FDA Approval for Bevacizumab
- Persistent, Recurrent, or Metastatic Cervical Cancer in Combination with Chemotherapy
- Metastatic Colorectal Cancer in Combination with Fluoropyrimidine-based Chemotherapy
- Metastatic HER2 Negative Breast Cancer
- Metastatic Renal Cell Carcinoma
- Second-Line Treatment of Glioblastoma
- First-Line Treatment of Non-Small Cell Lung Cancer (NSCLC)
- Second-Line Treatment of Metastatic Colorectal Cancer
- First-Line Treatment of Metastatic Colorectal Cancer
- Drug Warnings Issued
Full prescribing information is available, including clinical trial information, safety, dosing, drug–drug interactions, and contraindications.
Persistent, Recurrent, or Metastatic Cervical Cancer in Combination with Chemotherapy
On August 14, 2014, the U. S. Food and Drug Administration approved bevacizumab solution for intravenous infusion (Avastin®, Genentech, Inc.) in combination with paclitaxel and either cisplatin or topotecan for the treatment of persistent, recurrent, or metastatic cervical cancer.
The approval is based on the results of an international randomized trial (four-arm 2x2 factorial design) with two primary comparisons of overall survival. The first comparison was between bevacizumab and chemotherapy versus chemotherapy (paclitaxel and cisplatin or paclitaxel and topotecan) alone. The second comparison was between the platinum doublet (paclitaxel and cisplatin) versus non-platinum doublet chemotherapy (i.e., paclitaxel and topotecan), irrespective of the addition of bevacizumab.
The trial enrolled 452 patients: 227 patients were assigned to receive chemotherapy and bevacizumab, and 225 patients were assigned to receive chemotherapy alone. The chemotherapy could be either paclitaxel in combination with cisplatin or paclitaxel in combination with topotecan.
Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal. All enrolled patients had high performance status (GOG status of 0 or 1); 80 percent had received prior radiation, and 74 percent had received prior chemotherapy concurrent with radiation.
The key efficacy assessment in the first primary comparison demonstrated a statistically significant improvement in overall survival in patients who received bevacizumab and chemotherapy compared with those who received chemotherapy alone (HR=0.74; 95 percent CI: 0.58, 0.94; p= 0.013, log-rank test). The median survival of patients who received bevacizumab and chemotherapy was 16.8 months (95 percent CI: 14.1, 19), compared with 12.9 months (95 percent CI: 10.9, 15) for those who received chemotherapy alone.
In the second primary comparison, patients who received paclitaxel plus topotecan (with or without bevacizumab) arms did not demonstrate an improvement in overall survival compared with patients who received paclitaxel plus cisplatin (with or without bevacizumab) [HR 1.15 (95 percent CI: 0.91, 1.46)]. However, the hazard ratios for addition of bevacizumab to either chemotherapy regimen were similar (HR 0.72 for paclitaxel/cisplatin and HR 0.76 for paclitaxel/topotecan). The results suggest that the regimen of paclitaxel with topotecan plus bevacizumab is an acceptable alternative for women with advanced cervical cancer who are not candidates for platinum treatment.
The most common adverse reactions (seen in at least 20 percent of patients) in patients treated with bevacizumab and chemotherapy were fatigue, decreased appetite, high blood pressure, high blood sugar, hypomagnesemia, urinary tract infection, headache, and decreased weight. Gastrointestinal perforations were reported in 3.2 percent of bevacizumab-treated patients, all of whom had had prior pelvic radiation. Gastrointestinal–vaginal fistulae occurred in 8.2 percent of bevacizumab‑treated patients and 0.9 percent of patients who did not receive bevacizumab, all of whom also had had prior pelvic radiation. Several other grade 3 or greater adverse reactions were also more common in patients receiving chemotherapy plus bevacizumab than in patients who received chemotherapy, including venous thromboembolic events, hemorrhage, high blood pressure, proteinuria, and wound healing complications.
The recommended dose of bevacizumab is 15 mg/kg every 3 weeks as an intravenous infusion (IV) administered in combination with paclitaxel and cisplatin or paclitaxel and topotecan. The dosing regimens used in the clinical trial were as follows and repeated every 21 days:
- Day 1: paclitaxel 135 mg/m2 IV over 24 hours, Day 2: cisplatin 50 mg/m2 IV plus bevacizumab;
or Day 1: paclitaxel 175 mg/m2 IV over 3 hours, Day 2: cisplatin 50 mg/m2 IV plus bevacizumab;
or Day 1: paclitaxel 175 mg/m2 IV over 3 hours plus cisplatin 50 mg/m2 IV plus bevacizumab
- Day 1: paclitaxel 175 mg/m2 over 3 hours plus bevacizumab, Days 1-3: topotecan 0.75 mg/m2 over 30 minutes.
