23-25 the intent of this analysis was to better define the efficacy of bevacizumab in combination with FU/LV. The safety profile from each trial is reported separately.17-19 Interpreting safety differences between the two groups in the combined analysis is complicated by the inclusion of irinotecan in the combined control group. While no new bevacizumab safety concerns were identified, the risk of such treatment should not be minimized but, instead, considered in balance with the benefit of increased survival.
Over the past few years, several new chemotherapy agents have demonstrated a survival benefit over the long-standing "standard" therapy for first-line CRC treatment: FU modulated with leucovorin. Irinotecan provided a 2.2-month survival improvement when added to a bolus FU/LV regimen,1 but was associated with a significant increase in diarrhea. Oxaliplatin provided a 1.5-month improvement in survival when added to an infusional FU/LV regimen, but was associated with significant increases in diarrhea, neutropenia, and clinically significant neurosensory toxicity.16 Our combined analysis suggests that bevacizumab provides a 3.3-month improvement in survival, with the most significant toxicity being an increase in clinically significant hypertension (grade 3 per National Cancer Institute toxicity criteria, version 2.0). It is worth noting the impact of the FU/LV-based combinations on the end point of progression-free survival in this analysis: irinotecan, 4.3 to 7.0 months (increase of 2.7 months); oxaliplatin, 6.2 to 9.0 months (increase of 2.8 months); and bevacizumab, 5.6 to 8.8 months (increase of 3.2 months).
As new agents have become available for patients with metastatic CRC, there has been a logical evolution in the exploration of therapeutic combinations. In the pivotal bevacizumab study,7 the addition of bevacizumab to IFL was well tolerated and associated with a substantial (4.7-month) improvement in survival. Ongoing clinical trials are evaluating the addition of bevacizumab to oxaliplatin and infused FU plus LV (the FOLFOX regimen), as well as to irinotecan in combination with infusional FU/LV (the FOLFIRI regimen), and capcitabine-based regimens containing oxaliplatin or irinotecan. Retrospective analyses have suggested that optimal patient outcome in metastatic CRC may be achieved by exposing patients to all active agents.26,27 The apparent superiority of FOLFOX to IFL with respect to prolonging survival may be due, in part, to imbalances in the percentage of patients receiving all active chemotherapy agents, which favored the FOLFOX group.2
Because oxaliplatin and irinotecan have toxicities that may require treatment discontinuation in many patients, even in the setting of ongoing tumor control, regimens with planned sequences of agents are being explored and seem promising.28 The benefit that has been shown with the addition of BV to FU/LV or IFL may enable the evaluation of a variety of sequencing strategies to optimize disease control while preserving quality of life. One such strategy might involve an aggressive induction of limited duration with either irinotecan- or oxaliplatin-based chemotherapy in combination with bevacizumab, followed by a maintenance period with FU/LV/BV.
In conclusion, we have shown that bevacizumab, when added to first-line FU/LV chemotherapy in patients with metastatic colorectal cancer, provides statistically significant and clinically meaningful improvements in response rate, progression-free survival, and overall survival. Although the precise role of this regimen relative to oxaliplatin- and irinotecan-based strategies in the first-line setting remains undefined, FU/LV/BV should be considered an option for patients with previously untreated metastatic colorectal cancer.
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: Julie Hambleton, Genentech; Robert D. Mass, Genentech; Somnath Sarkar, Genentech. Consultant/Advisory Role: Herbert I. Hurwitz, Genentech, GlaxoSmithKline, Pfizer; Emily Bergsland, Genentech. Stock Ownership: Julie Hambleton, Genentech; Robert D. Mass, Genentech; Somnath Sarkar, Genentech. Honoraria: Fairooz F. Kabbinavar, Genentech. Research Funding: Herbert I. Hurwitz, AstraZeneca, Bristol-Myers Squibb, Cephalon, Genentech, GlaxoSmithKline, Pfizer, Sanofi-Synthelabo. 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.
Acknowledgment
We are indebted to Linda Phillips (Genentech Inc) for her editorial assistance.
NOTES
Supported by Genentech Inc.
Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan Study Group. N Engl J Med 343:905-914, 2000
Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004
Algire GH, Chalkley HW, Legallais FY, et al: Vascular reactions of normal and malignant tissue in vivo, I. Vascular reactions of mice to wounds and to normal and neoplastic transplants. J Natl Cancer Inst 6:73-85, 1945
Ferrara N, Davis-Smyth T: The biology of vascular endothelial growth factor. Endocr Rev 18:4-25, 1997
Kim KJ, Li B, Winer J, et al: Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362:841-844, 1993
Presta LG, Chen H, O'Connor SJ, et al: Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57:4593-4599, 1997
Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004
Rougier P, Bugat R, Douillard JY, et al: Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 15:251-260, 1997
Freyer G, Rougier P, Bugat R, et al: Prognostic factors for tumour response, progression-free survival and toxicity in metastatic colorectal cancer patients given irinotecan (CPT-11) as second-line chemotherapy after 5FU failure: CPT-11 F205, F220, F221 and V222 study groups. Br J Cancer 83:431-437, 2000
Knight RD, Miller LL, Pirotta N, et al: First-line irinotecan (C), fluorouracil (F), leucovorin (L) especially improves survival (OS) in metastatic colorectal cancer (MCRC) patients (PT) with favorable prognostic indicators. Proc Am Soc Clin Oncol 19:255a, 2000 (abstr 991)
Food and Drug Administration Center for Drug Evaluation and Research [FDA CDER] Camptosar (irinotecan, CPT-11): First-line therapy of metastatic colorectal cancer. Presented at the 65th Meeting of the Oncologic Drugs Advisory Committee, March 16, 2000. http://www.fda.gov/ohrms/dockets/ac/00/slides/3592sle.ppt
Bleiberg H, Cvitkovic E: Characterisation and clinical management of CPT-11 (irinotecan)-induced adverse events: The European perspective. Eur J Cancer 32A:S18-S23, 1996 (suppl 3)
Food and Drug Administration Center for Drug Evaluation and Research [FDA CDER] CPT-11 for the treatment of patients with metastatic colorectal cancer that has progressed following initial 5-FU based chemotherapy. Presented at the 50th Meeting of the Oncologic Drugs Advisory Committee, June 13, 1996
Rougier P, Bugat R: CPT-11 in the treatment of colorectal cancer: Clinical efficacy and safety profile. Semin Oncol 23:34-41, 1996
Rothenberg ML, Cox JV, DeVore RF, et al: A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer 85:786-795, 1999
de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000
Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60-65, 2003
Kabbinavar FF, Schulz J, McCleod M, et al: Addition of bevacizumab to bolus 5-FU/leucovorin in first-line metastatic colorectal cancer: Results of a randomized phase II trial. J Clin Oncol 23: 10.1200/JCO.2005.05.112
Hurwitz H, Fehrenbacher L, Hainsworth J, et al: Bevacizumab in combination with 5-fluorouracil and leucovorin: A promising regimen for first-line metastatic colorectal cancer. Gastrointestinal Cancers Symposium, San Francisco, CA, 2004, pp 182 (abstr 286)
Petrelli N, Douglass HO Jr, Herrera L, et al: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: A prospective randomized phase III trial: Gastrointestinal Tumor Study Group. J Clin Oncol 7:1419-1426, 1989
Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982
Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000
Thirion P, Michiels S, Pignon JP, et al: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: An updated meta-analysis. J Clin Oncol 22:3766-3775, 2004
Folprecht G, Cunningham D, Ross P, et al: Efficacy of 5-fluorouracil-based chemotherapy in elderly patients with metastatic colorectal cancer: A pooled analysis of clinical trials. Ann Oncol 15:1330-1338, 2004
Langendijk JA, Leemans ChR, Buter J, et al: The additional value of chemotherapy to radiotherapy in locally advanced nasopharyngeal carcinoma: A meta-analysis of the published literature. J Clin Oncol 22:4604-4612, 2004
Grothey A, Sargent D, Goldberg RM, et al: Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 22:1209-1214, 2004
Hedrick EE, Hurwitz H, Sarkar S, et al: Post-progression therapy (PPT) effect on survival in AVF2107, a phase III trial of bevacizumab in first-line treatment of metastatic colorectal cancer (mCRC). Proc Am Soc Clin Oncol 23:249s, 2004 (suppl; abstr 3517)
Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22:229-237, 2004(Fairooz F. Kabbinavar, Ju)
Genentech Inc, South San Francisco
University of California San Francisco, San Francisco, CA
Duke University, Durham, NC
ABSTRACT
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/fluourouracil (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 .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.
