AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Bevacizumab

• Bevacizumab-adcd

• Bevacizumab-awwb

• Bevacizumab-bvzr

• Bevacizumab-maly

Bevacizumab, bevacizumab-adcd, bevacizumab-awwb, bevacizumab-bvzr, and bevacizumab-maly, recombinant humanized monoclonal antibodies, are antineoplastic agents.1,  90,  91,  92,  93

Bevacizumab-adcd (Vegzelma^®), bevacizumab-awwb (Mvasi^®), bevacizumab-bvzr (Zirabev^®), and bevacizumab-maly (Alymsys^®) are biosimilar to bevacizumab (Avastin^®).90,  91,  92,  93,  172 FDA defines a biosimilar as a biological product that is highly similar to an FDA-licensed reference biological with the exception of minor differences in clinically inactive components and for which there are no clinically meaningful differences in safety, purity, or potency.170,  171 The claim of biosimilarity is based on a totality-of-evidence approach, which includes consideration of data from analytical, animal, and clinical studies (e.g., human pharmacokinetic and pharmacodynamic studies, clinical immunogenicity assessment, additional comparative clinical studies).171 Therefore, biosimilarity may be established even when there are formulation or minor structural differences as long as these differences are not clinically meaningful.171 Biosimilars are approved through an abbreviated licensure pathway that establishes biosimilarity between the proposed biological and the reference biological but does not independently establish safety and effectiveness of the proposed biological.171 In order to be considered an interchangeable biosimilar, a biological product must meet additional requirements beyond demonstrating biosimilarity to its reference product; these requirements include demonstrating that the biological product can be expected to produce the same clinical results as the reference product in any given patient and, for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is no greater than the risk of using the reference product without such alteration or switch.169 Biosimilar products that are interchangeable can be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.169 None of the currently available bevacizumab biosimilars have interchangeable data at this time.172

In this monograph, unless otherwise stated, the term “bevacizumab products” refers to bevacizumab (the reference drug) and its biosimilars (bevacizumab-adcd, bevacizumab-awwb, bevacizumab-bvzr, and bevacizumab-maly).

Several bevacizumab biosimilars are available.90,  91,  92,  93 Biosimilarity of these products has been demonstrated for the indications described in Table 1.90,  91,  92,  93,  172

Biosimilarity to originator bevacizumab is additionally supported by comparative clinical studies in patients with non-small cell lung cancer.139,  140,  141,  142

Colorectal Cancer

Bevacizumab products are used in combination with IV fluorouracil-based chemotherapy for the first- or second-line treatment of metastatic colorectal cancer.1,  90,  91,  92,  93

Bevacizumab products are also used in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for the second-line treatment of metastatic colorectal cancer in patients who have progressed on a first-line bevacizumab product-containing regimen.1,  90,  91,  92,  93

Bevacizumab products are not indicated for the adjuvant treatment of colon cancer.1,  90,  91,  92,  93

Clinical Experience

First- or Second-line Treatment in Combination with Fluorouracil-based Chemotherapy

The indication for use of bevacizumab in combination with IV fluorouracil-based chemotherapy for the first- or second-line treatment of metastatic colorectal cancer is based mainly on the results of 2 randomized, controlled clinical studies (AVF2107g and E3200) and a single-arm study (TRC-0301).1,  4,  21,  22

In AVF2107g, a phase 3, randomized, double-blind, active-controlled study, 813 patients with previously untreated metastatic colorectal cancer received either a placebo (administered every 2 weeks) or bevacizumab (5 mg/kg administered by IV infusion every 2 weeks until disease progression occurred) in conjunction with a combination irinotecan/fluorouracil/leucovorin regimen.1,  4 The combination regimen consisted of irinotecan 125 mg/m², fluorouracil 500 mg/m², and leucovorin 20 mg/m², administered as an IV bolus injection once weekly for 4 out of every 6 weeks.1,  4 Patients who received bevacizumab in combination with the irinotecan/fluorouracil/leucovorin regimen had a higher median overall response rate (45 versus 35%, respectively) and prolonged median overall survival (20.3 versus 15.6 months, respectively), median progression-free survival (10.6 versus 6.2 months, respectively), and median duration of response (10.4 versus 7.1 months, respectively) than patients receiving placebo in conjunction with the same combination regimen.1,  4 This phase 3 study also initially randomized some patients into a third group receiving fluorouracil/leucovorin and bevacizumab; enrollment of patients into this treatment group was discontinued after 110 patients had been enrolled, in accordance with the protocol-specified adaptive design.1 Among the 110 patients receiving bevacizumab (5 mg/kg administered by IV infusion every 2 weeks) with fluorouracil and leucovorin (each 500 mg/m² IV once weekly for 6 out of every 8 weeks), the objective response rate was 39%, median overall survival was 18.3 months, median progression-free survival was 8.8 months, and median duration of response was 8.5 months.1,  18

In E3200, an open-label, randomized, 3-arm, active-controlled, multicenter clinical study, 829 patients with previously-treated metastatic colorectal cancer received bevacizumab in combination with FOLFOX4 (i.e., fluorouracil/leucovorin and oxaliplatin), FOLFOX4 alone, or bevacizumab alone.1,  21 Patients had received prior treatment with irinotecan, with or without fluorouracil, as initial therapy for metastatic disease (99%) or irinotecan and fluorouracil as adjuvant therapy (1%).1 The FOLFOX4 regimen consisted of oxaliplatin 85 mg/m² and leucovorin 200 mg/m² concurrently IV, then fluorouracil 400 mg/m² by IV bolus, followed by fluorouracil 600 mg/m² by continuous IV infusion on day 1; and leucovorin 200 mg/m² IV, then fluorouracil 400 mg/m² by IV bolus, followed by fluorouracil 600 mg/m² by continuous IV infusion on day 2; with treatment cycles repeated every 2 weeks.1,  21 Bevacizumab was administered at a dose of 10 mg/kg every 2 weeks.1 For patients receiving the combination of the 2 regimens, bevacizumab was administered prior to the FOLFOX4 regimen on day 1 of the treatment cycle.1,  21 The median age of patients was 61 years, 40% were female, 87% were white, and 49% had an ECOG performance status of 0.1 Most patients (80%) had received adjuvant chemotherapy, and 26% had received prior radiation therapy.1 Following an interim analysis that showed decreased survival in patients receiving bevacizumab alone compared with those receiving FOLFOX4 alone, the bevacizumab monotherapy arm was closed to accrual after enrollment of 244 of the planned 290 patients.1 In patients receiving bevacizumab in combination with FOLFOX4, median overall survival was prolonged (13 versus 10.8 months), and progression-free survival and overall response rate based on investigator assessment were higher than in patients receiving FOLFOX4 alone.1,  21

In TRC-0301, a multicenter, single-arm, open-access protocol, 339 patients received bevacizumab in combination with fluorouracil/leucovorin (administered by either IV infusion or rapid IV injection) for metastatic colorectal cancer with disease progression following both irinotecan-containing and oxaliplatin-containing regimens.1,  22 Most patients (73%) received concurrent fluorouracil and leucovorin according to a rapid IV injection (“bolus”) regimen.1 Among the first 100 evaluable patients, there was one objective partial response for an overall response rate of 1%.1,  22 The median progression-free survival of the first 100 evaluable patients was 3.5 months, and the median overall survival was 9 months.22

Second-line Treatment After Progression on Bevacizumab-containing Regimen

The indication for use of bevacizumab in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for the second-line treatment of metastatic colorectal cancer in patients who have progressed on a first-line bevacizumab product-containing regimen is based mainly on the results of a randomized, controlled, open-label study (ML18147).1,  94 ML18147 enrolled 820 patients with metastatic colorectal cancer that had progressed on a first-line bevacizumab-containing regimen; patients were excluded if they had progressed within 3 months of initiating first-line chemotherapy or if they had received bevacizumab for less than 3 consecutive months in the first-line setting.1,  94 Patients were randomized in a 1:1 ratio to receive bevacizumab (5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks) or no bevacizumab; all patients received second-line chemotherapy with a fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based regimen.1,  94 The choice of second-line chemotherapy regimen was based on the first-line chemotherapy regimen.1,  94 The median age of patients was 63 years; 64% were male, and 58% had received irinotecan-based therapy as first-line treatment.1 Patients who received bevacizumab plus chemotherapy demonstrated longer overall survival and progression-free survival than those who received chemotherapy alone.1,  94 Median overall survival was 11.2 and 9.8 months among patients who received bevacizumab plus chemotherapy and patients who received chemotherapy alone, respectively; median progression-free survival was 5.7 and 4.1 months, respectively.1,  94

Other Uses in Colorectal Cancer

Bevacizumab also has been used in combination with oxaliplatin-containing regimens† as first-line therapy for metastatic colorectal cancer.38,  97 In a randomized phase 3 trial, the addition of bevacizumab to oxaliplatin-containing chemotherapy (either capecitabine and oxaliplatin [XELOX] or fluorouracil/leucovorin and oxaliplatin [FOLFOX4]) in first-line therapy for metastatic colorectal cancer prolonged median progression-free survival, but no difference in overall survival was observed.38 Another randomized controlled trial compared fluorouracil/leucovorin plus irinotecan and bevacizumab (FOLFIRI plus bevacizumab) to fluorouracil/leucovorin plus oxaliplatin, irinotecan, and bevacizumab (FOLFOXIRI plus bevacizumab) for the first-line treatment of metastatic colorectal cancer.97 In this study, FOLFOXIRI plus bevacizumab prolonged progression-free survival (but not overall survival) compared to FOLFIRI plus bevacizumab; however, the incidence of adverse events was also increased with FOLFOXIRI plus bevacizumab.97

Bevacizumab has also been used in combination with trifluridine/tipiracil for the treatment of refractory metastatic colorectal cancer†; in the SUNLIGHT trial, trifluridine/tipiracil plus bevacizumab prolonged overall survival compared to trifluridine/tipiracil alone in patients who had received no more than 2 previous chemotherapy regimens for the treatment of advanced colorectal cancer.99

Bevacizumab has been investigated as an adjunct to standard chemotherapy regimens for adjuvant therapy following surgery in patients with early-stage (i.e., stage II or III)† colon cancer; however, efficacy was not demonstrated in this setting and this use is not recommended.95

Clinical Perspective

The American Society of Clinical Oncology (ASCO) guideline on metastatic colorectal cancer recommends the use of a chemotherapy (doublet or triplet) backbone as first-line therapy for previously untreated, unresectable microsatellite stable (MSS) or proficient mismatch repair (pMMR) metastatic colorectal cancer, in combination with anti-vascular endothelial growth factor (VEGF) antibodies (e.g., bevacizumab).12004 Doublet chemotherapy regimens include folinic acid/fluorouracil/oxaliplatin and folinic acid/fluorouracil/irinotecan.12004 Capecitabine plus oxaliplatin may be used as a substitute for folinic acid/fluorouracil/oxaliplatin.12004 Triplet chemotherapy includes folinic acid/fluorouracil/oxaliplatin/irinotecan.12004