Metastatic Colorectal Cancer in Combination with Fluoropyrimidine-based Chemotherapy
On January 23, 2013, the Food and Drug Administration (FDA) approved bevacizumab (Avastin®, made by Genentech U.S., Inc.) for use in combination with fluoropyrimidine–irinotecan- or fluoropyrimidine–oxaliplatin-based chemotherapy for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed (i.e., the cancer continues to grow or spread) while on first-line treatment with a bevacizumab-containing regimen. Bevacizumab is a recombinant humanized monoclonal antibody that binds to human vascular endothelial growth factor (VEGF), thereby preventing the interaction of VEGF with its receptors on the surface of endothelial cells.
This approval is based on the results of a randomized, open-label, multinational clinical trial conducted in patients with mCRC that had progressed during, or within 3 months of, discontinuation of first-line bevacizumab-based combination chemotherapy with fluoropyrimidine–oxaliplatin or fluoropyrimidine–irinotecan.
In the clinical trial, 820 patients were randomly assigned to receive chemotherapy alone (N=411) or chemotherapy in combination with bevacizumab (N=409). Patients received chemotherapy with either fluoropyrimidine–irinotecan-based therapy or fluoropyrimidine–oxaliplatin-based therapy, depending on their prior treatment (i.e., patients who received prior treatment with oxaliplatin received irinotecan-based therapy and patients who received prior treatment with irinotecan received oxaliplatin-based therapy). The treatment cycles for both groups were repeated every 2 or 3 weeks, depending on the chemotherapy regimen used, and bevacizumab was administered at a dose of 5 mg/kg by intravenous infusion every two weeks or 7.5 mg/kg by intravenous infusion every three weeks. Bevacizumab was continued until disease progression or unacceptable toxicity.
The primary efficacy endpoint was overall survival (OS). Treatment assignment was stratified by first-line treatment (irinotecan-based vs. oxaliplatin-based), time to progression on first-line treatment (more than 9 months vs. 9 months or less), time since last dose of bevacizumab (more than 42 days vs. 42 days or less), and Eastern Cooperative Oncology Group (ECOG) performance status (0–1 vs. 2).
The median age of the study population was 63 years, 64 percent were men, and 96 percent had an ECOG performance status of 0 or 1. Chemotherapy plus bevacizumab was associated with a statistically significant improvement in OS compared with chemotherapy alone (hazard ratio 0.81 [95% CI 0.69, 0.94], p=0.0062). Median OS was 11.2 months for patients receiving chemotherapy plus bevacizumab and 9.8 months for patients receiving chemotherapy alone. Progression-free survival (PFS) was also statistically significantly improved in patients who received chemotherapy plus bevacizumab compared with those who received chemotherapy alone (hazard ratio 0.68 [95% CI 0.59, 0.78], p<0.0001). Median PFS was 5.7 months for patients receiving chemotherapy plus bevacizumab and 4.0 months for patients receiving chemotherapy alone.
No new safety concerns were observed in this trial. The safety data were consistent with the known safety profile established in previously approved indications.
The recommended bevacizumab dose and schedule in patients receiving bevacizumab in combination with fluoropyrimidine–irinotecan- or fluoropyrimidine–oxaliplatin-based chemotherapy after progression on a first-line bevacizumab-containing regimen is 5 mg/kg administered every 2 weeks or 7.5 mg/kg administered every 3 weeks as an intravenous infusion.
Metastatic HER2-Negative Breast Cancer
On November 18, 2011, Food and Drug Administration Commissioner Margaret Hamburg revoked the agency’s accelerated approval of the breast cancer indication for bevacizumab (Avastin®, made by Genentech). Bevacizumab used for metastatic breast cancer has not been shown to provide a benefit, in terms of delay in the growth of tumors, that would justify its serious and potentially life-threatening risks. Nor is there evidence that use of bevacizumab will either help women with breast cancer live longer or improve their quality of life.
This decision involves bevacizumab used in combination with the cancer drug paclitaxel for those patients who have not been treated with chemotherapy for their form of metastatic breast cancer known as HER2 negative. This indication must now be removed from bevacizumab's product labeling.
Bevacizumab will still remain on the market as an approved treatment for certain types of colon, lung, kidney and brain cancer (glioblastoma multiforme).
