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Bevacizumab-nwgd is a vascular endothelial growth factor inhibitor. Bevacizumab-nwgd is a recombinant humanized monoclonal IgG1 antibody that contains humanframework regions and murine complementarity-determining regions. Bevacizumab-nwgd has an approximate molecular weight of 149 kDa. Bevacizumab-nwgd isproduced in a mammalian cell (Chinese Hamster Ovary) expression system.
Jobevne (bevacizumab-nwgd) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale brown solution in a single-dose vial for intravenoususe. Jobevne contains bevacizumab-nwgd at a concentration of 25 mg/mL in either a 100 mg/4 mL or 400 mg/16 mL single-dose vial.
Each mL of solution contains 25 mg bevacizumab-nwgd, dibasic sodium phosphate (1.2 mg), monobasic sodium phosphate (4.5 mg), polysorbate 20 (0.4 mg), trehalose(54.3 mg) and Water for Injection, USP. Sodium hydroxide and phosphoric acid may be used to adjust pH to 6.2 during manufacturing.
Jobevne, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first-or second-line treatment of patients with metastatic colorectalcancer (mCRC).
Jobevne, in combination with fluoropyrimidine-irinotecan-or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product-containing regimen.
Jobevne is not indicated for adjuvant treatment of colon cancer [see Clinical Studies].
Jobevne, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastaticnon–squamous non–small cell lung cancer (NSCLC).
Jobevne is indicated for the treatment of recurrent glioblastoma (GBM) in adults.
Jobevne, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell carcinoma (mRCC).
Jobevne, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastaticcervical cancer.
Jobevne, in combination with carboplatin and paclitaxel, followed by Jobevne as a single agent, is indicated for the treatment of patients with stage III or IV epithelialovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection.
Jobevne, in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan, is indicated for the treatment of patients with platinum-resistant recurrentepithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens.
Jobevne, in combination with carboplatin and paclitaxel, or with carboplatin and gemcitabine, followed by Jobevne as a single agent, is indicated for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.
Withhold for at least 28 days prior to elective surgery. Do not administer Jobevne until at least 28 days following major surgery and until adequate wound healing.
The recommended dosage when Jobevne is administered in combination with intravenous fluorouracil-based chemotherapy is:
The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with carboplatin and paclitaxel.
The recommended dosage is 10 mg/kg intravenously every 2 weeks.
The recommended dosage is 10 mg/kg intravenously every 2 weeks in combination with interferon alfa.
The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with paclitaxel and cisplatin or in combination with paclitaxel and topotecan.
The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with carboplatin and paclitaxel for up to 6 cycles, followed by Jobevne 15 mg/kgevery 3 weeks as a single agent for a total of up to 22 cycles or until disease progression, whichever occurs earlier.
Platinum Resistant
The recommended dosage is 10 mg/kg intravenously every 2 weeks in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan (every week).
The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with topotecan (every 3 weeks).
Platinum Sensitive
The recommended dosage is 15 mg/kg intravenously every 3 weeks, in combination with carboplatin and paclitaxel for 6 to 8 cycles, followed by Jobevne 15 mg/kgevery 3 weeks as a single agent until disease progression.
The recommended dosage is 15 mg/kg intravenously every 3 weeks, in combination with carboplatin and gemcitabine for 6 to 10 cycles, followed by Jobevne 15 mg/kgevery 3 weeks as a single agent until disease progression.
Table 1 describes dosage modifications for specific adverse reactions . No dose reductions for Jobevne are recommended.
Table 1: Dosage Modifications for Adverse Reactions
| Adverse Reaction | Severity | Dosage Modification |
| Gastrointestinal Perforations and Fistulae [see WARNINGS AND PRECAUTIONS]. |
|
Discontinue Jobevne |
| Wound Healing Complications [see WARNINGS AND PRECAUTIONS]. |
|
Withhold Jobevne until adequate wound healing. The safety of resumption of bevacizumab products after resolution of wound healing complications has not been established |
|
Discontinue Jobevne | |
| Hemorrhage [see WARNINGS AND PRECAUTIONS)]. |
|
Discontinue Jobevne |
|
Withhold Jobevne | |
| Thromboembolic Events [see WARNINGS AND PRECAUTIONS]. |
|
Discontinue Jobevne |
|
Discontinue Jobevne | |
| Hypertension [see WARNINGS AND PRECAUTIONS]. |
|
Discontinue Jobevne |
|
Withhold Jobevne until controlled with medical management; resume once controlled | |
| Posterior Reversible Encephalopathy Syndrome (PRES) [see WARNINGS AND PRECAUTIONS]. |
|
Discontinue Jobevne |
| Renal Injury and Proteinuria [see WARNINGS AND PRECAUTIONS]. |
|
Discontinue Jobevne |
|
Withhold Jobevne until proteinuria less than 2 grams per 24 hours | |
| Infusion-Related Reactions [see WARNINGS AND PRECAUTIONS]. |
|
Discontinue Jobevne |
|
Interrupt infusion; resume at a decreased rate of infusion after symptoms resolve | |
|
Decrease infusion rate | |
| Congestive Heart Failure [see WARNINGS AND PRECAUTIONS]. | Any | Discontinue Jobevne |
Injection: 100 mg/4 mL (25 mg/mL) or 400 mg/16 mL (25 mg/mL) clear to slightly opalescent, colorless to pale brown solution in a single-dose vial.
Jobevne (bevacizumab-nwgd) injection is a clear to slightly opalescent, colorless to pale brown, sterile solution for intravenous infusion supplied as single-dose vials inthe following strengths:
100 mg/4 mL (25 mg/mL): carton of one vial (NDC 83257-009-11).
400 mg/16 mL (25 mg/mL): carton of one vial (NDC 83257-010-11).
Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton until time of use to protect from light. Do not freeze or shake the vial or carton.
Manufactured by:Biocon Biologics Inc.245 Main St, 2nd FloorCambridge, MA 02142, U.S.A.U.S. License No. 2324. Revised: Apr 2025
The following clinically significant adverse reactions are described elsewhere in the labeling:
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared torates in the clinical studies of another drug and may not reflect the rates observed in practice.
The safety data in Warnings and Precautions and described below reflect exposure to bevacizumab in 4463 patients including those with mCRC (AVF2107g, E3200),non-squamous NSCLC (E4599), GBM (EORTC 26101), mRCC (BO17705), cervical cancer (GOG-0240), and epithelial ovarian, fallopian tube, or primary peritonealcancer (MO22224 AVF4095, GOG-0213, and GOG-0218) or another cancers at the recommended dose and schedule for a median of 6 to 23 doses. The most commonadverse reactions observed in patients receiving bevacizumab as a single agent or in combination with other anti-cancer therapies at a rate > 10% were epistaxis,headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.
Across clinical studies, bevacizumab was discontinued in 8% to 22% of patients because of adverse reactions [see Clinical Studies].
The safety of bevacizumab was evaluated in 392 patients who received at least one dose of bevacizumab in a double-blind, active-controlled study (AVF2107g), whichcompared bevacizumab (5 mg/kg every 2 weeks) with bolus-IFL to placebo with bolus-IFL in patients with mCRC [see Clinical Studies]. Patients wererandomized (1:1:1) to placebo with bolus-IFL, bevacizumab with bolus-IFL, or bevacizumab with fluorouracil and leucovorin. The demographics of the safetypopulation were similar to the demographics of the efficacy population. All Grades 3-4 adverse reactions and selected Grades 1-2 adverse reactions (i.e., hypertension,proteinuria, thromboembolic events) were collected in the entire study population. Adverse reactions are presented in Table 2.
Table 2: Grades 3-4 Adverse Reactions Occurring at Higher Incidence (≥ 2%) in Patients Receiving Bevacizumab vs. Placebo in Study AVF2107g
| Adverse Reaction* | Bevacizumab with IFL (N = 392) |
Placebo with IFL (N = 396) |
| Hematology | ||
| Leukopenia | 37% | 31% |
| Neutropenia | 21% | 14% |
| Gastrointestinal | ||
| Diarrhea | 34% | 25% |
| Abdominal pain | 8% | 5% |
| Constipation | 4% | 2% |
| Vascular | ||
| Hypertension | 12% | 2% |
| Deep vein thrombosis | 9% | 5% |
| Intra-abdominal thrombosis | 3% | 1% |
| Syncope | 3% | 1% |
| General | ||
| Asthenia | 10% | 7% |
| Pain | 8% | 5% |
| *NCI-CTC version 3. | ||
The safety of bevacizumab was evaluated in 521 patients in an open-label, active-controlled study (E3200) in patients who were previously treated with irinotecan andfluorouracil for initial therapy for mCRC. Patients were randomized (1:1:1) to FOLFOX4, bevacizumab (10 mg/kg every 2 weeks prior to FOLFOX4 on Day 1) withFOLFOX4, or bevacizumab alone (10 mg/kg every 2 weeks). Bevacizumab was continued until disease progression or unacceptable toxicity.
The demographics of the safety population were similar to the demographics of the efficacy population.
Selected Grades 3-5 non-hematologic and Grades 4-5 hematologic occurring at a higher incidence (≥ 2%) in patients receiving bevacizumab with FOLFOX4compared to FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%),dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) andheadache (3% vs. 0%). These data are likely to under-estimate the true adverse reaction rates due to the reporting mechanisms.