Non-small Cell Lung Cancer

Bevacizumab products are used in combination with carboplatin and paclitaxel for the first-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous non-small cell lung cancer.1,  90,  91,  92,  93

Clinical Experience

Use in Combination with Carboplatin and Paclitaxel

The indication for use of bevacizumab in combination with carboplatin and paclitaxel for the first-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous non-small cell lung cancer is based principally on the results of a randomized, active-controlled, open-label, multicenter study (E4599).1,  11 In E4599, 878 chemotherapy-naive patients with locally advanced, metastatic, or recurrent nonsquamous non-small cell lung cancer were randomized to receive paclitaxel and carboplatin either with or without bevacizumab.1,  11 Patients received paclitaxel 200 mg/m² and carboplatin (dose required to obtain an AUC of 6 mg/mL per minute) both by IV infusion on day 1 with bevacizumab 15 mg/kg by IV infusion on day 1 or the same regimen of paclitaxel/carboplatin alone (without bevacizumab); each regimen was administered every 21 days for up to 6 cycles.1,  11 Upon completion or discontinuance of chemotherapy, patients receiving bevacizumab continued to receive bevacizumab alone until disease progression or intolerable toxicity occurred.1,  11 Most of the patients (89%) had newly diagnosed disease (stage IV in 76%), 46% were female, 43% were 65 years of age or older (median age: 63 years), and 28% of the patients had at least a 5% weight loss at the time of entry to the study.1 Excluded from the study were patients with disease of predominantly squamous histology, CNS metastasis, gross hemoptysis (0.5 teaspoon of red blood or more), unstable angina, and those receiving anticoagulant therapy.1,  11 The median overall survival was prolonged (12.3 versus 10.3 months) in patients receiving chemotherapy (paclitaxel and carboplatin) and bevacizumab compared with those receiving chemotherapy alone for advanced nonsquamous non-small cell lung cancer.1,  11 Subgroup analysis suggested that the benefit of the addition of bevacizumab to this chemotherapy regimen was less certain in women, patients 65 years of age or older, and patients with at least a 5% weight loss at study entry.1,  11

Other Uses in Non-small Cell Lung Cancer

Bevacizumab has been investigated for use in combination with cisplatin and gemcitabine† for the first-line treatment of locally advanced, metastatic, or recurrent nonsquamous non-small cell lung cancer.1,  98 In a randomized, double-blind, placebo-controlled study, 1043 patients with locally advanced, metastatic, or recurrent nonsquamous non-small cell lung cancer were randomized to receive bevacizumab 7.5 mg/kg in combination with cisplatin and gemcitabine, bevacizumab 15 mg/kg in combination with cisplatin and gemcitabine, or cisplatin and gemcitabine with placebo.1,  98 Most of the patients (77%) had stage IV disease, 8% had recurrent disease, 36% were female, and 29% were 65 years of age or older.1 Patients receiving bevacizumab 7.5 or 15 mg/kg in combination with cisplatin and gemcitabine had longer progression-free survival, but not a significantly longer overall survival, compared with patients receiving cisplatin and gemcitabine alone.1

Bevacizumab has also been used in combination with carboplatin and pemetrexed† for the first-line treatment of stage IIIB or IV nonsquamous non-small cell lung cancer.102 In the randomized, open-label PointBreak trial, 939 patients were randomly assigned to receive paclitaxel 200 mg/m²or pemetrexed 500 mg/m², both in combination with carboplatin (AUC of 6 mg/mL per minute) and bevacizumab 15 mg/kg.102 Treatment was administered every 3 weeks for up to 4 cycles; then, maintenance therapy with pemetrexed plus bevacizumab (for the pemetrexed group) or bevacizumab alone (for the paclitaxel group) was administered.102 In this trial, overall survival was similar between treatment groups; however, progression-free survival was prolonged in the group that received pemetrexed.102

Bevacizumab has also been used in combination with cisplatin and pemetrexed† for the first-line treatment of unresectable locally advanced, metastatic, or recurrent nonsquamous non-small cell lung cancer.103 In the randomized, open-label AVAPERL trial, all patients were treated with an induction regimen of cisplatin 75 mg/m², pemetrexed 500 mg/m², and bevacizumab 7.5 mg/kg every 3 weeks for up to 4 cycles; patients who responded or had stable disease after induction treatment were randomized in a 1:1 ratio to maintenance therapy with bevacizumab plus pemetrexed or bevacizumab alone.103 In this trial, disease control was achieved in 71.9% of patients after induction therapy, with 22.7% achieving a partial response and 49.2% achieving stable disease (no complete responses were reported).103 Among the patients who went on to receive maintenance therapy, pemetrexed plus bevacizumab maintenance therapy improved progression-free survival compared to bevacizumab maintenance therapy alone.103

Bevacizumab has also been used in combination with atezolizumab, paclitaxel, and carboplatin† for the initial treatment of metastatic nonsquamous non-small cell lung cancer; in the IMpower150 trial, adding atezolizumab to a regimen of bevacizumab, paclitaxel, and carboplatin prolonged progression-free survival as well as overall survival among patients with previously untreated metastatic nonsquamous non-small cell lung cancer.104

Bevacizumab has also been used in combination with erlotinib for the treatment of advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer†.100,  101 In an open-label, randomized trial (NEJ026) conducted in Japan, 224 patients with stage IIIB or IV EGFR mutation-positive non-small cell lung cancer or recurrent EGFR mutation-positive non-small cell lung cancer were randomized to receive erlotinib 150 mg once daily plus IV bevacizumab 15 mg/kg once every 21 days or erlotinib monotherapy.100,  101 At a prespecified interim analysis, progression-free survival was 16.9 months in patients receiving erlotinib in combination with bevacizumab versus 13.3 months in those receiving erlotinib monotherapy.100 At a median follow-up of 39.2 months, median overall survival with combination therapy was 50.7 months compared to 46.2 months with erlotinib alone.101

Clinical Perspective

Patients with locally advanced, unresectable non-small cell lung cancer are typically treated with radiation therapy and/or chemotherapy (depending on the sites of tumor involvement and the patient's performance status).105,  106 Treatment selection in newly-diagnosed metastatic non-small cell lung cancer is based on patient comorbidities, performance status, tumor histology, and the molecular and immunologic features of the cancer (e.g., the presence or absence of specific driver alterations).105,  107,  108 For the first-line treatment of patients with stage IV nonsquamous non-small cell lung cancer without driver alterations, ASCO states that a regimen of atezolizumab, carboplatin, and paclitaxel (with or without bevacizumab) may be offered in the absence of contraindications to bevacizumab.108 Other regimens may be preferred in patients whose tumors express programmed death ligand 1 (PD-L1).108 Consult the ASCO guidelines for further information on recommended regimens for the treatment of non-small cell lung cancer.106,  107,  108

Glioblastoma

Bevacizumab products are used for the treatment of recurrent glioblastoma in adults.1,  90,  91,  92,  93

Clinical Experience

The current indication for use of bevacizumab in the management of recurrent glioblastoma is based principally on the results of 3 studies (EORTC 26101, AVF3708g, and NCI 06-C-0064E).1,  45,  46,  47,  109

In the multicenter, randomized, open-label EORTC 26101 study, 432 patients with recurrent glioblastoma were randomized in a 2:1 ratio to receive either bevacizumab (10 mg/kg every 2 weeks) with lomustine (90 mg/m² every 6 weeks) or lomustine alone (110 mg/m² every 6 weeks).1,  109 Study treatment was continued until disease progression or unacceptable toxicity occurred.1 All patients had been previously treated with radiotherapy and temozolomide.1 The median age of patients enrolled in the trial was 57 years; 24.8% were over 65 years of age, 61% were male, and 50% were receiving corticosteroids at the time of randomization.1 Overall survival was not prolonged among patients who received bevacizumab plus lomustine compared to those who received lomustine alone; however, patients who received bevacizumab plus lomustine had a longer progression-free survival (4.2 months versus 1.5 months with lomustine alone).1 Among patients receiving corticosteroids at the time of randomization, more patients receiving bevacizumab plus lomustine discontinued corticosteroids during the trial (23% versus 12% with lomustine alone).1

In the phase 2, open-label, multicenter, randomized, noncomparative AVF3708g study, 167 patients with previously treated glioblastoma were randomized to receive either bevacizumab (10 mg/kg administered by IV infusion every 2 weeks) alone or bevacizumab in combination with irinotecan (340 mg/m² in patients receiving enzyme-inducing antiepileptic drugs or 125 mg/m² in those not receiving enzyme-inducing antiepileptic drugs, administered by IV infusion over 90 minutes every 2 weeks); treatment was continued until disease progression or unacceptable toxicity occurred, up to a maximum of 104 weeks.45 Patients enrolled in this study had received prior radiation therapy and chemotherapy (i.e., temozolomide); patients with recent brain hemorrhage were excluded.45 Of the 85 patients randomized to receive bevacizumab monotherapy, the median age was 54 years (range: 23-78 years), 31.8% were female, 81.2% were in first relapse, and 44.7 or 55.3% had a Karnofsky performance status of 90-100 or 70-80, respectively;45 the mean treatment duration was 4.8 months (range: 0-12.9 months).47 Treatment with bevacizumab monotherapy resulted in an objective response rate of 25.9% (partial responses only), a median duration of response of 4.2 months, a 6-month progression-free survival rate of 36%, and a median overall survival of 9.3 months.1,  47 In addition, corticosteroid dosage decreased by a median of 37.5% at the time of response compared with baseline.47

In the single-arm, single-institution NCI 06-C-0064E study, patients with previously treated glioblastoma received bevacizumab (10 mg/kg administered by IV infusion every 2 weeks).1,  46 All patients had documented disease progression after receiving temozolomide and radiation therapy.46 Treatment with bevacizumab resulted in an objective response rate of 19.6% (partial responses only) and a median duration of response of 3.9 months.1,  47

Clinical Perspective

The ASCO has published a guideline on the treatment of diffuse astrocytic and oligodendroglial tumors in adults.300 Recommended therapy depends on the World Health Organization (WHO) tumor classification; the WHO classification system for CNS tumors was updated in 2021, and the ASCO guideline provides recommendations based on both the 2016 and 2021 WHO classifications.300 The 2021 classification system is primarily based on molecular characteristics of the tumor (i.e., isocitrate dehydrogenase [IDH] mutant versus wildtype, 1p19q codeleted versus non-codeleted).300 Tumors with wildtype IDH are classified as glioblastomas in the 2021 classification, while tumors with mutant IDH are classified as either oligodendrogliomas (if 1p19q codeleted) or astrocytomas (if 1p19q non-codeleted).300 In previous WHO classifications, IDH-wildtype tumors could be classified as diffuse astrocytoma (WHO grade 2), anaplastic astrocytoma (WHO grade 3), or glioblastoma (WHO grade 4).300 In previous WHO classifications, IDH-wildtype tumors could be classified as diffuse astrocytoma (WHO grade 2), anaplastic astrocytoma (WHO grade 3), or glioblastoma (WHO grade 4).300