Bevacizumab was approved for metastatic breast cancer in February 2008 under the FDA’s accelerated approval program, which allows a drug to be approved based on data that are not sufficiently complete to permit full approval. The accelerated approval program provides earlier patient access to promising new drugs to treat serious or life-threatening conditions while confirmatory clinical trials are conducted. If the clinical trials do not justify the continued approval of the drug or a specific drug indication, the agency may revoke its approval. In this case, the accelerated approval was based on promising results from one study that suggested that the drug could provide a meaningful increase in the amount of time from when treatment is started until the tumor grows or the death of the patient.
After the accelerated approval of bevacizumab for breast cancer, the drug’s sponsor, Genentech, completed two additional clinical trials and submitted the data from those studies to the FDA. These data showed only a small effect on tumor growth without evidence that patients lived any longer or had a better quality of life compared to taking standard chemotherapy alone – not enough to outweigh the risk of taking the drug.
FDA's Center for Drug Evaluation and Research, which is responsible for the approval of this drug, ultimately concluded that the results of these additional studies did not justify continued approval and notified Genentech it was proposing to withdraw approval of the indication. Genentech did not agree with the Center’s evaluation of the data and, following the procedures set out in FDA regulations, requested a hearing on the Center’s withdrawal proposal, with a decision to be made by the Commissioner. That hearing took place June 28-29, 2011.
Dr. Hamburg has now made her decision based on a review of the arguments and evidence presented at the hearing, briefs filed by both CDER and Genentech before and after the hearing, public comments and data from multiple clinical trials.
On June 29, 2011, the FDA’s Oncologic Drugs Advisory Committee recommended withdrawing approval of bevacizumab (Avastin®, made by Genentech) for breast cancer. The FDA Center for Drug Evaluation and Research and Genentech are scheduled to provide additional written submissions by July 28, 2011, and the docket will remain open for public comment until that date.
The Center for Drug Evaluation and Research will await the FDA Commissioner's final decision on Avastin’s use for breast cancer. The Commissioner’s decision related to breast cancer will not affect Avastin’s approved indications for use in colon, lung, kidney, and brain cancers. Regardless of the final decision on breast cancer approval, Avastin will remain on the market.
On December 16, 2010, the FDA announced that the agency is recommending removing the breast cancer indication from the label for bevacizumab (Avastin) because the drug has not been shown to be safe and effective for that use.
The drug itself is not being removed from the market and today’s action will not have any immediate impact on its use in treating breast cancer. Today’s action will not affect the approvals for colon, kidney, brain, and lung cancers.
Oncologists currently treating patients with Avastin for metastatic breast cancer should use their medical judgment when deciding whether a patient should continue treatment with the drug or consider other therapeutic options.
On February 22, 2008, the FDA granted accelerated approval for bevacizumab (Avastin®, made by Genentech) to be used in combination with paclitaxel (Taxol®) for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer.
The approval was based on the demonstration of an improvement in progression-free survival (PFS) in patients receiving bevacizumab with paclitaxel compared to those receiving paclitaxel alone as a first-line treatment for metastatic breast cancer. No data are currently available that demonstrate an improvement in disease-related symptoms or increased overall survival with bevacizumab in breast cancer.
The efficacy and safety of bevacizumab as first-line treatment of patients with metastatic breast cancer was studied in a single, open-label, randomized, multicenter study (Study 7 or E2100). Patients who had not received chemotherapy for locally recurrent or metastatic breast cancer were randomized to receive either paclitaxel (N=354 patients) alone at 90 mg/m2 weekly for three doses with one week rest (28-day cycle) or in combination with bevacizumab 10 mg/kg every 14 days (N=368 patients). Patients with HER2-overexpressing breast cancer were not eligible unless they had received prior therapy with trastuzumab (Herceptin®).
The addition of bevacizumab to paclitaxel resulted in an improvement in PFS with no significant improvement in overall survival. The median PFS was 11.3 months (95 percent CI 10.5,13.3) and 5.8 months (95 percent CI 5.4, 8.2) months for the bevacizumab plus paclitaxel arms versus the paclitaxel alone, respectively (p<0.0001, HR 0.48, 95 percent CI 0.39, 0.61) Partial response rates in patients with measurable disease were higher with bevacizumab plus paclitaxel: 48.9 percent versus 22.2 percent (p<0.001). No complete responses were observed.
The efficacy and safety of bevacizumab as a second and third line treatment of patients with metastatic breast cancer were studied in a single open-label randomized study (Study 8 or AVF2119). Patients who had received prior anthracycline and taxane therapy in the adjuvant setting or for their metastatic breast cancer were randomized to receive either capecitabine alone or in combination with bevacizumab. The study enrolled 462 patients. The study failed to demonstrate a statistically significant effect on PFS or overall survival. The product labeling specifies that bevacizumab is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.