INTRODUCTION
Despite recent advances achieved by combining new chemotherapeutic agents with fluorouracil and leucovorin (FU/LV), the overall survival of metastatic colorectal cancer (CRC) remains modest, and treatment-associated toxicity can be significant.1,2 Newer approaches to CRC therapy have focused on targeting cellular signaling, including the epidermal growth factor and vascular endothelial growth factor (VEGF) pathways.
Establishing a blood supply (angiogenesis) is critical to tumor growth and progression, as evidenced by local increases in vascular density that precede the rapid growth of transplanted tumors.3 There are several VEGF family members that have differential effects on angiogenesis.4 The discovery that VEGF, a homodimeric glycoprotein produced by normal and neoplastic cells, is a central mediator of angiogenesis led to exploration of VEGF effects on tumor growth. The potential of VEGF as an anticancer target was supported by the demonstration that a murine anti-VEGF monoclonal antibody was capable of inhibiting subcutaneous tumor growth in murine tumor models.5
Subsequently, a humanized variant of an anti-VEGF monoclonal antibody,6 bevacizumab (rhuMAb VEGF; Avastin; Genentech Inc, South San Francisco, CA), has been evaluated as an antiangiogenic cancer therapy in many tumor types. In patients with metastatic CRC, the addition of bevacizumab (BV) to chemotherapy has been shown to improve survival. In a large, phase III, randomized, double-blind, placebo-controlled clinical trial of patients with previously untreated metastatic CRC,7 the addition of bevacizumab to irinotecan/fluourouracil (FU)/leucovorin (LV; IFL) increased median survival from 15.6 months to 20.3 months, corresponding to a 34% reduction in the hazard of death (P .0001). Similar increases occurred in progression-free survival (6.2 v 10.6 months; hazard ratio, 0.54; P < .0001), response rate (34.8% v 44.8%; P = .0036), and duration of response (7.1 v 10.4 months; hazard ratio, 0.62; P = .0014).
Although irinotecan-based regimens such as IFL offer improved antitumor efficacy and survival relative to FU-based chemotherapy, some patients with metastatic CRC are not appropriate candidates for irinotecan, either because of its toxicity—particularly neutropenia and delayed diarrhea—or because they have characteristics suggesting they are less likely to benefit. Predictors of a poorer response to or increased toxicity with irinotecan include advanced age, low performance status, and low serum albumin level.8-15 Oxaliplatin-based regimens such as FOLFOX (oxaliplatin and infused FU/LV) offer an alternative; however, both acute and chronic neurotoxicity associated with oxaliplatin may be limiting.16 Based on these observations, various regimens have emerged as standard options in first-line therapy, including the use of FU/LV for selected patients who are not considered optimal candidates for irinotecan- or oxaliplatin-based therapies. The addition of BV to FU/LV may be an attractive alternative first-line regimen in these selected patients with metastatic CRC, despite the uncommon but serious BV-associated adverse events of GI perforation, arterial thromboembolic events, and potential wound healing issues.
Three clinical trials have evaluated the addition of BV to FU/LV chemotherapy. The first (Study 1) was a phase II study in which 104 patients were randomized to either FU/LV combined with one of two doses of BV or to FU/LV alone.17 A second, larger phase II trial (Study 2) randomized 209 patients to FU/LV/BV or to FU/LV alone.18 The third trial (Study 3) was the above-mentioned phase III, randomized, controlled study,7 which in addition to the two main treatment groups included 110 patients who received BV in combination with FU/LV. This third treatment group was enrolled only until a planned interim safety analysis established an acceptable safety profile for the IFL/BV treatment group.