Concurrent temozolomide and radiation therapy should be offered to people with newly diagnosed IDH-wildtype, CNS WHO grade 4 glioblastoma, and 6 months of adjuvant temozolomide should be offered to patients who receive concurrent temozolomide and radiation therapy.300 Patients with older age, poor performance status, or concerns about toxicity or prognosis may be considered for treatment with best supportive care alone, hypofractionated radiation therapy alone, or temozolomide alone.300 Bevacizumab is not recommended for people with newly-diagnosed IDH-wildtype, CNS WHO grade 4 glioblastoma.300 No recommendation for or against any therapeutic strategy could be made for the treatment of recurrent IDH-wildtype, CNS WHO grade 4 glioblastoma.300 Drugs that have been studied in this setting include temozolomide, lomustine, carmustine, and bevacizumab; ASCO recommends that patients with recurrent glioblastoma are referred for participation in a clinical trial when possible.300

Renal Cell Carcinoma

Bevacizumab products are used in combination with interferon alfa for the treatment of metastatic renal cell carcinoma.1,  90,  91,  92,  93 Bevacizumab is designated an orphan drug by FDA for use in this condition.63

Clinical Experience

The current indication for use of bevacizumab in combination with interferon alfa in patients with metastatic renal cell carcinoma is based principally on the results of a multicenter, randomized, double-blind, placebo-controlled study (BO17705 [AVOREN]).1,  49

In the BO17705/AVOREN study, 649 patients with previously untreated metastatic renal cell carcinoma (predominantly [more than 50%] clear-cell histology) who had undergone nephrectomy (or partial nephrectomy) were randomized to receive bevacizumab (10 mg/kg administered by IV infusion every 2 weeks) in combination with interferon alfa (9 million units by subcutaneous injection 3 times weekly) or interferon alfa in combination with placebo; treatment was continued until disease progression or unacceptable toxicity occurred (up to a maximum of 52 weeks for interferon alfa).1,  49 The median age of the patients was 60 years (range: 18-82 years), and 70% were male; 28, 56, or 8% of patients had Motzer scores of 0 (favorable risk), 1-2 (intermediate risk), or 3-5 (poor risk), respectively.1 In this study, patients receiving bevacizumab in combination with interferon alfa had prolonged median progression-free survival (10.2 versus 5.4 months) and a higher overall response rate (30 versus 12%), but similar median overall survival (23 versus 21 months), compared with those receiving interferon alfa alone.1

Clinical Perspective

Prognosis is generally poor in patients with metastatic renal cell carcinoma, including those who have undergone complete tumor resection.110 First-line therapy with vascular endothelial growth factor receptor (VEGFR) inhibitors has been shown to provide benefits in patients with advanced renal cell carcinoma; however, relapsed or refractory renal cell carcinoma eventually develops in most patients.111 Combination regimens (e.g., immune checkpoint inhibitor in combination with a tyrosine kinase inhibitor) have become a standard for the treatment of advanced renal cell carcinoma.110 Bevacizumab with or without interferon alfa may be considered for third- or fourth-line therapy.110

The ASCO recommends that all patients with metastatic renal cell carcinoma who require systemic therapy in the first-line setting undergo risk stratification.112 Patients with intermediate- or poor-risk disease should be offered combination treatment with 2 immune checkpoint inhibitors (i.e., ipilimumab and nivolumab) or an immune checkpoint inhibitor in combination with a VEGFR tyrosine kinase inhibitor (e.g., pembrolizumab plus axitinib, nivolumab plus cabozantinib, avelumab plus axitinib, pembrolizumab plus lenvatinib).112 Treatment selection should be based on adverse events, comorbid conditions, provider experience, and treatment cost.112 Patients with favorable-risk disease who require systemic therapy may be offered an immune checkpoint inhibitor in combination with a VEGFR tyrosine kinase inhibitor.112

Cervical Cancer

Bevacizumab products are used in combination with paclitaxel and cisplatin or paclitaxel and topotecan for the treatment of persistent, recurrent, or metastatic cervical cancer.1,  90,  91,  92,  93

Clinical Experience

The current indication for use of bevacizumab in combination with paclitaxel and cisplatin or paclitaxel and topotecan for the treatment of persistent, recurrent, or metastatic cervical cancer is based principally on the results of a randomized, 4-arm, multicenter study (GOG-0240).1,  113,  114 In the GOG-0240 trial, 452 patients with persistent, recurrent, or metastatic cervical cancer were randomized in a 1:1:1:1 ratio to receive paclitaxel plus cisplatin and bevacizumab, paclitaxel plus cisplatin alone, paclitaxel plus topotecan and bevacizumab, or paclitaxel plus topotecan alone.1,  113 Dosage regimens for each drug were as follows (based on a 21-day cycle): bevacizumab was administered IV at 15 mg/kg on day 1; cisplatin was administered IV at 50 mg/m² on day 1; topotecan was administered IV at 0.75 mg/m² on days 1-3; and paclitaxel was administered IV at 135 mg/m² or 175 mg/m²on day 1 (175 mg/m² if used in combination with topotecan).113 Treatment was continued until disease progression or unacceptable toxicity occurred.1,  113 The median age of the patients enrolled was 48 years (range: 20-85 years); 78% were white, 80% had received prior radiation, and 74% had received prior chemotherapy concurrent with radiation.1 Overall survival was improved when bevacizumab was added to chemotherapy (either paclitaxel plus cisplatin or paclitaxel plus topotecan).1,  113,  114 Median overall survival was 16.8 months among patients who received bevacizumab plus chemotherapy compared to 12.9 months among patients who received chemotherapy alone.1 Response rate was also increased with bevacizumab plus chemotherapy over chemotherapy alone (45% versus 34%).1

Clinical Perspective

Options for the treatment of stage IVB and recurrent cervical cancer include immunotherapy (e.g., pembrolizumab), radiation plus chemotherapy, palliative chemotherapy, and other systemic treatments (e.g., bevacizumab); of these, only immunotherapy is likely to be curative in this setting.115 An ASCO guideline on the treatment of cervical cancer recommends chemotherapy (paclitaxel plus cisplatin or carboplatin) plus bevacizumab for the treatment of stage IVB cervical cancer, with or without individualized radiotherapy and/or palliative care.116 A rapid update of this guideline states that clinicians may offer upfront pembrolizumab and chemotherapy (with or without bevacizumab) to eligible patients with persistent, recurrent, or metastatic cervical carcinoma, with or without individualized radiotherapy and/or palliative care.117

Ovarian Cancer

Bevacizumab products (except bevacizumab-maly [Alymsys^®]) are used in combination with carboplatin and paclitaxel and subsequently as monotherapy for the treatment of stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection.1,  91,  92,  93

Bevacizumab products are also used in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for the treatment of platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who received no more than 2 prior chemotherapy regimens.1,  90,  91,  92,  93

Bevacizumab products (except bevacizumab-maly [Alymsys^®]) are also used in combination with carboplatin and paclitaxel, or with carboplatin and gemcitabine, and subsequently as monotherapy for the treatment of platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.1,  91,  92,  93

Bevacizumab has been designated an orphan drug by FDA for the treatment of ovarian cancer, fallopian tube carcinoma, and primary peritoneal carcinoma.63

Clinical Experience

Stage III-IV Disease Following Surgical Resection

The indication for use of bevacizumab in the treatment of stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection is based principally on the results of a multicenter, randomized, double-blind, placebo-controlled trial (GOG-0218).1,  72,  118 In the GOG-0218 trial, 1873 patients were randomized in a 1:1:1 ratio to receive bevacizumab plus carboplatin and paclitaxel followed by bevacizumab alone (CPB15+); bevacizumab plus carboplatin and paclitaxel followed by placebo alone (CPB15); or placebo plus carboplatin and paclitaxel followed by placebo alone (CPP).1,  72 Carboplatin was administered at the dose required to obtain an AUC of 6 mg/mL per minute, while paclitaxel was administered at a dose of 175 mg/m² and bevacizumab was administered at a dose of 15 mg/kg.1,  72 All treatments were administered on day 1 of each 3-week treatment cycle; carboplatin and paclitaxel were administered for the first 6 cycles, and bevacizumab or placebo was administered beginning in cycle 2 for up to 22 cycles (depending on treatment assignment).1,  72

The median age of patients in the GOG-0218 study was 60 years (range: 22-89 years), and 28% of patients were over 65 years of age.1 Most patients had epithelial ovarian cancer (83%), while 15% had primary peritoneal cancer and 2% had fallopian tube cancer.1 Serous adenocarcinoma was the most common histologic type.1 Approximately 34% of patients had resected International Federation of Gynecology and Obstetrics (FIGO) stage III cancer with residual disease <1 cm, 40% had resected FIGO stage III cancer with residual disease >1 cm, and 26% had resected FIGO stage IV disease.1 Median progression-free survival was prolonged in the CPB15+ group compared to the CPB15 and CPP groups (18.2 months versus 12.8 and 12 months, respectively).1 Overall survival was similar between groups (43.8, 38.8, and 40.6 months for CPB15+, CPB15, and CPP, respectively).1

Platinum-resistant Recurrent Disease

The indication for use of bevacizumab in the treatment of platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who received no more than 2 prior chemotherapy regimens is based principally on the results of a multicenter, open-label, randomized study (MO22224).1,  119 In the MO22224 trial, 361 patients were randomized to receive either single-agent chemotherapy plus bevacizumab or single-agent chemotherapy alone.1,  119 Single-agent chemotherapy was selected by the investigator and could include any of the following regimens: paclitaxel 80 mg/m² on days 1, 8, 15, and 22 every 4 weeks; pegylated liposomal doxorubicin 40 mg/m² on day 1 every 4 weeks; topotecan 4 mg/m² on days 1, 8, and 15 every 4 weeks; or topotecan 1.25 mg/m² on days 1-5 every 3 weeks.1,  119 Bevacizumab was administered at a dosage of 10 mg/kg every 2 weeks (or 15 mg/kg every 3 weeks for patients receiving topotecan on an every-3-week schedule).119