Data collection in Trial 7 was limited to NCI-CTC grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events. A 20 percent increase in grade 3-5 adverse events was observed in the bevacizumab plus paclitaxel arm compared to paclitaxel alone. Severe and life-threatening adverse events occurring more frequently on the bevacizumab-containing arm included sensory neuropathy, hypertension, fatigue, infection without neutropenia, neutropenia, vomiting, diarrhea, bone pain, headache, proteinuria, and cerebrovascular ischemia. Fatal adverse reactions occurred in 6 of 363 (1.7 percent) of patients who received paclitaxel plus bevacizumab. Causes of death were gastrointestinal perforation (two patients), myocardial infarction (two patients), diarrhea/abdominal pain/weakness/hypotension (two patients).
The most serious, and sometimes fatal, bevacizumab adverse events have been previously described in product labeling and include gastrointestinal perforation, wound healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome, congestive heart failure, and neutropenic sepsis. The most common bevacizumab adverse events previously described in product labeling include asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis, and proteinuria.
Metastatic Renal Cell Carcinoma
On July 31, 2009, the FDA granted approval for the use of Bevacizumab (Avastin®, made by Genentech, Inc.) in combination with interferon alfa for the treatment of patients with metastatic renal cell carcinoma. The approval was based on results from the BO17705 trial, which demonstrated a 5-month improvement in median progression-free survival (PFS) in patients treated with bevacizumab.
The BO17705 trial was a randomized, double-blind, placebo-controlled, multinational clinical trial conducted in patients with metastatic renal cell carcinoma who had undergone nephrectomy. The study compared the combination of bevacizumab plus interferon alfa-2a to interferon alfa-2a plus placebo. This trial was conducted by Hoffmann-La-Roche in Europe, Asia, and Australia. The primary outcome measure of the trial, assessed by study investigators, was PFS. The determination of PFS by an independent review committee, blinded to treatment assignment, supported the investigators' PFS assessment.
A total of 649 patients (327 treated with bevacizumab plus interferon, 322 treated with interferon plus placebo) were enrolled. The median PFS was 10.2 months for the bevacizumab plus interferon arm compared to 5.4 months for the interferon and placebo arm [hazard ratio (HR), 0.60 (95 percent CI: 0.49, 0.72), p < 0.0001]. The independent review committee's analysis of 569 patients with radiographs available for review yielded similar results [median PFS, 10.4 versus 5.5 months; HR, 0.57 (95 percent CI: 0.45, 0.72)].
The BO17705 trial did not demonstrate a statistically significant advantage in overall survival for patients treated with bevacizumab plus interferon compared with patients who received interferon plus placebo treatment [HR, 0.86 (95 percent CI: 0.72, 1.04), p= 0.13].
Additional support for the results of the BO17705 trial was provided by the published results of the 90206 trial, a randomized, open-label study of bevacizumab plus interferon alfa-2b compared with interferon alfa-2b alone in patients with metastatic renal cell carcinoma. The Cancer and Leukemia Group B conducted this trial in North America. A similar prolongation in PFS was reported in the 90206 trial with a median PFS of 8.4 months for patients treated with the bevacizumab combination versus 4.9 months for patients who received single-agent interferon alfa-2b. An improvement in overall survival was not observed.
In the BO17705 trial, the combination of bevacizumab plus interferon alfa-2a resulted in a higher overall incidence of toxicities, and more severe toxicities, than observed with interferon alfa-2a alone.
Serious adverse events were reported in 31 percent of patients treated with bevacizumab plus interferon and in 19 percent of patients treated with interferon plus placebo. NCI CTCAE grade 3 and greater adverse events were reported in 63 percent of patients treated with bevacizumab plus interferon versus 47 percent of patients who received interferon plus placebo. Grade 3 and greater adverse events attributable to bevacizumab (≥ 2 percent greater incidence in the bevacizumab plus interferon arm compared with the interferon plus placebo arm) included bleeding, hypertension, proteinuria, and venous or arterial thrombosis. Two patients with grade 5 bleeding events (ruptured aneurysm and hemoptysis), two patients with hypertensive encephalopathy, and four patients with grade 4 pulmonary embolism were reported among those who were treated with bevacizumab plus interferon.