The safety of bevacizumab was evaluated as first-line treatment in 422 patients with unresectable NSCLC who received at least one dose of bevacizumab in an active-controlled, open-label, multicenter trial (E4599) [see Clinical Studies]. Chemotherapy na?ve patients with locally advanced, metastatic or recurrent non?squamous NSCLC were randomized (1:1) to receive six 21-day cycles of paclitaxel and carboplatin with or without bevacizumab (15 mg/kg every 3 weeks). Aftercompletion or upon discontinuation of chemotherapy, patients randomized to receive bevacizumab continued to receive bevacizumab alone until disease progression oruntil unacceptable toxicity. The trial excluded patients with predominant squamous histology (mixed cell type tumors only), CNS metastasis, gross hemoptysis (½teaspoon or more of red blood), unstable angina, or receiving therapeutic anticoagulation. The demographics of the safety population were similar to the demographicsof the efficacy population.
Only Grades 3-5 non-hematologic and Grades 4-5 hematologic adverse reactions were collected. Grades 3-5 non-hematologic and Grades 4-5 hematologic adversereactions occurring at a higher incidence (≥ 2%) in patients receiving bevacizumab with paclitaxel and carboplatin compared with patients receiving chemotherapyalone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thromboembolism (5%vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs.1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).
The safety of bevacizumab was evaluated in a multicenter, randomized, open-label study (EORTC 26101) in patients with recurrent GBM following radiotherapy andtemozolomide of whom 278 patients received at least one dose of bevacizumab and are considered safety evaluable [see Clinical Studies]. Patients wererandomized (2:1) to receive bevacizumab (10 mg/kg every 2 weeks) with lomustine or lomustine alone until disease progression or unacceptable toxicity. Thedemographics of the safety population were similar to the demographics of the efficacy population. In the bevacizumab with lomustine arm, 22% of patientsdiscontinued treatment due to adverse reactions compared with 10% of patients in the lomustine arm. In patients receiving bevacizumab with lomustine, the adversereaction profile was similar to that observed in other approved indications.
The safety of bevacizumab was evaluated in 337 patients who received at least one dose of bevacizumab in a multicenter, double-blind study (BO17705) in patientswith mRCC. Patients who had undergone a nephrectomy were randomized (1:1) to receive either bevacizumab (10 mg/kg every 2 weeks) or placebo with interferon alfa[see Clinical Studies]. Patients were treated until disease progression or unacceptable toxicity. The demographics of the safety population were similar to thedemographics of the efficacy population.
Grades 3-5 adverse reactions occurring at a higher incidence (> 2%) were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs.1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcerhemorrhage, gingival bleeding, hemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Adversereactions are presented in Table 3.
Table 3: Grades 1-5 Adverse Reactions Occurring at Higher Incidence (≥ 5%) of Patients Receiving Bevacizumab vs. Placebo with Interferon Alfa in StudyBO17705
| Adverse Reaction* | Bevacizumab with Interferon Alfa (N = 337) |
Placebo with Interferon Alfa (N = 304) |
| Metabolism and nutrition | ||
| Decreased appetite | 36% | 31% |
| Weight loss | 20% | 15% |
| General | ||
| Fatigue | 33% | 27% |
| Vascular | ||
| Hypertension | 28% | 9% |
| Respiratory, thoracic and mediastinal | ||
| Epistaxis | 27% | 4% |
| Dysphonia | 5% | 0% |
| Nervous system | ||
| Headache | 24% | 16% |
| Gastrointestinal | ||
| Diarrhea | 21% | 16% |
| Renal and urinary | ||
| Proteinuria | 20% | 3% |
| Musculoskeletal and connective tissue | ||
| Myalgia | 19% | 14% |
| Back pain | 12% | 6% |
| *NCI-CTC version 3. | ||
The following adverse reactions were reported at a 5-fold greater incidence in patients receiving bevacizumab with interferon-alfa compared to patients receivingplacebo with interferon-alfa and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs. 0); blurred vision (8 vs. 0); gingivitis (8 vs. 1);gastroesophageal reflux disease (8 vs. 1); tinnitus (7 vs. 1); tooth abscess (7 vs. 0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0);gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).
The safety of bevacizumab was evaluated in 218 patients who received at least one dose of bevacizumab in a multicenter study (GOG-0240) in patients with persistent,recurrent, or metastatic cervical cancer [see Clinical Studies]. Patients were randomized (1:1:1:1) to receive paclitaxel and cisplatin with or without bevacizumab(15 mg/kg every 3 weeks), or paclitaxel and topotecan with or without bevacizumab (15 mg/kg every 3 weeks). The demographics of the safety population were similarto the demographics of the efficacy population.
Grades 3-4 adverse reactions occurring at a higher incidence (≥ 2%) in 218 patients receiving bevacizumab with chemotherapy compared to 222 patients receivingchemotherapy alone were abdominal pain (12% vs. 10%), hypertension (11% vs. 0.5%), thrombosis (8% vs. 3%), diarrhea (6% vs. 3%), anal fistula (4% vs. 0%),proctalgia (3% vs. 0%), urinary tract infection (8% vs. 6%), cellulitis (3% vs. 0.5%), fatigue (14% vs. 10%), hypokalemia (7% vs. 4%), hyponatremia (4% vs. 1%),dehydration (4% vs. 0.5%), neutropenia (8% vs. 4%), lymphopenia (6% vs. 3%), back pain (6% vs. 3%), and pelvic pain (6% vs. 1%). Adverse reactions are presentedin Table 4.
Table 4: Grades 1-4 Adverse Reactions Occurring at Higher Incidence (≥ 5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study GOG-0240
| Adverse Reaction* | Bevacizumab with Chemotherapy (N = 218) |
Chemotherapy (N = 222) |
| General | ||
| Fatigue | 80% | 75% |
| Peripheral edema | 15% | 22% |
| Metabolism and nutrition | ||
| Decreased appetite | 34% | 26% |
| Hyperglycemia | 26% | 19% |
| Hypomagnesemia | 24% | 15% |
| Weight loss | 21% | 7% |
| Hyponatremia | 19% | 10% |
| Hypoalbuminemia | 16% | 11% |
| Vascular | ||
| Hypertension | 29% | 6% |
| Thrombosis | 10% | 3% |
| Infections | ||
| Urinary tract infection | 22% | 14% |
| Infection | 10% | 5% |
| Nervous system | ||
| Headache | 22% | 13% |
| Dysarthria | 8% | 1% |
| Psychiatric | ||
| Anxiety | 17% | 10% |
| Respiratory, thoracic and mediastinal | ||
| Epistaxis | 17% | 1% |
| Renal and urinary | ||
| Increased blood creatinine | 16% | 10% |
| Proteinuria | 10% | 3% |
| Gastrointestinal | ||
| Stomatitis | 15% | 10% |
| Proctalgia | 6% | 1% |
| Anal fistula | 6% | 0% |
| Reproductive system and breast | ||
| Pelvic pain | 14% | 8% |
| Hematology | ||
| Neutropenia | 12% | 6% |
| Lymphopenia | 12% | 5% |
| *NCI-CTC version 3. | ||
The safety of bevacizumab was evaluated in GOG-0218, a multicenter, randomized, double-blind, placebo controlled, three arm study, which evaluated the addition ofbevacizumab to carboplatin and paclitaxel for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube or primary peritoneal cancer followinginitial surgical resection [see Clinical Studies]. Patients were randomized (1:1:1) to carboplatin and paclitaxel without bevacizumab (CPP), carboplatin andpaclitaxel with bevacizumab for up to six cycles (CPB15), or carboplatin and paclitaxel with bevacizumab for six cycles followed by bevacizumab as a single agent forup to 16 additional doses (CPB15+). Bevacizumab was given at 15 mg/kg every three weeks. On this trial, 1215 patients received at least one dose of bevacizumab. Thedemographics of the safety population were similar to the demographics of the efficacy population.
Grades 3-4 adverse reactions occurring at a higher incidence (≥2%) in either of the bevacizumab arms versus thecontrol arm were fatigue (CPB15+ -9%, CPB15 -6%,CPP -6%), hypertension (CPB15+ -10%, CPB15 -6%,CPP -2%), thrombocytopenia (CPB15+ -21%, CPB15 -20%, CPP -15%) and leukopenia (CPB15+ -51%,CPB15-53%, CPP -50%). Adverse reactions are presented in Table 5.
Table 5: Grades 1-5 Adverse Reactions Occurring at Higher Incidence (≥ 5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in GOG-0218
| Adverse Reaction* | Bevacizumab with carboplatin and paclitaxel followed by bevacizumab alone† N = (608) |
Bevacizumab with carboplatin and paclitaxel‡ (N = 607) |
Carboplatin and paclitaxel§ (N = 602) |
| General | |||
| Fatigue | 80% | 72% | 73% |
| Gastrointestinal | |||
| Nausea | 58% | 53% | 51% |
| Diarrhea | 38% | 40% | 34% |
| Stomatitis | 25% | 19% | 14% |
| Musculoskeletal and connective tissue | |||
| Arthralgia | 41% | 33% | 35% |
| Pain in extremity | 25% | 19% | 17% |
| Muscular weakness | 15% | 13% | 9% |
| Nervous system | |||
| Headache | 34% | 26% | 21% |
| Dysarthria | 12% | 10% | 2% |
| Vascular | |||
| Hypertension | 32% | 24% | 14% |
| Respiratory, thoracic and mediastinal | |||
| Epistaxis | 31% | 30% | 9% |
| Dyspnea | 26% | 28% | 20% |
| Nasal mucosal disorder | 10% | 7% | 4% |
| *NCI-CTC version 3, †CPB15,+ ‡CPB15, §CPP |
|||
The safety of bevacizumab was evaluated in 179 patients who received at least one dose of bevacizumab in a multicenter, open-label study (MO22224) in whichpatients were randomized (1:1) to bevacizumab with chemotherapy or chemotherapy alone in patients with platinum resistant, recurrent epithelial ovarian, fallopiantube, or primary peritoneal cancer that recurred within < 6 months from the most recent platinum based therapy [see Clinical Studies]. Patients were randomizedto receive bevacizumab 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks. Patients had received no more than 2 prior chemotherapy regimens. The trial excludedpatients with evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. Patients weretreated until disease progression or unacceptable toxicity. Forty percent of patients on the chemotherapy alone arm received bevacizumab alone upon progression. Thedemographics of the safety population were similar to the demographics of the efficacy population.