The median age of patients in the MO22224 trial was 61 years (range: 25-84 years), and 37% of patients were greater than 65 years of age.1 At baseline, 79% of patients had measurable disease; 73% had a platinum-free interval of 3-6 months and 27% had a platinum-free interval of <3 months.1 Progression-free survival was prolonged in the bevacizumab plus chemotherapy group (6.7 months versus 3.4 months with chemotherapy alone); however, overall survival was not substantially different between groups (16.6 months with bevacizumab plus chemotherapy versus 13.3 months with chemotherapy alone).1,  119 Among the patients with measurable disease at baseline, a response was observed in 28 and 13% of those receiving bevacizumab plus chemotherapy or chemotherapy alone, respectively.1 The median duration of response was 9.4 months in the bevacizumab plus chemotherapy group and 5.4 months in the chemotherapy alone group.1

Platinum-sensitive Recurrent Disease

The indication for use of bevacizumab in the treatment of platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer is based principally on the results of a randomized, double-blind, placebo-controlled study (AVF4095g) and a randomized, controlled, open-label study (GOG-0213).1,  120,  121,  122

In the AVF4095g study, 484 patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who had not received prior chemotherapy in the recurrent setting or prior bevacizumab treatment were randomized in a 1:1 ratio to receive bevacizumab (15 mg/kg on day 1) or placebo in conjunction with carboplatin (AUC of 4 mg/mL per minute on day 1) and gemcitabine (1000 mg/m² on days 1 and 8).1,  120 Treatment cycles were 3 weeks in length; bevacizumab or placebo was administered in conjunction with carboplatin and gemcitabine for 6-10 cycles, then continued as monotherapy until disease progression or unacceptable toxicity occurred.1,  120 The median age of patients in the AVF4095g trial was 61 years (range: 28-87 years), and 37% of patients were >65 years of age.1 At baseline, all patients had measurable disease; 42% had a platinum-free interval of 6-12 months and 58% had a platinum-free interval of >12 months.1 Progression-free survival was improved with the addition of bevacizumab to chemotherapy; median progression-free survival was 12.4 months among patients who received bevacizumab and 8.4 months among patients who received placebo.1,  120 The overall response rate was 78.5 and 57.4% for patients who received bevacizumab or placebo, respectively.1,  120 Overall survival was not substantially improved when bevacizumab was added to chemotherapy.1,  121

In the GOG-0213 study, 674 patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who had not received >1 previous chemotherapy regimen were randomized in a 1:1 ratio to receive bevacizumab 15 mg/kg plus chemotherapy (carboplatin [AUC of 5 mg/mL per minute] and paclitaxel [175 mg/m²]) followed by bevacizumab monotherapy or chemotherapy alone.1,  122 Treatments were administered every 3 weeks; chemotherapy was administered for 6-8 cycles, and bevacizumab was continued until disease progression or unacceptable toxicity occurred.1,  122 The median age of patients in the GOG-0213 trial was 60 years (range: 23-85 years), and 33% of patients were greater than 65 years of age.1 At baseline, 83% of patients had measurable disease; 26% had a platinum-free interval of 6-12 months and 74% had a platinum-free interval of >12 months.1 Median progression-free survival was 13.8 months in the bevacizumab plus chemotherapy group and 10.4 months in the chemotherapy alone group; overall survival was 42.6 months and 37.3 months, respectively.1 Among patients with measurable disease at baseline, the overall response rate was 78% with bevacizumab plus chemotherapy and 56% with chemotherapy alone.1

Clinical Perspective

Newly-diagnosed Advanced Ovarian Cancer

Newly-diagnosed advanced ovarian cancer (stage III-IV) is typically treated with surgery followed by platinum-based chemotherapy.124 In some cases, platinum-based chemotherapy may also be administered before surgery, and other agents, such as bevacizumab and poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors, may be used as adjunctive treatments.124

A guideline from ASCO provides recommendations for the treatment of newly-diagnosed advanced ovarian cancer.123 In this guideline, ASCO recommends primary cytoreductive surgery for patients who have a high likelihood of achieving complete cytoreduction with acceptable morbidity; patients who are fit for primary cytoreductive surgery but are unlikely to have complete cytoreduction and patients who have a high perioperative risk profile should receive neoadjuvant chemotherapy with a platinum-taxane doublet regimen.123 Patients demonstrating a response or stable disease after ≤4 cycles of neoadjuvant chemotherapy should undergo subsequent interval cytoreductive surgery.123 After interval cytoreductive surgery, chemotherapy (preferably with a platinum-taxane doublet) is recommended; bevacizumab may be added to chemotherapy after sufficient post-surgical healing has taken place.123 Maintenance therapy with bevacizumab or a PARP inhibitor should be offered after completion of primary chemotherapy.123,  126,  127

Recurrent Ovarian Cancer

Approximately 80% of patients with epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer will relapse after first-line treatment with platinum-based and taxane-based chemotherapy.124 If disease recurs <6 months after completion of a platinum-containing regimen, it is generally considered platinum-resistant; if it recurs >6 months after platinum therapy cessation, it is generally considered platinum-sensitive.124 For platinum-sensitive recurrence, re-treatment with a platinum-containing regimen should be considered.124 ASCO recommends combination chemotherapy with carboplatin, with or without bevacizumab, for the treatment of platinum-sensitive recurrent epithelial ovarian cancer.125 Maintenance therapy with a PARP inhibitor may be appropriate for some patients with platinum-sensitive recurrent disease (consult the ASCO guidelines on PARP inhibitor use in ovarian cancer for more information).126,  127 For platinum-resistant recurrence, platinum therapy is generally not useful.124 ASCO recommends single-agent non-platinum chemotherapy, with or without bevacizumab, for the treatment of platinum-resistant or platinum-refractory epithelial ovarian cancer.125

Hepatocellular Carcinoma

Bevacizumab is used in combination with atezolizumab for the treatment of unresectable or metastatic hepatocellular carcinoma in patients who have not received prior systemic therapy.1 Bevacizumab has been designated an orphan drug by FDA for this use.63

Clinical Experience

The indication for use of bevacizumab in the treatment of unresectable or metastatic hepatocellular carcinoma is based principally on the results of a randomized, multicenter, open-label trial (IMbrave150).1,  128,  129 The IMbrave150 study enrolled 501 patients with locally advanced unresectable and/or metastatic hepatocellular carcinoma who had not received prior systemic therapy.1,  128 Patients were excluded from the study if they had variceal bleeding within 6 months prior to the study, untreated or incompletely treated varices with bleeding, or high risk of bleeding; patients with Child-Pugh class B or C cirrhosis and patients with moderate to severe ascites were also excluded.1 Patients were randomized in a 2:1 ratio to receive atezolizumab (1200 mg IV every 3 weeks) plus bevacizumab (15 mg/kg IV every 3 weeks) or sorafenib (400 mg orally twice daily); treatment was continued until disease progression or unacceptable toxicity occurred.1,  128

The median age of patients in the IMbrave150 study was 65 years (range: 26-88 years); 83% of patients were male, and 57% of patients were Asian (40% of patients were from Asia, excluding Japan).1 Most patients had Barcelona Clinic Liver Cancer (BCLC) stage C disease at baseline (82%), and approximately 75% of patients presented with macrovascular invasion and/or extrahepatic spread.1 Median progression-free survival was prolonged with atezolizumab plus bevacizumab compared with sorafenib (6.8 versus 4.3 months, respectively).1,  128 Median overall survival was not estimable in the atezolizumab plus bevacizumab group and 13.2 months in the sorafenib group.1,  128 Based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, the overall response rate was 28% in the atezolizumab plus bevacizumab group and 12% in the sorafenib group; complete responses were achieved in 7 and 0% of patients in the atezolizumab plus bevacizumab and sorafenib groups, respectively.1 Based on the Modified RECIST Assessment for Hepatocellular Carcinoma, the overall response rate was 33% in the atezolizumab plus bevacizumab group and 13% in the sorafenib group; complete responses were achieved in 11 and 1.8% of patients in the atezolizumab plus bevacizumab and sorafenib groups, respectively.1 Duration of response (by both criteria) was not estimable in the atezolizumab plus bevacizumab group and 6.3 months in the sorafenib group.1 In a post-hoc updated analysis of overall survival, atezolizumab plus bevacizumab was found to prolong overall survival compared to sorafenib (median 19.2 months versus 13.4 months).129

Clinical Perspective

Guidelines for systemic therapy for advanced hepatocellular carcinoma have been published by ASCO.130 For first-line treatment of advanced hepatocellular carcinoma in patients with Child-Pugh class A liver disease and Easter Cooperative Oncology Group (ECOG) performance status of 0 or 1, atezolizumab plus bevacizumab or durvalumab plus tremelimumab may be offered.130 When choosing between these regimens, consider the risk of bleeding and thrombosis associated with bevacizumab.130 Sorafenib, lenvatinib, or durvalumab may also be offered as first-line treatment for these patients when there are contraindications to atezolizumab plus bevacizumab or durvalumab plus tremelimumab.130

A guideline on the treatment of hepatocellular carcinoma from the American Association for the Study of Liver Diseases (AASLD) provides similar recommendations, stating that atezolizumab plus bevacizumab or durvalumab plus tremelimumab are first-line therapies for advanced hepatocellular carcinoma in patients with Child-Pugh class A liver disease.131 In patients with contraindications to these therapies, AASLD recommends sorafenib or lenvatinib for first-line systemic treatment.131

Breast Cancer

First-line Treatment of Metastatic Breast Cancer

Although bevacizumab in combination with paclitaxel previously was labeled for use as first-line treatment of metastatic HER2-negative breast cancer †,   FDA rescinded approval for this indication on November 18, 2011;132 as a result, this indication no longer appears in bevacizumab's approved labeling.1 The AHFS Oncology Expert Committee concluded that use of bevacizumab in combination with paclitaxel for the first-line treatment of metastatic breast cancer currently is not fully established because of equivocal evidence; additional studies are needed to identify subgroups of patients who might derive clinical benefit from bevacizumab treatment.77

FDA Decisions Regarding Breast Cancer Indication

Bevacizumab (in combination with paclitaxel) received approval for use as first-line treatment of metastatic HER2-negative breast cancer in February 2008 under the principles and procedures of FDA's accelerated review process that allows approval based on analysis of surrogate markers of response (i.e., prolongation of progression-free survival) rather than clinical endpoints (e.g., prolongation of overall survival, amelioration of disease-related symptoms).54,  55,  65 Approval for this indication was based principally on the results of a single multicenter, open-label, randomized study (E2100) in which 722 patients received bevacizumab and paclitaxel or paclitaxel alone as first-line therapy for locally recurrent or metastatic breast cancer.15,  54,  55 Patients with HER2-overexpressing breast cancer were not eligible for the study unless they had received previous therapy with trastuzumab.15 Patients who had received hormonal therapy for metastatic disease or adjuvant therapy (chemotherapy or hormonal therapy) for breast cancer were eligible for the study.15 Patients who had received adjuvant taxane therapy were eligible for the study if they had completed treatment at least 12 months prior to entry to the study.15 Patients with CNS metastasis were excluded from the study.15 Treatment consisted of paclitaxel 90 mg/m² IV once weekly for 3 out of 4 weeks, with or without bevacizumab 10 mg/kg by IV infusion every 2 weeks, until disease progression or unacceptable toxicity occurred.15 Among patients randomized to receive the combination regimen in whom paclitaxel was withheld or discontinued, bevacizumab monotherapy was allowed to continue until disease progression or unacceptable toxicity occurred.15