The most common bevacizumab-related toxicities were bleeding/hemorrhage, hypertension, proteinuria and venous or arterial thromboembolic events. Among the 20 percent of patients with reports of proteinuria, the median onset of proteinuria was 5.6 months (range, 15 days to 37 months) after initiation of bevacizumab. The median time-to-resolution was 6.1 months. Proteinuria did not resolve in 40 percent of patients after a median follow-up of 11.2 months. Bevacizumab was permanently discontinued in 30 percent of the patients who developed proteinuria.
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Second-Line Treatment of Glioblastoma
On May 5, 2009, the FDA granted accelerated approval to bevacizumab injection (Avastin®, made by Genentech, Inc.) as a single agent for patients with glioblastoma, with progressive disease following prior therapy. The approval was based on demonstration of durable objective response rates observed in two single-arm trials, AVF3708g and NCI 06-C-0064E.
AVF3708g was an open-label, multi-center trial of randomly assigned patients with previously treated glioblastoma. Patients received bevacizumab (10 mg/kg IV) alone or bevacizumab plus irinotecan every 2 weeks until disease progression or unacceptable toxicity was noted. All patients received prior radiotherapy and temozolomide. Patients completed radiotherapy at least 8 weeks prior to receiving bevacizumab. Patients with active brain hemorrhage were excluded. Only efficacy data from the bevacizumab monotherapy arm (N=85) was used to support drug approval.
The efficacy of bevacizumab was demonstrated using response assessment based on WHO radiographic criteria. In addition, all responding patients must have had stable or decreasing corticosteroid use. Responses were observed in 25.9 percent (95 percent CI: 17.0 percent, 36.1 percent) of the patients. Median response duration was 4.2 months (95 percent CI: 3.0, 5.7 months). Radiologic assessment was performed using MR imaging (T1 and T2/FLAIR). MRI does not necessarily distinguish between tumor, edema and radiation necrosis.
NCI 06-C-0064E was a single-arm, single-site study of bevacizumab for the treatment of patients with previously treated gliomas. The study enrolled 56 patients with glioblastoma. All patients had documented disease progression after receiving temozolomide and radiation therapy. Patients received bevacizumab (10 mg/kg IV) every 2 weeks until disease progression or unacceptable toxicity was noted.
The objective response rate from the NCI 06-C-0064E study was 19.6 percent (95 percent CI: 10.9 percent, 31.3 percent), using the same response criteria as in AVF3708g. Median response duration was 3.9 months (95 percent CI: 2.4, 17.4).
Safety data was provided for study AVF3708g. In patients receiving bevacizumab monotherapy, the most frequently reported adverse events of any grade were infection, fatigue, headache, hypertension, epistaxis, and diarrhea. Bevacizumab was discontinued due to adverse events in 4.8 percent of patients. Two deaths (one retroperitoneal hemorrhage and one neutropenic infection) were possibly related to bevacizumab.
Grade 3-5 bevacizumab-related adverse events included bleeding/hemorrhage, CNS hemorrhage, hypertension, venous and arterial thromboembolic events, wound-healing complications, proteinuria, gastrointestinal perforation and reversible posterior leukoencephalopathy (RPLS). The attribution of certain adverse events (e.g., CNS hemorrhage, wound healing complications, and thromboembolic events) to either bevacizumab, underlying disease status, or both cannot be determined due to the single-arm, non-comparative study design.
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First-Line Treatment of Non-Small Cell Lung Cancer (NSCLC)
On October 11, 2006, the FDA granted approval for a labeling extension for bevacizumab (Avastin®, Genentech, Inc.), administered in combination with carboplatin and paclitaxel, for the initial systemic treatment of patients with unresectable, locally advanced, recurrent, or metastatic, non-squamous, non-small cell lung cancer. This recommendation is based on the demonstration of a statistically significant improvement in overall survival (OS) in patients receiving bevacizumab with carboplatin and paclitaxel compared to those receiving carboplatin and paclitaxel alone.
The primary trial (E4599) supporting this approval was a randomized, active controlled, open label, multi-center clinical trial evaluating bevacizumab plus carboplatin and paclitaxel (n=434) versus carboplatin and paclitaxel alone (n=444). (See the protocol summary.)
Patients with squamous histology, mixed cell tumors with predominant squamous cell histology, central nervous system metastases, gross hemoptysis (>1/2 tsp red blood), or unstable angina and those receiving therapeutic anticoagulation were excluded from the trial. Patients with squamous cell histology were excluded based on four patients with life-threatening or fatal hemoptysis among 13 patients with squamous cell histology enrolled in a randomized, active-control, phase II study (AVF0757g) who received chemotherapy with bevacizumab.