Grades 3-4 adverse reactions occurring at a higher incidence (≥ 2%) in 179 patients receiving bevacizumab with chemotherapy compared to 181 patients receivingchemotherapy alone were hypertension (6.7% vs. 1.1%) and palmar-plantar erythrodysaesthesia syndrome (4.5% vs. 1.7%).
Adverse reactions are presented in Table 6.
Table 6: Grades 2-4 Adverse Reactions Occurring at Higher Incidence (≥ 5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study MO22224
| Adverse Reaction* | Bevacizumab with Chemotherapy (N = 179) |
Chemotherapy (N = 181) |
| Hematology | ||
| Neutropenia | 31% | 25% |
| Vascular | ||
| Hypertension | 19% | 6% |
| Nervous system | ||
| Peripheral sensory neuropathy | 18% | 7% |
| General | ||
| Mucosal inflammation | 13% | 6% |
| Renal and urinary | ||
| Proteinuria | 12% | 0.6% |
| Skin and subcutaneous tissue | ||
| Palmar-plantar erythrodysaesthesia | 11% | 5% |
| Infections | ||
| Infection | 11% | 4% |
| Respiratory, thoracic and mediastinal | ||
| Epistaxis | 5% | 0% |
| *NCI-CTC version 3. | ||
Study AVF4095g
The safety of bevacizumab was evaluated in 247 patients who received at least one dose of bevacizumab in a double-blind study (AVF4095g) in patients with platinumsensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer [see Clinical Studies ]. Patients were randomized (1:1) to receive bevacizumab(15 mg/kg) or placebo every 3 weeks with carboplatin and gemcitabine for 6 to 10 cycles followed by bevacizumab or placebo alone until disease progression orunacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population.
Grades 3-4 adverse reactions occurring at a higher incidence (≥ 2%) in patients receiving bevacizumab with chemotherapy compared to placebo with chemotherapywere: thrombocytopenia (40% vs. 34%), nausea (4% vs. 1.3%), fatigue (6% vs. 4%), headache (4% vs. 0.9%), proteinuria (10% vs. 0.4%), dyspnea (4% vs. 1.7%),epistaxis (5% vs. 0.4%), and hypertension (17% vs. 0.9%). Adverse reactions are presented in Table 7.
Table 7: Grades 1-5 Adverse Reactions Occurring at a Higher Incidence (≥ 5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Placebo with Chemotherapy in Study AVF4095g
| Adverse Reaction* | Bevacizumab with Carboplatin and Gemcitabine (N = 247) |
Placebo with Carboplatin and Gemcitabine (N = 233) |
| General | ||
| Fatigue | 82% | 75% |
| Mucosal inflammation | 15% | 10% |
| Gastrointestinal | ||
| Nausea | 72% | 66% |
| Diarrhea | 38% | 29% |
| Stomatitis | 15% | 7% |
| Hemorrhoids | 8% | 3% |
| Gingival bleeding | 7% | 0% |
| Hematology | ||
| Thrombocytopenia | 58% | 51% |
| Respiratory, thoracic and mediastinal | ||
| Epistaxis | 55% | 14% |
| Dyspnea | 30% | 24% |
| Cough | 26% | 18% |
| Oropharyngeal pain | 16% | 10% |
| Dysphonia | 13% | 3% |
| Rhinorrhea | 10% | 4% |
| Sinus congestion | 8% | 2% |
| Nervous system | ||
| Headache | 49% | 30% |
| Dizziness | 23% | 17% |
| Vascular | ||
| Hypertension | 42% | 9% |
| Musculoskeletal and connective tissue | ||
| Arthralgia | 28% | 19% |
| Back pain | 21% | 13% |
| Psychiatric | ||
| Insomnia | 21% | 15% |
| Renal and urinary | ||
| Proteinuria | 20% | 3% |
| Injury and procedural | ||
| Contusion | 17% | 9% |
| Infections | ||
| Sinusitis | 15% | 9% |
| *NCI-CTC version 3 | ||
Study GOG-0213
The safety of bevacizumab was evaluated in an open-label, controlled study (GOG-0213) in 325 patients with platinum-sensitive recurrent epithelial ovarian, fallopiantube, or primary peritoneal cancer, who have not received more than one previous regimen of chemotherapy [see Clinical Studies]. Patients were randomized(1:1) to receive carboplatin and paclitaxel for 6 to 8 cycles or bevacizumab (15 mg/kg every 3 weeks) with carboplatin and paclitaxel for 6 to 8 cycles followed by bevacizumab as a single agent until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of theefficacy population.
Grades 3-4 adverse reactions occurring at a higher incidence (≥ 2%) in patients receiving bevacizumab with chemotherapy compared to chemotherapy alone were:hypertension (11% vs. 0.6%), fatigue (8% vs. 3%), febrile neutropenia (6% vs. 3%), proteinuria (8% vs. 0%), abdominal pain (6% vs. 0.9%), hyponatremia (4% vs.0.9%), headache (3% vs. 0.9%), and pain in extremity (3% vs. 0%). Adverse reactions are presented in Table 8.
Table 8: Grades1-5 Adverse Reactions Occurring at Higher Incidence (≥ 5) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alonein Study GOG-0213
| Adverse Reaction* | Bevacizumab with Carboplatin and Paclitaxel (N = 325) |
Carboplatin and Paclitaxel (N = 332) |
| Musculoskeletal and connective tissue | ||
| Arthralgia | 45% | 30% |
| Myalgia | 29% | 18% |
| Pain in extremity | 25% | 14% |
| Back pain | 17% | 10% |
| Muscular weakness | 13% | 8% |
| Neck pain | 9% | 0% |
| Vascular | ||
| Hypertension | 42% | 3% |
| Gastrointestinal | ||
| Diarrhea | 39% | 32% |
| Abdominal pain | 33% | 28% |
| Vomiting | 33% | 25% |
| Stomatitis | 33% | 16% |
| Nervous System | ||
| Headache | 38% | 20% |
| Dysarthria | 14% | 2% |
| Dizziness | 13% | 8% |
| Metabolism and nutrition | ||
| Decreased appetite | 35% | 25% |
| Hyperglycemia | 31% | 24% |
| Hypomagnesemia | 27% | 17% |
| Hyponatremia | 17% | 6% |
| Weight loss | 15% | 4% |
| Hypocalcemia | 12% | 5% |
| Hypoalbuminemia | 11% | 6% |
| Hyperkalemia | 9% | 3% |
| Respiratory, thoracic and mediastinal | ||
| Epistaxis | 33% | 2% |
| Dyspnea | 30% | 25% |
| Cough | 30% | 17% |
| Rhinitis allergic | 17% | 4% |
| Nasal mucosal disorder | 14% | 3% |
| Skin and subcutaneous tissue | ||
| Exfoliative rash | 23% | 16% |
| Nail disorder | 10% | 2% |
| Dry skin | 7% | 2% |
| Renal and urinary | ||
| Proteinuria | 17% | 1% |
| Increased blood creatinine | 13% | 5% |
| Hepatic | ||
| Increased aspartate aminotransferase | 15% | 9% |
| General | ||
| Chest pain | 8% | 2% |
| Infections | ||
| Sinusitis | 7% | 2% |
| *NCI-CTC version 3 | ||
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningfulcomparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those ofbevacizumab or of other bevacizumab products.
In clinical studies for adjuvant treatment of a solid tumor, 0.6% (14/2233) of patients tested positive for treatment-emergent anti-bevacizumab antibodies as detected byan electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme-linkedimmunosorbent assay (ELISA). The clinical significance of these anti-bevacizumab antibodies is not known.
The following adverse reactions have been identified during postapproval use of bevacizumab products. Because these reactions are reported voluntarily from apopulation of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
General: Polyserositis
Cardiovascular: Pulmonary hypertension, Mesenteric venous occlusion
Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration
Hemic and lymphatic: Pancytopenia
Hepatobiliary disorders: Gallbladder perforation
Musculoskeletal and Connective Tissue Disorders: Osteonecrosis of the jaw
Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria)
Respiratory: Nasal septum perforation
Vascular: Arterial (including aortic) aneurysms, dissections, and rupture
No clinically meaningful effect on the pharmacokinetics of irinotecan or its active metabolite SN38, interferon alfa, carboplatin or paclitaxel was observed whenbevacizumab was administered in combination with these drugs; however, 3 of the 8 patients receiving bevacizumab with paclitaxel and carboplatin had lowerpaclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel and carboplatin alone had a greater paclitaxelexposure at Day 63 than at Day 0.
Included as part of the PRECAUTIONS section.