Because the clinical trial experience with FU/LV/BV derives from groups of treated patients in similarly designed studies, none of which was large enough to show a statistically significant effect on overall survival, we performed a combined analysis of these three clinical trials, utilizing raw data from each, to enable evaluation of the regimen efficacy in a larger patient population. A combined analysis, based on pooled raw data from essentially similar trials, is considered more rigorous than a meta-analysis of summary statistics, which is typically performed when individual patient data from each study are not accessible or if the study designs are too different to justify pooling the raw data. Separate analyses of efficacy data from each of the three studies,17-19 utilizing the same patients included in the combined analyses reported in this article, indicated that in Studies 1 and 2, the duration of progression-free survival (PFS) with FU/LV/BV treatment was statistically significantly improved relative to the rate in the control comparator group. In Study 3, PFS was increased with the addition of BV to FU/LV, but the difference was not statistically significant. In all three studies, response rate with FU/LV/BV was increased (significantly increased in Study 1). Overall survival was longer with FU/LV/BV treatment in all three studies, but the increases were not statistically significant. Pooling of the data from the three studies allows evaluation of these three efficacy end points with greater statistical power to detect real differences between the groups of patients who were and were not treated with bevacizumab.
PATIENTS AND METHODS
End Points and Analysis Population
The primary objective of the analysis was to compare duration of survival in patients who received BV (5 mg/kg once every 2 weeks) plus FU/LV with the survival rates in a combined control group of patients who received either FU/LV or IFL alone for treatment of metastatic CRC. Secondary objectives included evaluation of progression-free survival and response rate.
The three studies contributing data to the combined analysis are schematically summarized in Figure 1. The investigative group comprised all patients randomized to FU/LV in combination with bevacizumab in the two phase II trials (Study 1 and Study 2) and in the phase III trial (Study 3). The combined control group comprised patients who were randomized to FU/LV treatment in the two phase II trials, or who were randomized to IFL/placebo treatment concurrently with those randomized to FU/LV/BV in the phase III trial.
Study Design of Three Trials
The three studies were multicenter, randomized trials conducted in patients with histologically confirmed, bidimensionally measurable, previously untreated metastatic CRC. The protocols were approved by the Institutional Review Boards of the participating centers, and the studies were conducted in accordance with the US Food and Drug Administration principles of Good Clinical Practice, as well as local ethical and legal requirements. Patients provided written informed consent for their study participation.
In all three studies, FU/LV chemotherapy (with or without the addition of bevacizumab) was administered in the weekly bolus schedule described by Petrelli et al.20 IFL was administered using the bolus schedule described by Saltz et al.1 Patients assigned to BV-containing regimens received bevacizumab by intravenous infusion once every 2 weeks.
Study 1. In the first phase II trial,17 104 patients were randomized to one of three treatment groups: a control group (FU/LV chemotherapy alone; n = 36) and two bevacizumab (5 or 10 mg/kg) plus FU/LV groups (n = 35 and n = 33, respectively). This was an open-label trial, and at the time of disease progression patients in the control group became eligible to receive bevacizumab.
Study 2. This second phase II trial18 was conducted in 209 patients who were not considered by their treating physician to be optimal candidates for first-line irinotecan-based therapy, and who were required to have at least one of the following features: advanced age ( 65 years), low serum albumin level ( 3.5 g/dL), poor Eastern Cooperative Oncology Group (ECOG) performance status21 (1 or 2), or a history of abdominal/pelvic radiotherapy. The patients were randomly assigned to receive BV plus FU/LV chemotherapy (n = 100) or FU/LV plus placebo (n = 104). Patients in the control group were not permitted to receive bevacizumab at the time of disease progression.
Study 3. In this phase III study,7 a total of 923 patients were randomized to one of three treatment groups: IFL + placebo (group 1, n = 411), IFL + BV (group 2, n = 402), or FU/LV + BV (group 3, n = 110). After 300 patients had been randomly assigned (approximately 100 patients per treatment group), enrollment to group 3 (FU/LV/BV) was suspended. For the combined analysis, only the 100 patients in the IFL/placebo group (group 1) who were enrolled concurrently with the 110 patients in the FU/LV/BV group (group 3) were included. Patients in the control group were not permitted to receive bevacizumab at the time of disease progression.
Statistical Considerations
The statistical rationale for a pooled analysis of raw data from three related trials is based on the fact that the trials used the same definitions and procedures for collecting data on baseline characteristics, primary and secondary efficacy end points, and safety assessments. The three trials used identical regimens of FU/LV, and we took the most conservative approach in assessing efficacy by including the IFL control group from Study 3.
For this combined analysis, demographic data (age, sex, and race/ethnicity) and baseline disease characteristics (site of primary disease, histologic cell type, years since diagnosis, number and location of metastatic sites, prior adjuvant therapy, and baseline ECOG performance status) for all randomized patients treated with FU/LV/BV were compared with those characteristics for the combined control group.