Because study E2100 was open-label and included patients without measurable disease, efficacy data from a planned interim analysis were subjected to independent, retrospective, blinded review.76 Although some data points were missing, this analysis of interim data confirmed a higher response rate and a progression-free survival benefit (11.3 versus 5.8 months) for combined therapy with bevacizumab and paclitaxel compared with paclitaxel alone, and achieved 76-80% concordance with investigator assessments of individual patient results.76 Final analyses performed by the investigators indicated that patients receiving bevacizumab and paclitaxel had longer progression-free survival (11.8 versus 5.9 months), similar overall survival (26.7 versus 25.2 months), and a higher response rate (36.9 versus 21.2%) compared with those receiving paclitaxel alone as first-line therapy for metastatic breast cancer.15

As a condition of the accelerated approval process, the manufacturer of bevacizumab was required to submit data from 2 controlled clinical studies (AVADO and RIBBON1) to confirm the progression-free survival benefit that was observed with use of bevacizumab in study E2100 and to provide additional information regarding effects of the drug on overall survival of patients with metastatic HER2-negative breast cancer.54 In the AVADO study, 736 patients were randomized to receive bevacizumab (7.5 or 15 mg/kg) plus docetaxel (100 mg/m²) or docetaxel (100 mg/m²) plus placebo every 3 weeks as first-line therapy for metastatic or locally recurrent HER2-negative breast cancer; bevacizumab or placebo was continued until disease progression or unacceptable toxicity occurred, while docetaxel was administered for up to 9 cycles.39 In the RIBBON1 study, 1237 patients were randomized to receive either bevacizumab (15 mg/kg every 3 weeks) or placebo in conjunction with a taxane- or anthracycline-based regimen or in conjunction with capecitabine as first-line therapy for metastatic or locally recurrent HER2-negative breast cancer; treatment was continued until disease progression or unacceptable toxicity occurred.73

In the AVADO study, objective response rates were higher for patients receiving bevacizumab 7.5 or 15 mg/kg plus docetaxel (55.2 or 64.1%, respectively) compared with those receiving docetaxel alone (46.4%).39 Inclusion of bevacizumab in the treatment regimen prolonged median progression-free survival by 0.8-1.9 months but did not prolong overall survival.39 Among patients receiving bevacizumab 7.5 mg/kg plus docetaxel, bevacizumab 15 mg/kg plus docetaxel, or docetaxel alone, median progression-free survival was 9, 10.1, or 8.2 months, respectively, and median overall survival was 30.8, 30.2, or 31.9 months, respectively.39

In the RIBBON1 study, patients receiving bevacizumab in conjunction with capecitabine or in conjunction with a taxane- or anthracycline-based regimen had higher objective response rates and longer progression-free survival than did those receiving either capecitabine or a taxane- or anthracycline-based regimen alone; inclusion of bevacizumab in the treatment regimen did not significantly prolong overall survival.65,  73 Patients receiving bevacizumab and capecitabine had a higher objective response rate (35.4 versus 23.6%) and longer median progression-free survival (8.6 versus 5.7 months), but not a significantly longer median overall survival (25.7 versus 22.8 months), compared with patients receiving capecitabine alone.65,  73 Similarly, patients receiving bevacizumab in conjunction with a taxane- or anthracycline-based regimen had a higher objective response rate (51.3 versus 37.9%) and longer median progression-free survival (9.2 versus 8 months) compared with patients receiving a taxane- or anthracycline-based regimen alone; inclusion of bevacizumab in these regimens did not provide an overall survival benefit (hazard ratio of 1.11 favoring the use of a taxane- or anthracycline-based regimen.65,  73

On November 18, 2011, after reviewing submissions from the manufacturer and FDA's Center for Drug Evaluation and Research (CDER), recommendations from the FDA Oncologic Drugs Advisory Committee (ODAC), and public comments, the FDA Commissioner issued a final decision to rescind approval of bevacizumab for use in combination with paclitaxel as first-line treatment of metastatic HER2-negative breast cancer, citing 3 main reasons for the decision: lack of clinical benefit, unfavorable benefit-to-risk ratio, and lack of other compelling reasons (i.e., special circumstances) to support continued accelerated approval.65 In evaluating clinical benefit, the commissioner noted that confirmatory studies (AVADO and RIBBON1) failed to verify the magnitude of effect on progression-free survival observed in study E2100, and that none of the 5 studies submitted by the manufacturer (E2100, AVADO, RIBBON1, AVF2119g, RIBBON2) demonstrated an overall survival benefit or an improvement in quality of life.65 In evaluating the regimen's safety profile, it was noted that the addition of bevacizumab to chemotherapy resulted in an increased risk of severe (grade 3 or greater) adverse effects (e.g., neutropenia, sensory neuropathy, hypertension, febrile neutropenia, proteinuria, arterial thromboembolic events, left ventricular systolic dysfunction, hemorrhage, wound healing complications, fistula formation, GI perforation) that was considered unacceptable for a regimen that has not demonstrated clinical benefit.65 In evaluating special circumstances that may justify continuing accelerated approval (e.g., until clinical benefit is fully established or until a subset of patients likely to benefit from therapy is identified), the commissioner concluded that continuing an approval that is no longer supported by current data and allowing a substantial length of time for additional studies to be completed would be inconsistent with the protection of public health.65 The commissioner noted that because FDA does not regulate the practice of medicine, clinicians may continue to prescribe bevacizumab for the treatment of metastatic breast cancer (i.e., unlabeled [off-label] use) despite withdrawal of approval for this use.65

AHFS Oncology Expert Committee Decision Regarding Use as First-line Therapy

The AHFS Oncology Expert Committee was concerned that the E2100 study failed to demonstrate an overall survival benefit despite showing prolonged disease-free survival in patients receiving combined therapy with bevacizumab and paclitaxel, and also was concerned by the failure of the confirmatory studies (AVADO and RIBBON1) to verify the same magnitude of effect on progression-free survival as observed in the E2100 study.77 These studies provide a basis for assessing tolerability of bevacizumab in patients with previously untreated metastatic breast cancer, but the results provide equivocal evidence of the drug's efficacy for this use.77 In the absence of additional data, attempts to identify subgroups of patients in whom bevacizumab might provide clinical benefit (e.g., prolonged progression-free survival, prolonged overall survival, improved quality of life) and achieve a favorable benefit-to-risk ratio are speculative; additional studies are needed to identify subgroups of patients with previously untreated metastatic breast cancer who might derive clinical benefit from bevacizumab treatment.77 Therefore, the committee concluded that use of bevacizumab in combination with paclitaxel for the first-line treatment of metastatic breast cancer currently is not fully established because of equivocal evidence.77

Previously Treated Metastatic Breast Cancer

The efficacy and safety of bevacizumab for the treatment of metastatic breast cancer† previously treated with cytotoxic chemotherapy has been studied in several randomized studies.14,  74

The first study (AVF2119g) was an open-label, randomized study in which 462 patients received either bevacizumab and capecitabine or capecitabine alone.14,  75 Patients with metastatic breast cancer who had received prior therapy with both an anthracycline (or anthracenedione) and a taxane and had received 1 or 2 prior chemotherapy regimens for metastatic disease were eligible to enroll in the study; patients who relapsed within 12 months of completing adjuvant anthracycline (or anthracenedione) and taxane therapy also were eligible to enroll in the study without having received additional chemotherapy.14 Patients with HER2-overexpressing breast cancer were not eligible for the study unless their disease had progressed following treatment with trastuzumab.14 Patients with CNS disease and those who had received prior therapy with bevacizumab or capecitabine were excluded from the study.14,  75 The mean age of patients was about 51 years (range: 29-78 years), about 81% were white, 47% had estrogen receptor-positive disease, and 37% had progesterone receptor-positive disease.14 Treatment consisted of capecitabine (1.25 g/m² orally twice daily on days 1-14 of each 3-week cycle) given alone or in combination with bevacizumab (15 mg/kg by IV infusion on day 1 of each 3-week cycle) for a maximum of 35 cycles or until disease progression or unacceptable toxicity occurred.14 Patients without disease progression following 35 cycles of therapy could continue to receive their assigned treatment in an extension study.14 Patients randomized to receive bevacizumab and capecitabine could continue to receive bevacizumab either alone or in combination with other therapies following initial disease progression.14

Patients receiving bevacizumab and capecitabine had higher response rates (19.8 versus 9.1%) but similar median progression-free survival (4.86 versus 4.17 months) and overall survival (15.1 months versus 14.5 months) compared with those receiving capecitabine alone.14

The second study (AVF3693g, RIBBON2) was a double-blind, placebo-controlled trial evaluating safety and efficacy of bevacizumab in combination with taxanes (paclitaxel, albumin-bound paclitaxel, or docetaxel), capecitabine, gemcitabine, or vinorelbine as second-line therapy for locally recurrent or metastatic breast cancer in 684 patients who had received one prior cytotoxic chemotherapy regimen for metastatic disease.65,  74 Patients with HER2-overexpressing breast cancer, those with untreated CNS metastases, and those who had received prior therapy with bevacizumab or other vascular endothelial growth factor (VEGF) inhibitors were not eligible to enroll in the study.74 The median age of patients was 55 years (range: 23-90 years) and about 72% had hormone receptor-positive disease.74 Patients were randomized in a 2:1 ratio to receive either bevacizumab (15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks depending on the chemotherapy regimen) or placebo in combination with the investigator-selected chemotherapy regimen.74 Most patients received a taxane (44.4%), gemcitabine (23.4%), or capecitabine (21.1%).74 Bevacizumab could be continued until disease progression or unacceptable toxicity occurred, up to a maximum of 36 months of therapy; the chemotherapy regimen could be continued until disease progression or unacceptable toxicity occurred.74 If chemotherapy was discontinued before disease progression occurred, patients could continue receiving bevacizumab (or placebo, as assigned) as monotherapy.74

At a median follow-up of 15 months, combined therapy with bevacizumab and chemotherapy prolonged median progression-free survival (7.2 versus 5.1 months) but was not associated with an overall survival benefit compared with chemotherapy alone;65,  74 in patients receiving bevacizumab and chemotherapy, median overall survival was 18 months and the one-year survival rate was 69.5%, compared with 16.4 months and 66.2%, respectively, for those receiving chemotherapy alone.74 No significant difference in objective response rate was observed between patients receiving bevacizumab in combination with chemotherapy and those receiving chemotherapy alone (39.5 and 29.6%, respectively).74 Subgroup analysis showed that the progression-free survival benefit observed when bevacizumab and chemotherapy were given in combination was not uniform across all 4 chemotherapy regimens.74 When bevacizumab was used in combination with capecitabine, gemcitabine, or a taxane, median progression-free survival was prolonged by 0.5-2.8 months (depending on the regimen) compared with the chemotherapy regimen alone; however, when bevacizumab was used in combination with vinorelbine, median progression-free survival was 1.3 months shorter than when vinorelbine was used alone.74