Serious, and sometimes fatal, gastrointestinal perforation occurred at a higher incidence in patients receiving bevacizumab products compared to patients receiving chemotherapy. The incidence ranged from 0.3% to 3% across clinical studies, with the highest incidence in patients with a history of prior pelvic radiation. Perforationcan be complicated by intra-abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of perforations occurred within 50 days of the first dose [see ADVERSE REACTIONS].
Serious fistulae (including, tracheoesophageal, bronchopleural, biliary, vaginal, renal and bladder sites) occurred at a higher incidence in patients receiving bevacizumabproducts compared to patients receiving chemotherapy. The incidence ranged from < 1% to 1.8% across clinical studies, with the highest incidence in patients with cervical cancer. The majority of fistulae occurred within 6 months of the first dose. Patients who develop a gastrointestinal vaginal fistula may also have a bowel obstruction and require surgical intervention, as well as a diverting ostomy.
Avoid Jobevne in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. Discontinue in patients who develop gastrointestinal perforation, tracheoesophageal fistula or any Grade 4 fistula. Discontinue inpatients with fistula formation involving any internal organ.
In a controlled clinical study in which bevacizumab was not administered within 28 days of major surgical procedures, the incidence of wound healing complications, including serious and fatal complications, was 15% in patients with mCRC who underwent surgery while receiving bevacizumab and 4% in patients who did not receive bevacizumab. In a controlled clinical study in patients with relapsed or recurrent GBM, the incidence of wound healing events was 5% in patients who receivedbevacizumab and 0.7% in patients who did not receive bevacizumab [see ADVERSE REACTIONS].
In patients who experience wound healing complications during Jobevne treatment, withhold Jobevne until adequate wound healing. Withhold for at least 28 days priorto elective surgery. Do not administer for at least 28 days following major surgery and until adequate wound healing. The safety of resumption of bevacizumab products after resolution of wound healing complications has not been established [see DOSAGE AND ADMINISTRATION].
Necrotizing fasciitis including fatal cases, has been reported in patients receiving bevacizumab, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Jobevne in patients who develop necrotizing fasciitis.
Bevacizumab products can result in two distinct patterns of bleeding: minor hemorrhage, which is most commonly Grade 1 epistaxis, and serious hemorrhage, which insome cases has been fatal. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding,occurred up to 5-fold more frequently in patients receiving bevacizumab compared to patients receiving chemotherapy alone. Across clinical studies, the incidence of Grades 3-5 hemorrhagic events ranged from 0.4% to 7% in patients receiving bevacizumab [see ADVERSE REACTIONS].
Serious or fatal pulmonary hemorrhage occurred in 31% of patients with squamous NSCLC and 4% of patients with non-squamous NSCLC receiving bevacizumabwith chemotherapy compared to none of the patients receiving chemotherapy alone.
Do not administer Jobevne to patients with recent history of hemoptysis of ½ teaspoon or more of red blood. Discontinue in patients who develop a Grades 3-4hemorrhage.
Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, and angina, occurred ata higher incidence in patients receiving bevacizumab compared to patients receiving chemotherapy. Across clinical studies, the incidence of Grades 3-5 ATE was 5% inpatients receiving bevacizumab with chemotherapy compared to ≤ 2% in patients receiving chemotherapy alone; the highest incidence occurred in patients with GBM.The risk of developing ATE was increased in patients with a history of arterial thromboembolism, diabetes, or > 65 years [see Use In Specific Populations].
Discontinue in patients who develop a severe ATE. The safety of reinitiating bevacizumab products after an ATE is resolved is not known.
An increased risk of venous thromboembolic events (VTE) was observed across clinical studies [see ADVERSE REACTIONS]. In Study GOG-0240, Grades 3-4 VTEoccurred in 11% of patients receiving bevacizumab with chemotherapy compared with 5% of patients receiving chemotherapy alone. In EORTC 26101, the incidence ofGrades 3-4 VTE was 5% in patients receiving bevacizumab with chemotherapy compared to 2% in patients receiving chemotherapy alone.
Discontinue Jobevne in patients with a Grade 4 VTE, including pulmonary embolism.
Severe hypertension occurred at a higher incidence in patients receiving bevacizumab products as compared to patients receiving chemotherapy alone. Across clinicalstudies, the incidence of Grades 3-4 hypertension ranged from 5% to 18%.
Monitor blood pressure every two to three weeks during treatment with Jobevne. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly.Continue to monitor blood pressure at regular intervals in patients with Jobevne-induced or -exacerbated hypertension after discontinuing Jobevne. Withhold Jobevne inpatients with severe hypertension (such as Grade 3 and above) until controlled with medical management; resume once controlled with medical management.Discontinue in patients who develop hypertensive crisis or hypertensive encephalopathy.
Posterior reversible encephalopathy syndrome (PRES) was reported in < 0.5% of patients across clinical studies. The onset of symptoms occurred from 16 hours to 1year after the first dose. PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologicdisturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of PRES.
Discontinue Jobevne in patients who develop PRES. Symptoms usually resolve or improve within days after discontinuing bevacizumab products, although somepatients have experienced ongoing neurologic sequelae. The safety of reinitiating bevacizumab products in patients who developed PRES is not known.
The incidence and severity of proteinuria was higher in patients receiving bevacizumab as compared to patients receiving chemotherapy. Grade 3 (defined as urinedipstick 4+ or > 3.5 grams of protein per 24 hours) to Grade 4 (defined as nephrotic syndrome) ranged from 0.7% to 7% in clinical studies. The overall incidence ofproteinuria (all grades) was only adequately assessed in Study BO17705, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (15 days to 37months) after initiating bevacizumab. Median time to resolution was 6.1 months (95% CI: 2.8, 11.3). Proteinuria did not resolve in 40% of patients after median follow-up of 11.2 months and required discontinuation of bevacizumab in 30% of the patients who developed proteinuria [see ADVERSE REACTIONS].
In an exploratory, pooled analysis of patients from seven randomized clinical studies, 5% of patients receiving bevacizumab with chemotherapy experienced Grades 2-4(defined as urine dipstick 2+ or greater or > 1 gram of protein per 24 hours or nephrotic syndrome) proteinuria. Grades 2-4 proteinuria resolved in 74% of patients.Bevacizumab was reinitiated in 42% of patients. Of the 113 patients who reinitiated bevacizumab, 48% experienced a second episode of Grades 2-4 proteinuria.
Nephrotic syndrome occurred in < 1% of patients receiving bevacizumab across clinical studies, in some instances with fatal outcome. In a published case series, kidneybiopsy of 6 patients with proteinuria showed findings consistent with thrombotic microangiopathy. Results of a retrospective analysis of 5805 patients who receivedbevacizumab with chemotherapy and 3713 patients who received chemotherapy alone, showed higher rates of elevated serum creatinine levels (between 1.5 to 1.9 timesbaseline levels) in patients who received bevacizumab. Serum creatinine levels did not return to baseline in approximately one-third of patients who receivedbevacizumab.
Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Jobevne therapy. Patients with a 2+ orgreater urine dipstick reading should undergo further assessment with a 24-hour urine collection. Withhold for proteinuria greater than or equal to 2 grams per 24 hoursand resume when less than 2 grams per 24 hours. Discontinue in patients who develop nephrotic syndrome.
Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24-hour urine protein [Pearson Correlation 0.39(95% CI: 0.17, 0.57)].
Infusion-related reactions reported across clinical studies and postmarketing experience include hypertension, hypertensive crises associated with neurologic signs andsymptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, anaphylactoid/anaphylactic reactions, chest pain, headaches, rigors, and diaphoresis. In clinicalstudies, infusion-related reactions with the first dose occurred in < 3% of patients and severe reactions occurred in 0.4% of patients.
Decrease the rate of infusion for mild, clinically insignificant infusion-related reactions. Interrupt the infusion in patients with clinically significant infusion-relatedreactions and consider resuming at a slower rate following resolution. Discontinue in patients who develop a severe infusion-related reaction and administer appropriatemedical therapy (e.g., epinephrine, corticosteroids, intravenous antihistamines, bronchodilators and/or oxygen).
Based on its mechanism of action and findings from animal studies, bevacizumab products may cause fetal harm when administered to pregnant women. Congenitalmalformations were observed with the administration of bevacizumab to pregnant rabbits during organogenesis every 3 days at a dose as low as a clinical dose of 10mg/kg. Furthermore, animal models link angiogenesis and VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal development, and postnataldevelopment. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment withJobevne and for 6 months after the last dose [see Use In Specific Populations].
The incidence of ovarian failure was 34% vs. 2% in premenopausal women receiving bevacizumab with chemotherapy as compared to those receiving chemotherapyalone for adjuvant treatment of a solid tumor. After discontinuing bevacizumab, recovery of ovarian function at all time points during the post-treatment period wasdemonstrated in 22% of women receiving bevacizumab. Recovery of ovarian function is defined as resumption of menses, a positive serum β-HCG pregnancy test, oran FSH level < 30 mIU/mL during the post-treatment period. Long-term effects of bevacizumab products on fertility are unknown. Inform females of reproductivepotential of the risk of ovarian failure prior to initiating Jobevne [see ADVERSE REACTIONS, Use In Specific Populations].
Jobevne is not indicated for use with anthracycline-based chemotherapy. The incidence of Grade ≥ 3 left ventricular dysfunction was 1% in patients receivingbevacizumab compared to 0.6% of patients receiving chemotherapy alone. Among patients who received prior anthracycline treatment, the rate of CHF was 4% forpatients receiving bevacizumab with chemotherapy as compared to 0.6% for patients receiving chemotherapy alone.