Among the 878 randomized patients, the median age was 63, 46 percent were female, no patients had received prior chemotherapy, 76 percent had stage IV disease, 12 percent had stage IIIB disease with malignant pleural effusion, 11 percent had recurrent disease, and 40 percent had an ECOG performance status of 0.
OS, the primary endpoint, was significantly longer in patients receiving bevacizumab in combination with paclitaxel and carboplatin as compared to those receiving paclitaxel and carboplatin alone (median OS 12.3 vs 10.3 mos; hazard ratio 0.80, p=0.013 stratified log rank test). Although a consistent effect was observed across most subgroups, in an exploratory analysis, evidence of a survival benefit was not observed in women (HR 0.99; 95 percent CI 0.79, 1.25).
In E4599, data collection was limited to NCI-CTC grade 3-5 adverse events. Severe and life-threatening adverse events occurring more frequently in patients receiving bevacizumab and chemotherapy were
- neutropenia (27 percent vs. 17 percent)
- fatigue (16 percent vs. 13 percent)
- hypertension (8 percent vs. 0.7 percent)
- infection without neutropenia (7 percent vs. 3 percent)
- thrombosis/embolism (5 percent vs. 3 percent)
- pneumonitis or pulmonary infiltrate (5 percent vs. 3 percent)
- infection with grade 3 or 4 neutropenia (5 percent vs. 2 percent)
- febrile neutropenia (5 percent vs. 2 percent)
- hyponatremia (4 percent vs. 1 percent)
- proteinuria (3 percent vs. 0)
- headache (3 percent vs. 0.5 percent)
Fatal, treatment-related adverse events in patients receiving bevacizumab were pulmonary hemorrhage (2.3 percent vs. 0.5 percent), gastrointestinal hemorrhage CNS infarction, gastrointestinal perforation, myocardial infarction, and neutropenic sepsis.
The most serious, and sometimes fatal, bevacizumab toxicities are gastrointestinal perforation, wound healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome, congestive heart failure, and neutropenic sepsis. The most common adverse events in patients receiving bevacizumab are asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis, and proteinuria.
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Second-Line Treatment of Metastatic Colorectal Cancer
On June 20, 2006, the FDA granted approval for a labeling extension for bevacizumab (Avastin®, made by Genentech), administered in combination with intravenous 5-fluorouracil-based chemotherapy, for the second-line treatment of metastatic carcinoma of the colon or rectum. This recommendation is based on the demonstration of a statistically significant improvement in overall survival (OS) in patients receiving bevacizumab plus FOLFOX4 (5-flourouracil, leucovorin, and oxaliplatin) when compared to those receiving FOLFOX4 alone.
The trial (E3200) supporting this approval was an openlabel, randomized, three-arm, active-controlled, multicenter clinical trial evaluating bevacizumab alone (n=244), bevacizumab plus FOLFOX4 (n=293), and FOLFOX4 alone (n=292). Following a planned interim analysis, the bevacizumab monotherapy arm was closed to accrual based on evidence of decreased survival in patients treated with bevacizumab alone compared with FOLFOX4 alone.
Patients entered on the trial had progressive or recurrent disease following prior 5-FU and irinotecan-based therapy. Patients (99 percent) received irinotecan with or without 5-FU as initial therapy for metastatic disease; those who received adjuvant irinotecan-based chemotherapy were required to have recurred within six months of completing therapy.
In both the combination and monotherapy arms, bevacizumab was administered at a dose of 10 mg/kg every two weeks. The FOLFOX4 regimen, administered every two weeks, consisted of oxaliplatin 85 mg/m2 and leucovorin 200 mg/m2 administered concurrently as an intravenous infusion, then 5FU 400 mg/m2 IV bolus followed by 5FU 600 mg/m2 continuous intravenous infusion on Day 1. On Day 2, patients received leucovorin 200 mg/m2 IV, then 5FU 400 mg/m2 IV bolus followed by 5FU 600 mg/m2 continuous intravenous infusion. When given in combination with FOLFOX4, bevacizumab was administered on Day 1 prior to oxaliplatin and leucovorin.
Among the 829 randomized patients, the median age was 61 years and 49 percent had an ECOG performance status of 0. Twenty-six percent had received prior radiation therapy, 80 percent received prior adjuvant chemotherapy, and all received prior irinotecan therapy.