Although combined therapy with bevacizumab and chemotherapy prolonged progression-free survival in the RIBBON2 study, the same benefit was not observed in the AVF2119g study;14,  74 in addition, combined therapy did not prolong overall survival in either study.14,  74 Therefore, usefulness of the drug in combination with chemotherapy for the treatment of metastatic breast cancer previously treated with cytotoxic chemotherapy is unclear.78 Use of bevacizumab in combination with chemotherapy for the treatment of metastatic breast cancer previously treated with cytotoxic chemotherapy currently is not fully established because of equivocal evidence.78

Other Uses

Bevacizumab has been used in combination with pemetrexed and cisplatin for the treatment of malignant pleural mesothelioma†.137,  138 Guidelines from ASCO state that pemetrexed plus platinum-based chemotherapy, with or without bevacizumab, may be offered as a first-line systemic therapy for patients with epithelioid histology; chemotherapy should not be offered to patients with nonepithelioid histology who have not received any prior systemic therapy, unless there are contraindications to first-line immunotherapy.138 In patients who have received first-line immunotherapy, pemetrexed plus platinum chemotherapy, with or without bevacizumab, may be offered as an initial chemotherapy treatment option.138

Intravitreal injection† of bevacizumab has been used for the treatment of neovascular age-related macular degeneration†.41,  85,  86,  87,  88,  89,  133,  134,  135 Results of several randomized controlled studies suggest that intravitreal bevacizumab has similar efficacy as ranibizumab in improving visual acuity.41,  87,  88,  89,  133,  134 In one study, the incidence of serious systemic adverse effects (primarily hospitalizations) appeared to be higher with bevacizumab compared with ranibizumab;41 however, other studies, including a systematic review of 9 randomized controlled studies, directly comparing intravitreal injections of bevacizumab and ranibizumab in patients with neovascular age-related macular degeneration have found no such difference.87,  88 The American Academy of Ophthalmology recommends intravitreal injections of anti-VEGF agents (including bevacizumab) as first-line therapy for neovascular age-related macular degeneration.135

Intravitreal injection† of bevacizumab also has been used for the treatment of diabetic macular edema†.81,  83,  84 Results of a study comparing intravitreal ranibizumab, aflibercept, and bevacizumab for the treatment of diabetic macular edema suggest that the relative treatment effect of these drugs may be dependent upon a patient's baseline visual acuity.83,  84 The American Academy of Ophthalmology states that intravitreal anti-VEGF agents (including bevacizumab) are recommended first-line for the treatment of center-involved diabetic macular edema with vision loss.136

General

Patient Monitoring

• Evaluate patients with hepatocellular carcinoma for varices within 6 months of treatment initiation.1
• Monitor blood pressure every 2-3 weeks during treatment; continue monitoring at regular intervals after treatment discontinuation in patients with bevacizumab-induced or -exacerbated hypertension.1
• Monitor proteinuria with serial dipstick urinalyses during treatment; perform 24-hour urine collection for further assessment in patients with a 2+ or greater urine dipstick reading.1

Other General Considerations

• Do not administer within 28 days prior to elective surgery.1
• Do not administer for at least 28 days following major surgery, until adequate wound healing occurs.1

Administration

Bevacizumab products are administered by IV infusion.1,  90,  91,  92,  93

Bevacizumab products are commercially available in single-dose vials at a concentration of 25 mg/mL.1,  90,  91,  92,  93

For IV infusion, the appropriate dose of the bevacizumab product should be withdrawn into a syringe and diluted in a total volume of 100 mL of 0.9% sodium chloride using aseptic technique.1,  90,  91,  92,  93 Bevacizumab product infusions should not be administered or mixed with dextrose solutions.1,  90,  91,  92,  93 Any unused portion left in the vial should be discarded since the injection contains no preservative.1,  90,  91,  92,  93

The initial dose of bevacizumab products should be infused over 90 minutes; if the first infusion is tolerated, the second dose may be infused over 60 minutes.1,  90,  91,  92,  93 If this second infusion also is tolerated, all subsequent doses may be infused over 30 minutes.1,  90,  91,  92,  93 One institution has reported use of shorter infusion times for bevacizumab at an infusion rate of 0.5 mg/kg per minute.43

The manufacturers state that no incompatibilities have been observed between originator bevacizumab, bevacizumab-awwb (Mvasi^®), bevacizumab-bvzr (Zirabev^®), or bevacizumab-maly (Alymsys^®) and polyvinylchloride or polyolefin bags.1,  90,  91,  93 No incompatibilities have been observed between bevacizumab-adcd (Vegzelma^®) and polyolefin (polypropylene and polyethylene) bags.92

Bevacizumab product vials should be protected from light and stored in the original carton at 2-8°C until use; freezing should be avoided.1,  90,  91,  92,  93 The injection should not be shaken prior to use.1,  90,  91,  92,  93 Once diluted, originator bevacizumab and bevacizumab-awwb (Mvasi^®) may be stored at 2-8°C for up to 8 hours, bevacizumab-maly (Alymsys^®) may be stored at 2-8°C for up to 12 hours, and bevacizumab-bvzr (Zirabev^®) may be stored at 2-8°C for up to 16 days.1,  90,  91,  93 Diluted bevacizumab-adcd (Vegzelma^®) may be stored at 2-8°C for up to 24 hours or at room temperature (up to 30°C) for up to 4 hours.92

Dosage

Colorectal Cancer

For the first- or second-line treatment of metastatic colorectal cancer, the dosage of bevacizumab or biosimilars (bevacizumab-adcd, bevacizumab-awwb, bevacizumab-bvzr, and bevacizumab-maly) depends on the concomitant chemotherapy regimen.1,  90,  91,  92,  93 When administered in combination with IFL (IV irinotecan/fluorouracil/leucovorin), the dosage of bevacizumab or biosimilars is 5 mg/kg by IV infusion every 2 weeks.1,  90,  91,  92,  93 When administered in combination with FOLFOX4 (IV fluorouracil/leucovorin and oxaliplatin), the dosage of bevacizumab or biosimilars is 10 mg/kg by IV infusion every 2 weeks.1,  90,  91,  92,  93

When administered in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for the second-line treatment of metastatic colorectal cancer in patients who have progressed on a first-line bevacizumab product-containing regimen, the dosage of bevacizumab or biosimilars is 5 mg/kg by IV infusion every 2 weeks or 7.5 mg/kg by IV infusion every 3 weeks.1,  90,  91,  92,  93

Non-small Cell Lung Cancer

For the first-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous non-small cell lung cancer in combination with carboplatin and paclitaxel, the recommended dosage of bevacizumab or biosimilars (bevacizumab-adcd, bevacizumab-awwb, bevacizumab-bvzr, and bevacizumab-maly) is 15 mg/kg by IV infusion every 3 weeks.1,  90,  91,  92,  93

Glioblastoma

For the treatment of recurrent glioblastoma in adults, the recommended dosage of bevacizumab or biosimilars (bevacizumab-adcd, bevacizumab-awwb, bevacizumab-bvzr, and bevacizumab-maly) is 10 mg/kg by IV infusion every 2 weeks.1,  90,  91,  92,  93

Renal Cell Carcinoma

For the treatment of metastatic renal cell carcinoma in adults, the recommended dosage of bevacizumab or biosimilars (bevacizumab-adcd, bevacizumab-awwb, bevacizumab-bvzr, and bevacizumab-maly) is 10 mg/kg by IV infusion every 2 weeks when used in combination with interferon alfa.1,  90,  91,  92,  93

Cervical Cancer

For the treatment of persistent, recurrent, or metastatic cervical cancer, the recommended dosage of bevacizumab or biosimilars (bevacizumab-adcd, bevacizumab-awwb, bevacizumab-bvzr, and bevacizumab-maly) is 15 mg/kg IV every 3 weeks in combination with paclitaxel and cisplatin or paclitaxel and topotecan.1,  90,  91,  92,  93

Ovarian Cancer

For the treatment of stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection, the recommended dosage of bevacizumab or biosimilars (bevacizumab-adcd, bevacizumab-awwb, and bevacizumab-bvzr) is 15 mg/kg by IV infusion every 3 weeks in combination with carboplatin and paclitaxel for up to 6 cycles, followed by 15 mg/kg every 3 weeks as a single agent for a total of up to 22 cycles (or until disease progression, whichever occurs first).1,  91,  92,  93

For the treatment of platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who received no more than 2 prior chemotherapy regimens, the recommended dosage of bevacizumab or biosimilars (bevacizumab-adcd, bevacizumab-awwb, bevacizumab-bvzr, and bevacizumab-maly) depends on the concomitant chemotherapy regimen.1,  90,  91,  92,  93 When used in combination with paclitaxel, pegylated liposomal doxorubicin, or weekly topotecan, the recommended dosage of bevacizumab or biosimilars is 10 mg/kg by IV infusion every 2 weeks.1,  90,  91,  92,  93 When used in combination with an every-3-week regimen of topotecan, the recommended dosage of bevacizumab or biosimilars is 15 mg/kg by IV infusion every 3 weeks.1,  90,  91,  92,  93

For the treatment of platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, the recommended dosage of bevacizumab or biosimilars (bevacizumab-adcd, bevacizumab-awwb, and bevacizumab-bvzr) depends on the concomitant chemotherapy regimen.1,  91,  92,  93 When used in combination with carboplatin and paclitaxel, the recommended dosage of bevacizumab or biosimilars is 15 mg/kg IV every 3 weeks in combination with carboplatin and paclitaxel for 6-8 cycles; then, bevacizumab or its biosimilar should be administered as a single agent at a dosage of 15 mg/kg by IV infusion every 3 weeks until disease progression.1,  91,  92,  93 When used in combination with carboplatin and gemcitabine, the recommended dosage of bevacizumab or biosimilars is 15 mg/kg by IV infusion every 3 weeks in combination with carboplatin and gemcitabine for 6-10 cycles; then, bevacizumab or its biosimilar should be administered as a single agent at a dosage of 15 mg/kg by IV infusion every 3 weeks until disease progression.1,  91,  92,  93

Hepatocellular Carcinoma

For the treatment of unresectable or metastatic hepatocellular carcinoma in patients who have not received prior systemic therapy, the recommended dosage of bevacizumab is 15 mg/kg by IV infusion after administration of 1200 mg of IV atezolizumab on the same day, every 3 weeks until disease progression or unacceptable toxicity occurs.1 Consult the prescribing information for atezolizumab for additional recommended dosage information.1 Bevacizumab biosimilars are not labeled for this use.