In previously untreated patients with a hematological malignancy, the incidence of CHF and decline in left ventricular ejection fraction (LVEF) were increased inpatients receiving bevacizumab with anthracycline-based chemotherapy compared to patients receiving placebo with the same chemotherapy regimen. The proportionof patients with a decline in LVEF from baseline of ≥ 20% or a decline from baseline of 10% to < 50%, was 10% in patients receiving bevacizumab with chemotherapycompared to 5% in patients receiving chemotherapy alone. Time to onset of left-ventricular dysfunction or CHF was 1 to 6 months after the first dose in at least 85% ofthe patients and was resolved in 62% of the patients who developed CHF in the bevacizumab arm compared to 82% in the placebo arm. Discontinue Jobevne in patientswho develop CHF.
Bevacizumab products may increase the risk of developing gastrointestinal perforations and fistulae. Advise patients toimmediately contact their health care provider for high fever, rigors, persistent or severe abdominal pain, severe constipation, or vomiting [see WARNINGS AND PRECAUTIONS].
Bevacizumab products can increase the risk of wound healing complications. Instruct patients not to undergo surgerywithout first discussing this potential risk with their health care provider [see WARNINGS AND PRECAUTIONS].
Bevacizumab products can increase the risk of hemorrhage. Advise patients to immediately contact their health care provider for signs and symptoms ofserious or unusual bleeding including coughing or spitting blood [see WARNINGS AND PRECAUTIONS].
Bevacizumab products increase the risk of arterial and venous thromboembolic events. Advise patients to immediatelycontact their health care provider for signs and symptoms of arterial or venous thromboembolism [see WARNINGS AND PRECAUTIONS].
Bevacizumab products can increase blood pressure. Advise patients that they will undergo routine blood pressure monitoring and to contact their healthcare provider if they experience changes in blood pressure [see WARNINGS AND PRECAUTIONS].
Posterior reversible encephalopathy syndrome (PRES) has been associated with bevacizumab productstreatment. Advise patients to immediately contact their health care provider for new onset or worsening neurological function [see WARNINGS AND PRECAUTIONS].
Bevacizumab products increase the risk of proteinuria and renal injury, including nephrotic syndrome. Advise patients that treatment withJobevne requires regular monitoring of renal function and to contact their health care provider for proteinuria or signs and symptoms of nephrotic syndrome [see WARNINGS AND PRECAUTIONS].
Bevacizumab products can cause infusion-related reactions. Advise patients to contact their health care provider immediately for signs orsymptoms of infusion-related reactions [see WARNINGS AND PRECAUTIONS].
Bevacizumab products can increase the risk of developing congestive heart failure. Advise patients to contact their health care providerimmediately for signs and symptoms of CHF [see WARNINGS AND PRECAUTIONS].
Advise female patients that bevacizumab products may cause fetal harm and to inform their health care provider with a known or suspectedpregnancy [see WARNINGS AND PRECAUTIONS, Use In Specific Populations]. Advise females of reproductive potential to use effective contraception duringtreatment with Jobevne and for 6 months after the last dose [see Use In Specific Populations].
Bevacizumab products may lead to ovarian failure. Advise patients of potential options for preservation of ova prior to starting treatment [see WARNINGS AND PRECAUTIONS].
Advise women not to breastfeed during treatment with Jobevne and for 6 months after the last dose [see Use In Specific Populations].
No studies have been conducted to assess potential of bevacizumab products for carcinogenicity or mutagenicity.
Bevacizumab products may impair fertility. Female cynomolgus monkeys treated with 0.4 to 20 times the recommended human dose of bevacizumab exhibited arrestedfollicular development or absent corpora lutea, as well as dose-related decreases in ovarian and uterine weights, endometrial proliferation, and the number of menstrualcycles. Following a 4- or 12-week recovery period, there was a trend suggestive of reversibility. After the 12-week recovery period, follicular maturation arrest was nolonger observed, but ovarian weights were still moderately decreased. Reduced endometrial proliferation was no longer observed at the 12-week recovery time point;however, decreased uterine weight, absent corpora lutea, and reduced number of menstrual cycles remained evident.
Based on findings from animal studies and their mechanism of action [see CLINICAL PHARMACOLOGY], bevacizumab products may cause fetal harm in pregnantwomen. Limited postmarketing reports describe cases of fetal malformations with use of bevacizumab products in pregnancy; however, these reports are insufficient todetermine drug-associated risks. In animal reproduction studies, intravenous administration of bevacizumab to pregnant rabbits every 3 days during organogenesis atdoses approximately 1 to 10 times the clinical dose of 10 mg/kg produced fetal resorptions, decreased maternal and fetal weight gain and multiple congenitalmalformations including corneal opacities and abnormal ossification of the skull and skeleton including limb and phalangeal defects (see Data). Furthermore, animalmodels link angiogenesis and VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal development, and postnatal development. Advise pregnantwomen of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%,respectively.
Animal Data
Pregnant rabbits dosed with 10 mg/kg to 100 mg/kg bevacizumab (approximately 1 to 10 times the clinical dose of 10 mg/kg) every three days during the period oforganogenesis (gestation day 6-18) exhibited decreases in maternal and fetal body weights and increased number of fetal resorptions. There were dose-related increasesin the number of litters containing fetuses with any type of malformation (42% for the 0 mg/kg dose, 76% for the 30 mg/kg dose, and 95% for the 100 mg/kg dose) orfetal alterations (9% for the 0 mg/kg dose, 15% for the 30 mg/kg dose, and 61% for the 100 mg/kg dose). Skeletal deformities were observed at all dose levels, withsome abnormalities including meningocele observed only at the 100 mg/kg dose level. Teratogenic effects included: reduced or irregular ossification in the skull, jaw,spine, ribs, tibia and bones of the paws; fontanel, rib and hindlimb deformities; corneal opacity; and absent hindlimb phalanges.
No data are available regarding the presence of bevacizumab products in human milk, the effects on the breast fed infant, or the effects on milk production. Human IgGis present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of thepotential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with Jobevne and for 6 months after the last dose.
Females
Bevacizumab products may cause fetal harm when administered to a pregnant woman [see Use In Specific Populations]. Advise females of reproductive potentialto use effective contraception during treatment with Jobevne and for 6 months after the last dose.
Females
Bevacizumab products increase the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to thefirst-dose of Jobevne. Long-term effects of bevacizumab products on fertility are not known.
In a clinical study of 179 premenopausal women randomized to receive chemotherapy with or without bevacizumab, the incidence of ovarian failure was higher inpatients who received bevacizumab with chemotherapy (34%) compared to patients who received chemotherapy alone (2%). After discontinuing bevacizumab withchemotherapy, recovery of ovarian function occurred in 22% of these patients [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].
The safety and effectiveness of Jobevne in pediatric patients have not been established.
In published literature reports, cases of non-mandibular osteonecrosis have been observed in patients under the age of 18 years who received bevacizumab.Bevacizumab products are not approved for use in patients under the age of 18 years.
Antitumor activity was not observed among eight pediatric patients with relapsed GBM who received bevacizumab and irinotecan. Addition of bevacizumab to standardof care did not result in improved event-free survival in pediatric patients enrolled in two randomized clinical studies, one in high grade glioma (n = 121) and one inmetastatic rhabdomyosarcoma or non-rhabdomyosarcoma soft tissue sarcoma (n = 154).
Based on the population pharmacokinetics analysis of data from 152 pediatric and young adult patients with cancer (7 months to 21 years of age), bevacizumabclearance normalized by body weight in pediatrics was comparable to that in adults.
Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose(based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.
In an exploratory pooled analysis of 1745 patients from five randomized, controlled studies, 35% of patients were ≥ 65 years old. The overall incidence of ATE wasincreased in all patients receiving bevacizumab with chemotherapy as compared to those receiving chemotherapy alone, regardless of age; however, the increase in theincidence of ATE was greater in patients ≥ 65 years (8% vs. 3%) as compared to patients < 65 years (2% vs. 1%) [see WARNINGS AND PRECAUTIONS].
No Information provided
None.
Bevacizumab products bind VEGF and prevent the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGFwith its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Administration of bevacizumab toxenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression.
The pharmacokinetic profile of bevacizumab was assessed using an assay that measures total serum bevacizumab concentrations (i.e., the assay did not distinguishbetween free bevacizumab and bevacizumab bound to VEGF ligand). Based on a population pharmacokinetic analysis of 491 patients who received 1 to 20 mg/kg ofbevacizumab every week, every 2 weeks, or every 3 weeks, bevacizumab pharmacokinetics are linear and the predicted time to reach more than 90% of steady stateconcentration is 84 days. The accumulation ratio following a dose of 10 mg/kg of bevacizumab once every 2 weeks is 2.8.
Population simulations of bevacizumab exposures provide a median trough concentration of 80.3 mcg/mL on Day 84 (10, 90percentile: 45, 128) following a dose of5 mg/kg once every two weeks.
The mean (% coefficient of variation [CV%]) central volume of distribution is 2.9 (22%) L.
The mean (CV%) clearance is 0.23 (33) L/day. The estimated half-life is 20 days (11 to 50 days).
The clearance of bevacizumab varied by body weight, sex, and tumor burden. After correcting for body weight, males had a higher bevacizumab clearance (0.26 L/dayvs. 0.21 L/day) and a larger central volume of distribution (3.2 L vs. 2.7 L) than females. Patients with higher tumor burden (at or above median value of tumor surfacearea) had a higher bevacizumab clearance (0.25 L/day vs. 0.20 L/day) than patients with tumor burdens below the median. In Study AVF2107g, there was no evidenceof lesser efficacy (hazard ratio for overall survival) in males or patients with higher tumor burden treated with bevacizumab as compared to females and patients withlow tumor burden.