Overall survival, the trial’s primary endpoint, was significantly longer in patients receiving bevacizumab in combination with FOLFOX4 as compared to those receiving FOLFOX4 alone (median overall survival was 13.0 months vs. 10.8 months; hazard ratio 0.75, p=0.001 stratified log rank test). The survival benefit was also observed in subgroups defined by age (<65 vs. >65 yrs) and gender. Patients treated with the bevacizumab combination were reported by investigator assessment to have significantly longer progression-free survival and higher overall response rate.
The most serious, and sometimes fatal, bevacizumab toxicities are gastrointestinal perforation, wound healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome and congestive heart failure. The monthst common adverse events in patients receiving bevacizumab are asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis, and proteinuria.
In Trial E3200, data were collected only for NCI-CTC grade 3-5 adverse events. Therefore, these data are likely to under-estimate the true adverse event rates. In addition, neither the time of onset nor the time to resolution of adverse events were collected.
NCI-CTC grade 3-5 adverse events that were more common in patients receiving the bevacizumab compared to FOLFOX4 alone were
- fatigue (19 percent vs. 13 percent)
- diarrhea (18 percent vs. 13 percent)
- sensory neuropathy (17 percent vs. 9 percent)
- nausea (12 percent vs. 5 percent)
- vomiting (11 percent vs. 4 percent)
- dehydration (10 percent vs. 5 percent)
- hypertension (9 percent vs. 2 percent)
- abdominal pain (8 percent vs. 5 percent)
- hemorrhage (5 percent vs. 1 percent)
- other neurologic toxicities (5 percent vs. 3 percent)
- ileus (4 percent vs. 1 percent)
- headache (3 percent vs. 0)
Fatal, treatment-related adverse events in patients receiving bevacizumab in this study included CNS hemorrhage, gastrointestinal hemorrhage, and gastrointestinal perforation with sepsis.
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First-Line Treatment of Metastatic Colorectal Cancer
On February 26, 2004, the FDA approved bevacizumab (Avastin®, a trademark of Genentech, Inc.) as a first-line treatment for patients with metastatic colorectal cancer - cancer that has spread to other parts of the body. Bevacizumab, a monoclonal antibody, is the first product to be approved that works by preventing the formation of new blood vessels, a process known as angiogenesis.
Bevacizumab was shown to extend patients' lives by about five months when given intravenously as a combination treatment along with standard chemotherapy drugs for colon cancer (the "Saltz regimen" also known as IFL). IFL treatment includes ironotecan, 5-fluorouracil (5FU) and leucovorin.
Bevacizumab is a genetically engineered version of a mouse antibody that contains both human and mouse components. (Antibodies are substances produced by the body's immune system to fight foreign substances.) Special technology also allows it to be produced in large quantities in the laboratory.
This new monoclonal antibody is believed to work by targeting and inhibiting the function of a natural protein called "vascular endothelial growth factor" (VEGF) that stimulates new blood vessel formation. When VEGF is targeted and bound to bevacizumab, it cannot stimulate the growth of blood vessels, thus denying tumors blood, oxygen and other nutrients needed for growth.
Angiogenesis inhibitors such as bevacizumab have been studied, first in the laboratory and then in patients, for three decades with the hope they might prevent the growth of cancer. This is the first such product that has been proven to delay tumor growth and more importantly, significantly extend the lives of patients.
"The approval of [bevacizumab] is the result of many years of research and development exploring a promising new approach to fighting cancer, and it is one of a number of recent new treatments for colorectal cancer that taken together, have significantly improved the armamentarium for fighting this disease," said Mark B. McClellan, M.D., Ph.D., FDA Commissioner. "These medical achievements reflect the innovation of drug developers and the hard work of FDA's cancer review teams, and they are proof of the promise offered by biomedical innovation. The dedication of everyone involved in these efforts is making a real difference in the lives of cancer patients."
Colorectal cancer - cancer of the colon or rectum - is the third most common cancer affecting men and women in the U.S. and, according to the Centers for Disease Control and Prevention (CDC), is the second leading cause of cancer-related death. Colorectal cancer is also one of the most commonly diagnosed cancers in the U.S.; approximately 147,500 new cases were diagnosed in 2003.
The safety and efficacy of bevacizumab was primarily shown in a randomized, double-blind clinical trial of more than 800 patients with metastatic colorectal cancer designed to find out whether bevacizumab extended the lives of patients. Roughly half the patients received IFL, the standard chemotherapy combination, and the other half received bevacizumab once every two weeks in addition to IFL.
Overall, patients given bevacizumab in combination with IFL survived about five months longer and the average time before tumors started regrowing or new tumors appeared was four months longer than patients receiving IFL alone. The overall response rate to the treatment was 45 percent compared to 35 percent for the control arm of the trial.