Dosage Modifications for Toxicity

Bevacizumab product dosage reductions are not recommended in any patient; instead, the drug generally should either be temporarily suspended or permanently discontinued, according to causality (see Table 2).1,  90,  91,  92,  93

Special Populations

Hepatic Impairment

The manufacturers make no specific dosage recommendations for patients with hepatic impairment.1,  90,  91,  92,  93

Renal Impairment

The manufacturers make no specific dosage recommendations for patients with renal impairment.1,  90,  91,  92,  93

Geriatric Patients

The manufacturers make no specific dosage recommendations for geriatric patients.1,  90,  91,  92,  93

Contraindications

• None.1

Warnings/Precautions

GI Perforations and Fistulae

Severe GI perforation, sometimes fatal, occurs more frequently in patients receiving bevacizumab than in those receiving chemotherapy.1 GI perforation has been reported in 0.3-3% of patients receiving bevacizumab in clinical studies, with the highest incidence in patients with a history of prior pelvic radiation.1 GI perforation can be complicated by intra-abdominal abscess, fistula formation, and the need for diverting ostomies.1 The majority of cases occurred within the first 50 days of initiation of bevacizumab.1

Serious fistulae (including at tracheo-esophageal, bronchopleural, biliary, vaginal, renal, and bladder sites) occurred more frequently in patients receiving bevacizumab compared with those receiving chemotherapy.1 Incidence of fistulae ranged from <1 to 1.8% across clinical studies, with the highest incidence in patients with cervical cancer.1 Fistulae typically occurred during the first 6 months of bevacizumab therapy.1 Patients who develop a GI-vaginal fistula may also have a bowel obstruction and require surgical intervention, as well as a diverting ostomy.1

Avoid bevacizumab use in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination, bowel involvement on CT scan, or clinical symptoms of bowel obstruction.1 Bevacizumab should be permanently discontinued in patients who develop GI perforation, tracheo-esophageal fistula, any grade 4 fistula, or any fistula involving an internal organ.1

Surgery and Wound Healing Complications

In a controlled clinical study of metastatic colorectal cancer patients in whom bevacizumab was not administered within 28 days of major surgical procedures, wound healing complications, including serious and fatal complications, occurred in 15% of patients who underwent surgery while receiving bevacizumab compared with 4% of patients who underwent surgery and did not receive bevacizumab.1 In a controlled clinical study of patients with relapsed or recurrent glioblastoma, the incidence of wound healing complications was 5% in patients who received bevacizumab compared with 0.7% in patients who did not receive bevacizumab.1

Bevacizumab therapy should not be administered for at least 28 days following major surgery; it should only be administered after adequate wound healing has occurred.1 The manufacturer additionally recommends that bevacizumab be withheld at least 28 days prior to elective surgery.1 If wound healing complications occur during therapy, bevacizumab should be withheld until adequate wound healing has occurred.1 The safety of resuming bevacizumab after resolution of wound healing complications has not been established.1

Necrotizing fasciitis has been reported in patients receiving bevacizumab, including fatal cases.1 This is usually secondary to wound healing complications, GI perforation, or fistula formation.1 Bevacizumab should be discontinued in patients who develop necrotizing fasciitis.1

Hemorrhage

Severe or fatal hemorrhages, including hemoptysis, GI bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding, occurred up to fivefold more frequently in patients receiving bevacizumab than in those receiving chemotherapy alone.1

Grade 3 or greater hemorrhagic events have been reported in 0.4-7% of patients receiving bevacizumab in clinical studies.1 Serious or fatal pulmonary hemorrhage occurred in 31% of patients with squamous non-small cell lung cancer and 4% of patients with nonsquamous non-small cell lung cancer receiving bevacizumab with chemotherapy compared with 0% of patients receiving chemotherapy alone.1

Minor hemorrhagic events also have been reported more frequently in patients receiving bevacizumab.1 Grade 1 epistaxis was the most common minor hemorrhagic event reported in clinical studies.1

The manufacturer recommends an evaluation for the presence of varices within 6 months of bevacizumab initiation in patients with hepatocellular carcinoma.1 There is a lack of clinical data to support the safety of bevacizumab in hepatocellular carcinoma patients with variceal bleeding within 6 months prior to treatment, untreated or incompletely treated varices with bleeding, or high risk of bleeding since such patients were excluded from clinical trials.1

Patients with a history of recent hemoptysis (0.5 teaspoon of red blood or more) should not receive bevacizumab.1 Bevacizumab should be permanently discontinued in patients who develop grade 3 or 4 hemorrhage.1

Arterial Thromboembolic Events

Severe, sometimes fatal, arterial thromboembolic events (e.g., cerebral infarction, transient ischemic attacks [TIAs], myocardial infarction [MI], angina) occurred at a higher incidence in patients receiving bevacizumab compared with those receiving chemotherapy.1 Across clinical studies, grade 3 or greater arterial thromboembolic events have been reported in 5% of patients receiving bevacizumab in combination with chemotherapy compared with ≤2% of those receiving chemotherapy alone.1 The highest incidence occurred in patients with glioblastoma.1 The risk of arterial thromboembolic events in patients receiving bevacizumab in combination with chemotherapy was also increased in patients with a history of arterial thromboembolism, patients with diabetes, and patients older than 65 years of age.1

Bevacizumab should be permanently discontinued in patients who experience a severe arterial thromboembolic event.1 Whether bevacizumab therapy can be safely resumed following resolution of an arterial thromboembolic event has not been studied.1

Venous Thromboembolic Events

Venous thromboembolic events occurred more often in patients receiving bevacizumab with chemotherapy than in those receiving chemotherapy alone.1 In the GOG-0240 study, grade 3-4 venous thromboembolic events occurred in 11% of patients receiving bevacizumab plus chemotherapy and 5% of patients receiving chemotherapy alone.1 In the EORTC 26101 trial, grade 3-4 venous thromboembolic events occurred in 5% of patients receiving bevacizumab plus chemotherapy and 2% of patients receiving chemotherapy alone.1

Bevacizumab should be permanently discontinued in patients with a grade 4 venous thromboembolic event, including pulmonary embolism.1

Hypertension

The incidence of severe hypertension was increased in patients receiving bevacizumab compared with those receiving chemotherapy alone.1 Grade 3 or 4 hypertension occurred in 5-18% of patients receiving bevacizumab in clinical studies.1

Blood pressure should be monitored every 2-3 weeks during bevacizumab therapy.1 If hypertension occurs, patients should be treated with appropriate antihypertensive therapy, and blood pressure should be monitored regularly.1 Blood pressure monitoring should continue at regular intervals in patients with bevacizumab-induced or -exacerbated hypertension after discontinuing the drug.1

Temporary withholding of bevacizumab therapy is recommended in patients with severe hypertension that is not controlled with medical management; bevacizumab may be resumed once hypertension has been controlled.1 Bevacizumab should be permanently discontinued in patients who develop hypertensive crisis or hypertensive encephalopathy.1

Posterior Reversible Encephalopathy Syndrome

Posterior reversible encephalopathy syndrome (PRES) has occurred in patients receiving bevacizumab.1 This complication occurred in less than 0.5% of patients receiving bevacizumab in clinical studies.1

PRES is a neurological disorder that can present with headache, seizures, lethargy, confusion, blindness, and other visual and neurologic disturbances.1 Mild to severe hypertension also may occur.1 Magnetic resonance imaging is necessary to confirm the diagnosis of PRES.1 The onset of symptoms has occurred from 16 hours to 1 year after initiation of bevacizumab therapy.1

If PRES develops, bevacizumab should be permanently discontinued.1 Symptoms of PRES usually lessen or resolve within days of discontinuance of bevacizumab, but some patients have experienced ongoing neurologic sequelae.1 The safety of reinitiating bevacizumab therapy in patients who developed PRES is not known.1

Renal Injury and Proteinuria

Increased incidence and severity of proteinuria have been reported in patients receiving bevacizumab compared to patients receiving chemotherapy.1 Grade 3 (defined as urine dipstick 4+ or >3.5 g of protein in the urine collected over 24 hours) to grade 4 (defined as nephrotic syndrome) proteinuria occurred in 0.7-7% of patients receiving bevacizumab in clinical studies.1 In the BO17705 trial, proteinuria (all grades) was reported in 20% of those receiving bevacizumab.1 In this study, the median onset of proteinuria was 5.6 months (range: 15 days to 37 months) after initiation of bevacizumab; median time to resolution was 6.1 months.1 Proteinuria did not resolve in 40% of patients after a median follow-up of 11.2 months, and 30% of patients with proteinuria required permanent discontinuance of bevacizumab.1 In an exploratory pooled analysis of patients from 7 randomized clinical studies, 5% of patients receiving bevacizumab plus chemotherapy experienced grade 2-4 proteinuria (defined as urine dipstick 2+ or greater or >1 g of protein per 24 hours, or nephrotic syndrome).1 Proteinuria resolved in 74% of patients, and bevacizumab was reinitiated in 42% of patients.1 Of the patients who reinitiated bevacizumab, 48% experienced a second episode of grade 2-4 proteinuria.1

Nephrotic syndrome, sometimes fatal, occurred in less than 1% of patients receiving bevacizumab in clinical studies.1 In a published case series, kidney biopsy of 6 patients with proteinuria showed findings consistent with thrombotic microangiopathy.1 Results of a retrospective analysis of 5805 patients who received bevacizumab plus chemotherapy and 3713 patients who received chemotherapy alone showed higher rates of elevated serum creatinine levels (1.5-1.9 times baseline levels) in patients who received bevacizumab.1 Serum creatinine levels did not return to baseline in approximately one-third of patients who received bevacizumab.1

Patients receiving bevacizumab should be monitored via dipstick urine analysis for the development or worsening of proteinuria, with serial urinalyses during bevacizumab therapy.1 Patients with a 2+ or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection.1

Bevacizumab therapy should be interrupted for proteinuria of or exceeding 2 g per 24 hours and resumed when proteinuria declines below this level.1

Bevacizumab should be permanently discontinued in patients who develop nephrotic syndrome.1

Data from a postmarketing safety study showed poor correlation between urine protein/creatinine ratio (UPCR) and 24-hour urine protein.1

Infusion-related Reactions

In clinical studies, infusion-related reactions with the first bevacizumab dose were uncommon (occurring in less than 3% of patients).1 Severe infusion-related reactions occurred in 0.4% of patients receiving the drug.1 Infusion-related reactions reported with bevacizumab include hypertension, hypertensive crises associated with neurologic manifestations, wheezing, oxygen desaturation, grade 3 hypersensitivity, anaphylactoid/anaphylactic reactions, chest pain, headaches, rigors, and diaphoresis.1