Rabbits dosed with bevacizumab exhibited reduced wound healing capacity. Using full-thickness skin incision and partial thickness circular dermal wound models,bevacizumab dosing resulted in reductions in wound tensile strength, decreased granulation and re-epithelialization, and delayed time to wound closure.
The safety and efficacy of bevacizumab was evaluated in a double-blind, active-controlled study [AVF2107g (NCT00109070)] in 923 patients with previously untreatedmCRC who were randomized (1:1:1) to placebo with bolus-IFL (irinotecan 125 mg/m, fluorouracil 500 mg/m, and leucovorin 20 mg/mgiven once weekly for 4weeks every 6 weeks), bevacizumab (5 mg/kg every 2 weeks) with bolus-IFL, or bevacizumab (5 mg/kg every 2 weeks) with fluorouracil and leucovorin. Enrollment tothe bevacizumab with fluorouracil and leucovorin arm was discontinued after enrollment of 110 patients in accordance with the protocol-specified adaptive design.Bevacizumab was continued until disease progression or unacceptable toxicity or for a maximum of 96 weeks. The main outcome measure was overall survival (OS).
The median age was 60 years; 60% were male, 79% were White, 57% had an ECOG performance status of 0, 21% had a rectal primary and 28% received prioradjuvant chemotherapy. The dominant site of disease was extra-abdominal in 56% of patients and was the liver in 38% of patients.
The addition of bevacizumab improved survival across subgroups defined by age (< 65 years, ≥ 65 years) and sex. Results are presented in Table 9 and Figure 1.
Table 9: Efficacy Results in Study AVF2107g
| Efficacy Parameter | Bevacizumab with bolus-IFL (N = 402) |
Placebo with bolus-IFL (N = 411) |
| Overall Survival | ||
| Median, in months | 20.3 | 15.6 |
| Hazard ratio | 0.66 | |
| (95% CI) | (0.54, 0.81) | |
| p-value* | < 0.001 | |
| Progression-Free Survival | ||
| Median, in months | 10.6 | 6.2 |
| Hazard ratio | 0.54 | |
| (95% CI) | (0.45, 0.66) | |
| p-value* | < 0.001 | |
| Overall Response Rate | ||
| Rate (%) | 45% | 35% |
| p-value† | < 0.01 | |
| Duration of Response | ||
| Median, in months | 10.4 | 7.1 |
| *by stratified log-rank test. †by χ test. |
||
Figure 1: Kaplan-Meier Curves for Duration of Survival in Metastatic Colorectal Cancer in Study AVF2107g
 |
Among the 110 patients randomized to bevacizumab with fluorouracil and leucovorin, median OS was 18.3 months, median progression-free survival (PFS) was 8.8months, overall response rate (ORR) was 39%, and median duration of response was 8.5 months.
The safety and efficacy of bevacizumab were evaluated in a randomized, open-label, active-controlled study [E3200 (NCT00025337)] in 829 patients who werepreviously treated with irinotecan and fluorouracil for initial therapy for metastatic disease or as adjuvant therapy. Patients were randomized (1:1:1) to FOLFOX4 (Day1: oxaliplatin 85 mg/m² and leucovorin 200 mg/m² concurrently, then fluorouracil 400 mg/m² bolus followed by 600 mg/m² continuously; Day 2: leucovorin 200mg/m, then fluorouracil 400 mg/m² bolus followed by 600 mg/m² continuously; every 2 weeks), bevacizumab (10 mg/kg every 2 weeks prior to FOLFOX4 on Day 1)with FOLFOX4, or bevacizumab alone (10 mg/kg every 2 weeks). Bevacizumab was continued until disease progression or unacceptable toxicity. The main outcomemeasure was OS.
The bevacizumab alone arm was closed to accrual after enrollment of 244 of the planned 290 patients following a planned interim analysis by the data monitoringcommittee based on evidence of decreased survival compared to FOLFOX4 alone.
The median age was 61 years; 60% were male, 87% were White, 49% had an ECOG performance status of 0, 26% received prior radiation therapy, and 80% receivedprior adjuvant chemotherapy, 99% received prior irinotecan with or without fluorouracil for metastatic disease, and 1% received prior irinotecan and fluorouracil asadjuvant therapy.
The addition of bevacizumab to FOLFOX4 resulted in significantly longer survival as compared to FOLFOX4 alone; median OS was 13.0 months vs. 10.8 months[hazard ratio (HR) 0.75 (95% CI: 0.63, 0.89), p-value of 0.001 stratified log-rank test] with clinical benefit seen in subgroups defined by age (< 65 years, ≥ 65 years)and sex. PFS and ORR based on investigator assessment were higher in patients receiving bevacizumab with FOLFOX4.
The activity of bevacizumab with fluorouracil (as bolus or infusion) and leucovorin was evaluated in a single arm study [TRC-0301 (NCT00066846)] enrolling 339patients with mCRC with disease progression following both irinotecan-and oxaliplatin-based chemotherapy. Seventy-three percent of patients received concurrent bolus fluorouracil and leucovorin. One objective partial response was verified in the first 100 evaluable patients for an ORR of 1% (95% CI: 0%, 5.5%).
The safety and efficacy of bevacizumab were evaluated in a prospective, randomized, open-label, multinational, controlled study [ML18147 (NCT00700102)] in 820patients with histologically confirmed mCRC who had progressed on a first-line bevacizumab-containing regimen. Patients were excluded if they progressed within 3months of initiating first-line chemotherapy and if they received bevacizumab for less than 3 consecutive months in the first-line setting. Patients were randomized (1:1)within 3 months after discontinuing bevacizumab as first-line treatment to receive fluoropyrimidine-irinotecan-or fluoropyrimidine-oxaliplatin-based chemotherapywith or without bevacizumab (5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks). The choice of second-line treatment was contingent upon first-line chemotherapy.Second-line treatment was administered until progressive disease or unacceptable toxicity. The main outcome measure was OS. A secondary outcome measure wasORR.
The median age was 63 years (21 to 84 years); 64% were male, 52% had an ECOG performance status of 1, 44% had an ECOG performance status of 0, 58% receivedirinotecan-based therapy as first-line treatment, 55% progressed on first-line treatment within 9 months, and 77% received their last dose of bevacizumab as first-linetreatment within 42 days of being randomized. Second-line chemotherapy regimens were generally balanced between each arm.
The addition of bevacizumab to fluoropyrimidine-based chemotherapy resulted in a statistically significant prolongation of OS and PFS. There was no significantdifference in ORR. Results are presented in Table 10 and Figure 2.
Table 10: Efficacy Results in Study ML18147
| Efficacy Parameter | Bevacizumab with Chemotherapy (N = 409) |
Chemotherapy (N = 411) |
| Overall Survival* | ||
| Median, in months | 11.2 | 9.8 |
| Hazard ratio (95% CI) | 0.81 (0.69, 0.94) | |
| Progression-Free Survival† | ||
| Median, in months | 5.7 | 4.0 |
| Hazard ratio (95% CI) | 0.68 (0.59, 0.78) | |
| *p = 0.0057 by unstratified log-rank test. †p-value < 0.0001 by unstratified log-rank test. |
||
Figure 2: Kaplan-Meier Curves for Duration of Survival in Metastatic Colorectal Cancer in Study ML18147
 |
Lack of efficacy of bevacizumab as an adjunct to standard chemotherapy for the adjuvant treatment of colon cancer was determined in two randomized, open-label,multicenter clinical studies. The first study [BO17920 (NCT00112918)] was conducted in 3451 patients with high-risk stage II and III colon cancer, who had undergonesurgery for colon cancer with curative intent. Patients were randomized to receive bevacizumab at a dose equivalent to 2.5 mg/kg/week on either a 2-weekly schedulewith FOLFOX4 (N = 1155) or on a 3-weekly schedule with XELOX (N = 1145) or FOLFOX4 alone (N = 1151). The main outcome measure was disease free survival(DFS) in patients with stage III colon cancer.
The median age was 58 years; 54% were male, 84% were White and 29% were ≥ 65 years. Eighty-three percent had stage III disease.
The addition of bevacizumab to chemotherapy did not improve DFS. As compared to FOLFOX4 alone, the proportion of stage III patients with disease recurrence orwith death due to disease progression were numerically higher for patients receiving bevacizumab with FOLFOX4 or with XELOX. The hazard ratios for DFS were1.17 (95% CI: 0.98,1.39) for bevacizumab with FOLFOX4 versus FOLFOX4 alone and 1.07 (95% CI: 0.90, 1.28) for bevacizumab with XELOX versus FOLFOX4alone. The hazard ratios for OS were 1.31 (95% CI: 1.03, 1.67) and 1.27 (95% CI: 1, 1.62) for the comparison of bevacizumab with FOLFOX4 versus FOLFOX4 aloneand bevacizumab with XELOX versus FOLFOX4 alone, respectively. Similar lack of efficacy for DFS was observed in the bevacizumab-containing arms compared toFOLFOX4 alone in the high-risk stage II cohort.