Efficacy analyses were based on the intent-to-treat population. The primary efficacy end point, duration of survival, was defined as the time from randomization to death from any cause. Formal hypothesis testing using the stratified log-rank test was performed to determine whether survival was prolonged in the FU/LV/BV group compared with the combined control. The only stratification variable employed was the categoric variable "study." The purpose of the stratification was to adjust for differences in the patient populations across the three studies.
The Kaplan-Meier method was used to estimate the median survival time for each treatment group. A stratified log-rank test with = .05 (two-sided) was used to compare survival between treatment groups. Estimation of hazard ratio employed a stratified (by study) Cox model with an indicator variable for FU/LV/BV treatment.
Progression-free survival (time from randomization to disease progression or death as a result of any cause during first-line therapy) was compared between treatment groups using stratified log-rank tests, with = .05 (two-sided). Median time-to-disease progression during first-line therapy was estimated for each treatment group using Kaplan-Meier methods, and hazard ratio was estimated using a stratified Cox model. The null and alternative hypotheses regarding time-to-disease progression were considered in terms of the adjusted hazard ratio. An adjusted hazard ratio less than 1 (from stratified Cox model) would indicate that the duration of survival is prolonged for patients in the FU/LV/BV group compared with the survival rate in the combined control group.
Objective response during first-line therapy was defined as a complete response or partial response (per the Response Evaluation Criteria in Solid Tumors22) determined by investigators' assessment in Study 3 and by independent review for Studies 1 and 2. Objective response rates were compared between treatment arms using the 2 test. An estimate of objective response rate and its 95% CI was determined; the 95% CI was constructed using the normal approximation to the binomial distribution.
RESULTS
Patient Demographics
Table 1 lists by treatment group the distributions of patients in the efficacy analysis populations, overall and for each of the three trials. Demographics and other selected baseline characteristics of all randomized patients (Table 2) were well balanced between the treatment groups.
Efficacy
Survival duration. There were 165 and 151 deaths in the combined control group and in the FU/LV/BV group, respectively (Table 3). Stratified analysis showed a significant increase in median survival duration in the FU/LV/BV group (17.9 v 14.6 months). The stratified hazard ratio for death for patients treated with FU/LV/BV relative to those treated with FU/LV or IFL was 0.742 (95% CI, 0.59 to 0.93). Kaplan-Meier curves for duration of survival are shown in Figure 2.
Progression-free survival. A significant benefit in progression-free survival was observed in patients who received FU/LV/BV compared with those who received FU/LV or IFL (8.77 v 5.55 months; Table 4). The stratified hazard ratio was 0.63 (95% CI, 0.5 to 0.78). Kaplan-Meier curves for duration of progression-free survival are shown in Figure 3.
Response rate. A significant increase in the objective response rate (complete response + partial response) was noted in patients who received FU/LV/BV compared with those in the combined control group (34.1% v 24.5%; P = .019; see Table 4).
Safety
The safety analyses from the three individual studies have been reported previously.17-19 The safety analysis for the combined raw data is listed in Table 5. Interpreting differences between the two groups is complicated by the inclusion of irinotecan in the combined control group. Overall, no new bevacizumab safety events were noted.
DISCUSSION
This combined analysis of pooled individual patient data from three similarly designed clinical trials demonstrates that the addition of bevacizumab to FU/LV provides an important clinical benefit for the first-line treatment of metastatic CRC. This benefit includes significant improvements in response rate, progression-free survival, and most importantly, overall survival. The addition of bevacizumab to FU/LV improved survival by 3.3 months, from 14.6 to 17.9 months (hazard ratio, 0.74; P = .008), progression-free survival by 3.2 months, from 5.6 months to 8.8 months (hazard ratio, 0.63; P < .001), and response rate by nearly 10%, from 24.5% to 34.1%. One should note that the individual studies were underpowered to demonstrate overall survival benefit on their own, and proof of survival benefit with FU/LV and BV has yet to be shown in a single clinical trial. However, the inclusion of patients receiving IFL in the combined control group, though statistically conservative, may have resulted in an underestimate of the true magnitude of the benefit provided by the addition of BV to FU/LV.