Initial doses of bevacizumab should be infused slowly; if tolerated, the rate of IV infusion may be increased during administration of subsequent doses.1

For mild, clinically insignificant infusion-related reactions, the rate of bevacizumab infusion should be decreased.1 For clinically significant infusion-related reactions, the infusion should be interrupted; upon resolution, resuming the infusion at a slower rate may be considered.1 If a severe infusion-related reaction occurs, the infusion should be discontinued, and appropriate medical therapy (e.g., epinephrine, corticosteroids, IV antihistamines, bronchodilators and/or oxygen) initiated.1

Fetal/Neonatal Morbidity and Mortality

Based on its mechanism of action and findings from animal studies, bevacizumab may cause fetal harm when administered to pregnant women.1 When bevacizumab was administered to pregnant rabbits every 3 days during the period of organogenesis at a dosage as low as a clinical dosage of 10 mg/kg, congenital malformations were observed.1 Animal models also link angiogenesis, vascular endothelial growth factor (VEGF), and vascular endothelial growth factor receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development.1

Advise pregnant women of the potential risk to a fetus.1 Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of bevacizumab.1

Ovarian Failure

Ovarian failure has been reported more frequently in premenopausal women receiving bevacizumab with chemotherapy (34%) compared with those receiving chemotherapy alone (2%) for adjuvant treatment of a solid tumor.1 Following discontinuance of bevacizumab, recovery of ovarian function occurred in 22% of patients.1 The long-term effects of bevacizumab exposure on fertility are unknown.1 Females of reproductive potential should be informed of the risk of ovarian failure prior to initiating bevacizumab therapy.1

Congestive Heart Failure

Congestive heart failure has been reported in patients receiving bevacizumab.1 Grade 3 or greater left ventricular dysfunction was reported in 1% of patients receiving bevacizumab in clinical studies, compared to 0.6% of patients receiving chemotherapy alone.1 Among patients who had received prior anthracycline treatment, the rate of congestive heart failure was 4% for patients receiving bevacizumab with chemotherapy compared to 0.6% in patients receiving chemotherapy alone.1

In previously untreated patients with a hematological malignancy, congestive heart failure and decline in left ventricular ejection fraction were more common in patients receiving bevacizumab with anthracycline-based chemotherapy compared to patients receiving placebo with the same chemotherapy regimen.1 Time to onset of left ventricular dysfunction or congestive heart failure was 1-6 months after the first dose of bevacizumab in the majority of patients.1 The condition resolved in 62% of the patients who developed congestive heart failure in the bevacizumab arm of the study compared to 82% of patients in the placebo arm.1 Bevacizumab is not indicated for use with anthracycline-based chemotherapy.1

Bevacizumab should be discontinued in patients who develop congestive heart failure.1

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity.1 In clinical studies for adjuvant treatment of a solid tumor, 0.6% (14/2233) of patients tested positive for treatment-emergent anti-bevacizumab antibodies; among these patients, 3 patients tested positive for neutralizing antibodies against bevacizumab.1 The clinical significance of these antibodies is not known.1

Specific Populations

Pregnancy

Based on its mechanism of action and findings from animal studies, bevacizumab may cause fetal harm when administered to pregnant women.1 Limited postmarketing reports describe cases of fetal malformations with use of bevacizumab in pregnancy; however, these reports are insufficient to determine drug-associated risks.1 When bevacizumab was administered IV to pregnant rabbits every 3 days during the period of organogenesis at dosages approximately 1-10 times the clinical dosage of 10 mg/kg, fetal resorptions, decreased maternal and fetal weight gain, and multiple congenital malformations, including corneal opacities and abnormal ossification of the skull and skeleton (including limb and phalangeal defects), were observed.1 Animal models also link angiogenesis, VEGF, and VEGFR2 to critical aspects of female reproduction, embryofetal development, and postnatal development.1

Advise pregnant women of the potential risk to a fetus.1

Lactation

It is not known whether bevacizumab is distributed into milk.1 Human immunoglobulin G₁ (IgG₁) is distributed into milk; however, published data suggest that antibodies in breast milk do not enter the neonatal and infant circulation in substantial amounts.1 The effects of bevacizumab on the breast-fed infant and on milk production also are unknown.1 Because of the potential for serious adverse reactions in nursing infants, advise women not to breast-feed during treatment with bevacizumab and for 6 months after the last dose.1

Females and Males of Reproductive Potential

Bevacizumab may cause fetal harm when administered to pregnant women.1 Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of bevacizumab.1

Bevacizumab may increase the risk of ovarian failure and may impair fertility.1 In a clinical study of 179 premenopausal women, the incidence of ovarian failure was higher in patients who received bevacizumab plus chemotherapy than in patients who received chemotherapy alone (34 versus 2%, respectively).1 After discontinuing bevacizumab with chemotherapy, ovarian function recovered in 22% of these patients.1 Long-term effects of bevacizumab on fertility are unknown.1 Inform females of reproductive potential of the risk of ovarian failure prior to the first dose of bevacizumab.1

Pediatric Use

Safety and efficacy of bevacizumab have not been established in pediatric patients younger than 18 years of age.1

Addition of bevacizumab to standard of care did not improve event-free survival in pediatric patients with high-grade glioma, metastatic rhabdomyosarcoma, or non-rhabdomyosarcoma soft tissue sarcoma in 2 clinical studies.1 Antitumor activity was also not observed in 8 pediatric patients who received bevacizumab plus irinotecan for relapsed glioblastoma.1 Non-mandibular osteonecrosis has been reported in pediatric patients younger than 18 years of age who have received bevacizumab.1

Based on a population pharmacokinetic analysis of data from 152 pediatric and young adult patients with cancer (age range: 7 months to 21 years of age), the clearance of bevacizumab normalized by body weight in the pediatric patients was comparable to that in adults.1

Geriatric Use

Analysis of pooled data from 5 randomized controlled trials involving 1745 patients (35% were 65 years of age or older) showed that arterial thromboembolic events occurred more frequently in all patients receiving bevacizumab with chemotherapy compared with those receiving chemotherapy alone, regardless of age.1 However, the increase in the incidence of arterial thromboembolic events associated with concomitant bevacizumab therapy was greater in patients 65 years of age or older (8 versus 3%) compared with those younger than 65 years of age (2 versus 1%).1

Hepatic Impairment

The manufacturer does not provide any specific information regarding bevacizumab use in patients with hepatic impairment.1

Renal Impairment

The manufacturer does not provide any specific information regarding bevacizumab use in patients with renal impairment.1

Common Adverse Effects

Adverse effects reported in more than 10% of patients receiving bevacizumab (alone or with chemotherapy) include epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.1

Carboplatin

Pharmacokinetic interaction is unlikely (no clinically important effect on pharmacokinetics of carboplatin).1

Interferon Alfa

Pharmacokinetic interaction is unlikely (no clinically important effect on pharmacokinetics of interferon alfa).1

Irinotecan

Pharmacokinetic interaction is unlikely (no clinically important effect on pharmacokinetics of irinotecan or the active metabolite of irinotecan [SN38]).1

Paclitaxel

No clinically meaningful effect on the pharmacokinetics of paclitaxel was observed when bevacizumab was administered in combination with paclitaxel.1 However, limited data indicate that paclitaxel exposure after 4 treatment cycles decreased in patients receiving bevacizumab with paclitaxel and carboplatin (lower paclitaxel exposure observed on day 63 than on day 0) compared with patients receiving carboplatin and paclitaxel alone (higher paclitaxel exposure observed on day 63 than on day 0).1

Description

Bevacizumab, a recombinant humanized monoclonal antibody, is an antineoplastic agent.1 The drug is an IgG₁ antibody that contains human framework regions and murine complementarity-determining regions.1

Bevacizumab binds to human vascular endothelial growth factor (VEGF) and prevents interaction of VEGF with its receptors (Flt-1, KDR) on the surface of endothelial cells.1 In vitro models of angiogenesis have shown that interaction of VEGF with its receptors may lead to endothelial cell proliferation and new blood vessel formation.1 Evidence from animal models has suggested that administration of bevacizumab may reduce microvascular growth of tumors and inhibit metastatic disease progression.1

Bevacizumab pharmacokinetics are linear, and the predicted time to reach >90% of steady-state concentration is 84 days.1 The accumulation ratio following a dose of 10 mg/kg once every 2 weeks is 2.8.1 The estimated half-life of bevacizumab is 20 days.1 Clearance of bevacizumab is influenced by body weight, sex, and tumor burden.1 After correcting for body weight, males had a higher bevacizumab clearance and larger central volume of distribution than females.1 Patients with a higher tumor burden also had higher bevacizumab clearance than patients with a lower tumor burden.1

Advice to Patients

• Advise patients of the increased risk for GI perforation and fistula, and instruct them to immediately contact their clinician if they develop high fever, rigors, persistent or severe abdominal pain, severe constipation, or vomiting.1
• Inform patients of the increased risk of wound healing complications, and advise them not to undergo surgery without first discussing this potential risk with their clinician.1
• Inform patients of the increased risk of hemorrhage, and advise them to immediately contact their clinician if signs and symptoms of serious or unusual bleeding (including coughing or spitting blood) develop.1
• Inform patients of the increased risk for arterial and venous thromboembolic events, and advise patients to immediately contact their clinician if they develop signs and symptoms of arterial or venous thromboembolism.1
• Inform patients of the increased risk for hypertension, and advise them that they will need to undergo routine blood pressure monitoring during therapy.1 Advise patients to contact their clinician if they experience changes in blood pressure.1
• Inform patients of the risk for posterior reversible encephalopathy syndrome (PRES), and advise patients to immediately contact their clinician for new onset or worsening neurological function.1
• Inform patients of the increased risk for proteinuria and renal injury, including nephrotic syndrome.1 Advise patients that they will need to have their renal function monitored regularly during therapy, and instruct them to contact their clinician for proteinuria or signs or symptoms of nephrotic syndrome.1
• Inform patients of the risk for infusion-related reactions, and advise them to immediately contact their clinician if signs or symptoms of infusion-related reactions develop.1
• Inform patients of the risk for developing congestive heart failure, and advise them to immediately contact their clinician if signs and symptoms of congestive heart failure develop.1
• Advise female patients that bevacizumab may cause fetal harm and to inform their clinician of any known or suspected pregnancy.1 Advise females of reproductive potential to use effective contraception during bevacizumab therapy and for 6 months after the last dose.1
• Advise females that bevacizumab may cause ovarian failure, and advise them of potential options for preservation of ova prior to starting treatment.1
• Advise women to inform their clinician if they plan to breast-feed.1 Advise women not to breast-feed during treatment with bevacizumab and for 6 months after the last dose.1
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.1
• Advise patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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