In a second study [NSABP-C-08 (NCT00096278)], patients with stage II and III colon cancer who had undergone surgery with curative intent, were randomized toreceive either bevacizumab administered at a dose equivalent to 2.5 mg/kg/week with mFOLFOX6 (N = 1354) or mFOLFOX6 alone (N = 1356). The median age was57 years, 50% were male and 87% White. Seventy-five percent had stage III disease. The main outcome was DFS among stage III patients. The HR for DFS was 0.92(95% CI: 0.77, 1.10). OS was not significantly improved with the addition of bevacizumab to mFOLFOX6 [HR 0.96 (95% CI: 0.75,1.22)].
The safety and efficacy of bevacizumab as first-line treatment of patients with locally advanced, metastatic, or recurrent non–squamous NSCLC was studied in a single,large, randomized, active-controlled, open-label, multicenter study [E4599 (NCT00021060)]. A total of 878 chemotherapy-naïve patients with locally advanced,metastatic or recurrent non–squamous NSCLC were randomized (1:1) to receive six 21-day cycles of paclitaxel (200 mg/m) and carboplatin (AUC 6) with or withoutbevacizumab 15 mg/kg. After completing or discontinuing chemotherapy, patients randomized to receive bevacizumab continued to receive bevacizumab alone untildisease progression or until unacceptable toxicity. The trial excluded patients with predominant squamous histology (mixed cell type tumors only), CNS metastasis,gross hemoptysis (½ teaspoon or more of red blood), unstable angina, or receiving therapeutic anticoagulation. The main outcome measure was duration of survival.
The median age was 63 years; 54% were male, 43% were ≥ 65 years, and 28% had ≥ 5% weight loss at study entry. Eleven percent had recurrent disease. Of the 89%with newly diagnosed NSCLC, 12% had Stage IIIB with malignant pleural effusion and 76% had Stage IV disease.
OS was statistically significantly longer for patients receiving bevacizumab with paclitaxel and carboplatin compared with those receiving chemotherapy alone. MedianOS was 12.3 months vs. 10.3 months [HR 0.80 (95% CI: 0.68, 0.94), final p-value of 0.013, stratified log-rank test]. Based on investigator assessment which was notindependently verified, patients were reported to have longer PFS with bevacizumab with paclitaxel and carboplatin compared to chemotherapy alone. Results arepresented in Figure 3.
Figure 3: Kaplan-Meier Curves for Duration of Survival in First-Line Non-Squamous Non-Small Cell Lung Cancer in Study E4599
 |
In an exploratory analysis across patient subgroups, the impact of bevacizumab on OS was less robust in the following subgroups: women [HR 0.99 (95% CI: 0.79,1.25)], patients ≥ 65 years [HR 0.91 (95% CI: 0.72, 1.14)] and patients with ≥ 5% weight loss at study entry [HR 0.96 (95% CI: 0.73, 1.26)].
The safety and efficacy of bevacizumab in patients with locally advanced, metastatic or recurrent non-squamous NSCLC, who had not received prior chemotherapy wasstudied in another randomized, double-blind, placebo-controlled study [BO17704 (NCT00806923)]. A total of 1043 patients were randomized (1:1:1) to receivecisplatin and gemcitabine with placebo, bevacizumab 7.5 mg/kg or bevacizumab 15 mg/kg. The main outcome measure was PFS. Secondary outcome measure was OS.
The median age was 58 years; 36% were female and 29% were ≥ 65 years. Eight percent had recurrent disease and 77% had Stage IV disease.
PFS was significantly higher in both bevacizumab-containing arms compared to the placebo arm [HR 0.75 (95% CI: 0.62, 0.91), p-value of 0.0026 for bevacizumab 7.5mg/kg and HR 0.82 (95% CI: 0.68; 0.98), p-value of 0.0301 for bevacizumab 15 mg/kg]. The addition of bevacizumab to cisplatin and gemcitabine failed todemonstrate an improvement in the duration of OS [HR 0.93 (95% CI: 0.78; 1.11), p-value of 0.420 for bevacizumab 7.5 mg/kg and HR 1.03 (95% CI: 0.86, 1.23), p-value of 0.761 for bevacizumab 15 mg/kg].
The safety and efficacy of bevacizumab were evaluated in a multicenter, randomized (2:1), open-label study in patients with recurrent GBM (EORTC 26101,NCT01290939). Patients with first progression following radiotherapy and temozolomide were randomized (2:1) to receive bevacizumab (10 mg/kg every 2 weeks)with lomustine (90 mg/m² every 6 weeks) or lomustine (110 mg/m² every 6 weeks) alone until disease progression or unacceptable toxicity. Randomization wasstratified by World Health Organization performance status (0 vs. > 0), steroid use (yes vs. no), largest tumor diameter (≤ 40 vs. > 40 mm), and institution. The mainoutcome measure was OS. Secondary outcome measures were investigator-assessed PFS and ORR per the modified Response Assessment in Neuro-oncology (RANO)criteria, health related quality of life (HRQoL), cognitive function, and corticosteroid use.
A total of 432 patients were randomized to receive lomustine alone (N = 149) or bevacizumab with lomustine (N = 283). The median age was 57 years; 24.8% ofpatients were ≥ 65 years. The majority of patients with were male (61%); 66% had a WHO performance status score > 0; and in 56% the largest tumor diameter was ≤40 mm. Approximately 33% of patients randomized to receive lomustine received bevacizumab following documented progression.
No difference in OS (HR 0.91, p -value of 0.4578) was observed between arms; therefore, all secondary outcome measures are descriptive only. PFS was longer in thebevacizumab with lomustine arm [HR 0.52 (95% CI: 0.41, 0.64)] with a median PFS of 4.2 months in the bevacizumab with lomustine arm and 1.5 months in thelomustine arm. Among the 50% of patients receiving corticosteroids at the time of randomization, a higher percentage of patients in the bevacizumab with lomustinearm discontinued corticosteroids (23% vs. 12%).
The efficacy and safety of bevacizumab 10 mg/kg every 2 weeks in patients with previously treated GBM were evaluated in one single arm single center study (NCI 06-C-0064E) and a randomized noncomparative multicenter study [AVF3708g (NCT00345163)]. Response rates in both studies were evaluated based on modified WHOcriteria that considered corticosteroid use. In AVF3708g, the response rate was 25.9% (95% CI: 17%, 36.1%) with a median duration of response of 4.2 months (95%CI: 3, 5.7). In Study NCI 06-C-0064E, the response rate was 19.6% (95% CI: 10.9%, 31.3%) with a median duration of response of 3.9 months (95% CI: 2.4, 17.4).
The safety and efficacy of bevacizumab were evaluated in patients with treatment-naïve mRCC in a multicenter, randomized, double-blind, international study[BO17705 (NCT00738530)] comparing interferon alfa and bevacizumab versus interferon alfa and placebo. A total of 649 patients who had undergone a nephrectomywere randomized (1:1) to receive either bevacizumab (10 mg/kg every 2 weeks; N = 327) or placebo (every 2 weeks; N = 322) with interferon alfa (9 MIUsubcutaneously three times weekly for a maximum of 52 weeks). Patients were treated until disease progression or unacceptable toxicity. The main outcome measurewas investigator-assessed PFS. Secondary outcome measures were ORR and OS.
The median age was 60 years (18 to 82 years); 70% were male and 96% were White. The study population was characterized by Motzer scores as follows: 28%favorable (0), 56% intermediate (1-2), 8% poor (3-5), and 7% missing.
PFS was statistically significantly prolonged among patients receiving bevacizumab compared to placebo; median PFS was 10.2 months vs. 5.4 months [HR 0.60 (95%CI: 0.49, 0.72), p-value < 0.0001, stratified log-rank test]. Among the 595 patients with measurable disease, ORR was also significantly higher (30% vs. 12%, p-value <0.0001, stratified CMH test). There was no improvement in OS based on the final analysis conducted after 444 deaths, with a median OS of 23 months in the patientsreceiving bevacizumab with interferon alfa and 21 months in patients receiving interferon alone [HR 0.86, (95% CI: 0.72, 1.04)]. Results are presented in Figure 4.
Figure 4: Kaplan-Meier Curves for Progression-Free Survival in Metastatic Renal Cell Carcinoma in Study BO17705
 |
The safety and efficacy of bevacizumab were evaluated in patients with persistent, recurrent, or metastatic cervical cancer in a randomized, four-arm, multicenter studycomparing bevacizumab with chemotherapy versus chemotherapy alone [GOG-0240 (NCT00803062)]. A total of 452 patients were randomized (1:1:1:1) to receivepaclitaxel and cisplatin with or without bevacizumab, or paclitaxel and topotecan with or without bevacizumab.
The dosing regimens for bevacizumab, paclitaxel, cisplatin and topotecan were as follows:
Patients were treated until disease progression or unacceptable adverse reactions. The main outcome measure was OS. Secondary outcome measures included ORR.
The median age was 48 years (20 to 85 years). Of the 452 patients randomized at baseline, 78% of patients were White, 80% had received prior radiation, 74% hadreceived prior chemotherapy concurrent with radiation, and 32% had a platinum-free interval of less than 6 months. Patients had a GOG performance status of 0 (58%)or 1 (42%). Demographic and disease characteristics were balanced across arms.
Results are presented in Figure 5 and Table 11.
Figure 5: Kaplan-Meier Curves for Overall Survival in Persistent, Recurrent, or Metastatic Cervical Cancer in Study GOG-0240
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Table 11: Efficacy Results in Study GOG-0240
| Efficacy Parameter | Bevacizumab with Chemotherapy (N = 227) |
Chemotherapy (N = 225) |
| Overall Survival | ||
| Median, in months* | 16.8 | 12.9 |
| Hazard ratio (95% CI) | 0.74 (0.58, 0.94) | |
| p-value† | 0.0132 | |
| *Kaplan-Meier estimates. †log-rank test (stratified). |
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The ORR was higher in patients who received bevacizumab with chemotherapy [45% (95% CI: 39, 52)] compared to patients who received chemotherapy alone [34%(95% CI: 28,40)].