The analyses reported here used the combined data adjusted for population differences across the three studies. Analysis of pooled primary data from similar trials allows a more rigorous assessment of treatment efficacy than can be achieved by the meta-analysis approach, which combines summary statistics from trials that may have markedly different study designs. As with other published meta-analyses,23-25 the intent of this analysis was to better define the efficacy of bevacizumab in combination with FU/LV. The safety profile from each trial is reported separately.17-19 Interpreting safety differences between the two groups in the combined analysis is complicated by the inclusion of irinotecan in the combined control group. While no new bevacizumab safety concerns were identified, the risk of such treatment should not be minimized but, instead, considered in balance with the benefit of increased survival.
Over the past few years, several new chemotherapy agents have demonstrated a survival benefit over the long-standing "standard" therapy for first-line CRC treatment: FU modulated with leucovorin. Irinotecan provided a 2.2-month survival improvement when added to a bolus FU/LV regimen,1 but was associated with a significant increase in diarrhea. Oxaliplatin provided a 1.5-month improvement in survival when added to an infusional FU/LV regimen, but was associated with significant increases in diarrhea, neutropenia, and clinically significant neurosensory toxicity.16 Our combined analysis suggests that bevacizumab provides a 3.3-month improvement in survival, with the most significant toxicity being an increase in clinically significant hypertension (grade 3 per National Cancer Institute toxicity criteria, version 2.0). It is worth noting the impact of the FU/LV-based combinations on the end point of progression-free survival in this analysis: irinotecan, 4.3 to 7.0 months (increase of 2.7 months); oxaliplatin, 6.2 to 9.0 months (increase of 2.8 months); and bevacizumab, 5.6 to 8.8 months (increase of 3.2 months).
As new agents have become available for patients with metastatic CRC, there has been a logical evolution in the exploration of therapeutic combinations. In the pivotal bevacizumab study,7 the addition of bevacizumab to IFL was well tolerated and associated with a substantial (4.7-month) improvement in survival. Ongoing clinical trials are evaluating the addition of bevacizumab to oxaliplatin and infused FU plus LV (the FOLFOX regimen), as well as to irinotecan in combination with infusional FU/LV (the FOLFIRI regimen), and capcitabine-based regimens containing oxaliplatin or irinotecan. Retrospective analyses have suggested that optimal patient outcome in metastatic CRC may be achieved by exposing patients to all active agents.26,27 The apparent superiority of FOLFOX to IFL with respect to prolonging survival may be due, in part, to imbalances in the percentage of patients receiving all active chemotherapy agents, which favored the FOLFOX group.2
Because oxaliplatin and irinotecan have toxicities that may require treatment discontinuation in many patients, even in the setting of ongoing tumor control, regimens with planned sequences of agents are being explored and seem promising.28 The benefit that has been shown with the addition of BV to FU/LV or IFL may enable the evaluation of a variety of sequencing strategies to optimize disease control while preserving quality of life. One such strategy might involve an aggressive induction of limited duration with either irinotecan- or oxaliplatin-based chemotherapy in combination with bevacizumab, followed by a maintenance period with FU/LV/BV.
In conclusion, we have shown that bevacizumab, when added to first-line FU/LV chemotherapy in patients with metastatic colorectal cancer, provides statistically significant and clinically meaningful improvements in response rate, progression-free survival, and overall survival. Although the precise role of this regimen relative to oxaliplatin- and irinotecan-based strategies in the first-line setting remains undefined, FU/LV/BV should be considered an option for patients with previously untreated metastatic colorectal cancer.
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: Julie Hambleton, Genentech; Robert D. Mass, Genentech; Somnath Sarkar, Genentech. Consultant/Advisory Role: Herbert I. Hurwitz, Genentech, GlaxoSmithKline, Pfizer; Emily Bergsland, Genentech. Stock Ownership: Julie Hambleton, Genentech; Robert D. Mass, Genentech; Somnath Sarkar, Genentech. Honoraria: Fairooz F. Kabbinavar, Genentech. Research Funding: Herbert I. Hurwitz, AstraZeneca, Bristol-Myers Squibb, Cephalon, Genentech, GlaxoSmithKline, Pfizer, Sanofi-Synthelabo. 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.
Acknowledgment
We are indebted to Linda Phillips (Genentech Inc) for her editorial assistance.
NOTES
Supported by Genentech Inc.
Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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