Serious, but uncommon, side-effects of bevacizumab include formation of holes in the colon (gastrointestinal perforation) generally requiring surgery and sometimes leading to intra-abdominal infections, impaired wound healing, and bleeding from the lungs or internally. Other, more common, side-effects are high blood pressure, tiredness, blood clots, diarrhea, decreased white blood cells (lowering immunity to diseases) headache, appetite loss and mouth sores.
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Drug Warnings Issued
On September 30, 2011, the FDA issued a safety label update. The updated prescribing information includes new warnings regarding the risk of ovarian failure in premenopausal women, osteonecrosis of the jaw, and the risks of venous thromboembolic events (VTE) and bleeding in patients receiving anticoagulation therapy after a first VTE event while receiving bevacizumab.
The incidence of new cases of ovarian failure, defined as amenorrhea lasting 3 or more months, a follicle-stimulating hormone (FSH) level of at least 30 mIU/mL, and a negative serum β-HCG pregnancy test, was prospectively evaluated in a subset study of 179 women receiving mFOLFOX alone (N= 84) or mFOLFOX with bevacizumab (N=95) for adjuvant stage II and III colorectal cancer, a use for which bevacizumab is not approved. New cases of ovarian failure were identified in 34 percent (32/95) of women receiving bevacizumab in combination with chemotherapy compared with 2 percent (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of bevacizumab treatment, recovery of ovarian function was demonstrated in 22 percent (7/32) of these women. Recovery of ovarian function is defined as resumption of menses and an FSH level of less than 30 mIU/mL at any visit in the post-treatment period. Long-term effects of bevacizumab exposure on fertility are unknown. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with bevacizumab.
Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) was reported in patients receiving bevacizumab but not bisphosphonates in the post-marketing setting. The pathogenesis of this osteonecrosis is unclear. It is possible that the antiangiogenic properties of bevacizumab may result in bone tissue avascularization, leading to ischemic changes in the microvasculature of the jaw and resulting in osteonecrosis.
Venous Thromboembolic Events (VTE) and Bleeding Events for Patients Receiving Anti-Coagulation
In a randomized, 4-arm study in 1,401 patients with metastatic colorectal cancer (mCRC) prospectively evaluating the incidence of VTE (all grades), the overall incidence of a first VTE was higher in patients receiving bevacizumab plus chemotherapy (13.5 percent) than in patients receiving chemotherapy alone (9.6 percent). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the patients receiving bevacizumab plus chemotherapy and 43 in the patients receiving chemotherapy alone), the overall incidence of subsequent VTEs was also 31.5 percent higher among the patients treated with bevacizumab compared with 25.6 percent in patients treated with chemotherapy alone. In this subgroup of patients treated with anticoagulants, the majority of bleeding incidences were grade 1. The overall incidence of bleeding was 27.4 percent in the patients treated with bevacizumab compared with 20.9 percent in the patients treated with chemotherapy alone.
On September 24, 2007, the FDA issued a safety labeling update. The updated prescribing information notes that non-gastrointestinal fistula formation has been reported in patients treated with bevacizumab in controlled clinical studies (with an incidence of < 0.3%) and in post-marketing experience, in some cases with fatal outcome. Fistula formation involving the following areas of the body other than the gastrointestinal tract has been reported: tracheo-esophageal, bronchopleural, biliary, vaginal, and bladder. Events were reported throughout treatment with bevacizumab, with most events occurring within the first six months. Physicians are instructed to permanently discontinue bevacizumab in patients with fistula formation involving an internal organ.
On September 27, 2006, the FDA and Genentech, Inc. issued another important drug warning to healthcare providers that, for patients taking bevacizumab, there is evidence of an increased risk of reversible posterior leukoencephalopathy syndrome (RPLS), a rare brain-capillary leak syndrome associated with hypertension, fluid retention, and cytotoxic effects of immunosuppressive drugs on the vascular endothelium. There is also an increased risk of nasal septum perforation, so prescribing information has been revised to include that serious adverse effect.
On August 12, 2004, the FDA and Genentech, Inc. issued an important drug warning to healthcare providers that there is evidence of an increased risk of serious arterial thromboembolic events, including cerebrovascular accident, myocardial infarctions, transient ischemic attacks, and angina related to bevacizumab. The risk of fatal arterial thrombotic events is also increased. In randomized, active-controlled studies conducted in patients with metastatic colorectal cancer, the risks of a serious arterial thrombotic event was approximately two-fold higher in patients receiving infusional 5-FU based chemotherapy plus bevacizumab, with an estimated overall rate of up to 5 percent.
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.