Table 12: Efficacy Results in Study GOG-0240
| Efficacy Parameter | Topotecan and Paclitaxel with or without Bevacizumab (N = 223) |
Cisplatin and Paclitaxel with or without Bevacizumab (N = 229) |
| Overall Survival | ||
| Median, in months* | 13.3 | 15.5 |
| Hazard ratio (95% CI) | 1.15 (0.91, 1.46) | |
| p-value | 0.23 | |
| *Kaplan-Meier estimates. | ||
The HR for OS with bevacizumab with cisplatin and paclitaxel as compared to cisplatin and paclitaxel alone was 0.72 (95% CI: 0.51,1.02). The HR for OS withbevacizumab with topotecan and paclitaxel as compared to topotecan and paclitaxel alone was 0.76 (95% CI: 0.55, 1.06).
The safety and efficacy of bevacizumab were evaluated in a multicenter, randomized, double-blind, placebo controlled, three arm study [Study GOG-0218(NCT00262847)] evaluating the effect of adding bevacizumab to carboplatin and paclitaxel for the treatment of patients with stage III or IV epithelial ovarian, fallopiantube or primary peritoneal cancer (N=1873) following initial surgical resection. Patients were randomized (1:1:1) to one of the following arms:
The main outcome measure was investigator-assessed PFS. OS was a secondary outcome measure.
The median age was 60 years (range 22-89 years) and 28% of patients were > 65 years of age. Overall, approximately 50% of patients had a GOG PS of 0 at baseline,and 43% a GOG PS score of 1. Patients had either epithelial ovarian cancer (83%), primary peritoneal cancer (15%), or fallopian tube cancer (2%). Serousadenocarcinoma was the most common histologic type (85% in CPP and CPB15 arms, 86% in CPB15+ arm). Overall, approximately 34% of patients had resectedFIGO Stage III with residual disease < 1 cm, 40% had resected Stage III with residual disease > 1 cm, and 26% had resected Stage IV disease.
The majority of patients in all three treatment arms received subsequent antineoplastic treatment, 78.1% in the CPP arm, 78.6% in the CPB15 arm, and 73.2% in theCPB15+ arm. A higher proportion of patients in the CPP arm (25.3%) and CPB15 arm (26.6%) received at least one anti-angiogenic (including bevacizumab) treatmentafter discontinuing from study compared with the CPB15+ arm (15.6%).
Study results are presented in Table 13 and Figure 6.
Table 13: Efficacy Results in Study GOG-0218
| Efficacy Parameter | Bevacizumab with carboplatin and paclitaxel followed by bevacizumab alone (N = 623) |
Bevacizumab with carboplatin and paclitaxel (N = 625) |
Carboplatin and paclitaxel (N = 625) |
| Progression-Free Survival per Investigator | |||
| Median, in months | 18.2 | 12.8 | 12.0 |
| Hazard ratio (95% CI)* | 0.62 (0.52, 0.75) | 0.83 (0.70, 0.98) | |
| p-value† | < 0.0001 | NS | |
| Overall Survival‡ | |||
| Median, in months | 43.8 | 38.8 | 40.6 |
| Hazard ratio* (95% CI) | 0.89 (0.76, 1.05) | 1.06 (0.90, 1.24) | |
| *Relative to the control arm; stratified hazard ratio †Two-sided p-value based on re-randomization test ‡Final overall survival analysis |
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Figure 6: Kaplan-Meier Curves for Investigator-Assessed Progression-Free Survival in Stage III or IV Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal CancerFollowing Initial Surgical Resection in Study GOG-0218
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The safety and efficacy of bevacizumab were evaluated in a multicenter, open-label, randomized study [MO22224 (NCT00976911)] comparing bevacizumab withchemotherapy versus chemotherapy alone in patients with platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurredwithin < 6 months from the most recent platinum-based therapy (N = 361). Patients had received no more than 2 prior chemotherapy regimens. Patients received one ofthe following chemotherapy regimens at the discretion of the investigator: paclitaxel (80 mg/m² on days 1, 8, 15 and 22 every 4 weeks; pegylated liposomaldoxorubicin 40 mg/m² on day 1 every 4 weeks; or topotecan 4 mg/m² on days 1, 8 and 15 every 4 weeks or 1.25 mg/m² on days 1-5 every 3 weeks). Patients weretreated until disease progression, unacceptable toxicity, or withdrawal. Forty percent of patients on the chemotherapy alone arm received bevacizumab alone uponprogression. The main outcome measure was investigator-assessed PFS. Secondary outcome measures were ORR and OS.
The median age was 61 years (25 to 84 years) and 37% of patients were ≥ 65 years. Seventy-nine percent had measurable disease at baseline, 87% had baseline CA-125levels ≥ 2 times ULN and 31% had ascites at baseline. Seventy-three percent had a PFI of 3 months to 6 months and 27% had PFI of < 3 months. ECOG performancestatus was 0 for 59%, 1 for 34% and 2 for 7% of the patients.
The addition of bevacizumab to chemotherapy demonstrated a statistically significant improvement in investigator-assessed PFS, which was supported by aretrospective independent review analysis. Results for the ITT population are presented in Table 14 and Figure 7. Results for the separate chemotherapy cohorts arepresented in Table 15.
Table 14: Efficacy Results in Study MO22224
| Efficacy Parameter | Bevacizumab with Chemotherapy (N = 179) |
Chemotherapy (N = 182) |
| Progression-Free Survival per Investigator | ||
| Median (95% CI), in months | 6.8 (5.6, 7.8) | 3.4 (2.1, 3.8) |
| HR (95% CI)* | 0.38 (0.30, 0.49) | |
| p-value† | < 0.0001 | |
| Overall Survival | ||
| Median (95% CI), in months | 16.6 (13.7, 19.0) | 13.3 (11.9, 16.4) |
| HR (95% CI)* | 0.89 (0.69, 1.14) | |
| Overall Response Rate | ||
| Number of Patients with Measurable Disease at Baseline | 142 | 144 |
| Rate, % (95% CI) | 28% (21%, 36%) | 13% (7%, 18%) |
| Duration of Response | ||
| Median, in months | 9.4 | 5.4 |
| *per stratified Cox proportional hazards model. †per stratified log-rank test. |
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Figure 7: Kaplan-Meier Curves for Investigator-Assessed Progression-Free Survival in Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or PrimaryPeritoneal Cancer in Study MO22224
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Table 15: Efficacy Results in Study MO22224 by Chemotherapy
| Efficacy Parameter | Paclitaxel | Topotecan | Pegylated Liposomal Doxorubicin | |||
| Bevacizumab with Chemotherapy (N = 60) |
Chemotherapy (N = 55) |
Bevacizumab with Chemotherapy (N = 57) |
Chemotherapy (N = 63) |
Bevacizumab with Chemotherapy (N = 62) |
Chemotherapy (N = 64) |
|
| Progression-Free Survival per Investigator | ||||||
| Median, in months (95% CI) | 9.6(7.8, 11.5) | 3.9(3.5, 5.5) | 6.2(5.3, 7.6) | 2.1(1.9, 2.3) | 5.1(3.9, 6.3) | 3.5(1.9, 3.9) |
| Hazard ratio* (95% CI) | 0.47(0.31, 0.72) | 0.24(0.15, 0.38) | 0.47(0.32, 0.71) | |||
| Overall Survival | ||||||
| Median, in months (95% CI) | 22.4(16.7, 26.7) | 13.2(8.2, 19.7) | 13.8(11.0, 18.3) | 13.3(10.4, 18.3) | 13.7(11.0, 18.3) | 14.1(9.9, 17.8) |
| THazard ratio*(95% CI) | 0.64(0.41, 1.01) | 1.12(0.73, 1.73) | 0.94(0.63, 1.42) | |||
| Overall Response Rate | ||||||
| Number of patients with measurable disease atbaseline | 45 | 43 | 46 | 50 | 51 | 51 |
| Rate, %(95% CI) | 53(39, 68) | 30(17, 44) | 17(6, 28) | 2(0, 6) | 16(6, 26) | 8(0, 15) |
| Duration of Response | ||||||
| Median, in months | 11.6 | 6.8 | 5.2 | NE | 8.0 | 4.6 |
| *NE = Not Estimable †per stratified Cox proportional hazards model. |
||||||
The safety and efficacy of bevacizumab were evaluated in a randomized, double-blind, placebo-controlled study [AVF4095g (NCT00434642)] studying bevacizumabwith chemotherapy versus chemotherapy alone in the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritonealcancer who have not received prior chemotherapy in the recurrent setting or prior bevacizumab treatment (N = 484). Patients were randomized (1:1) to receivebevacizumab (15 mg/kg day 1) or placebo every 3 weeks with carboplatin (AUC 4, day 1) and gemcitabine (1000 mg/mon days 1 and 8) a for 6 to 10 cycles followedby bevacizumab or placebo alone until disease progression or unacceptable toxicity. The main outcome measures were investigator-assessed PFS. Secondary outcomemeasures were ORR and OS.
The median age was 61 years (28 to 87 years) and 37% of patients were ≥ 65 years. All patients had measurable disease at baseline, 74% had baseline CA-125 levels>ULN (35 U/mL). The PFI was 6 months to 12 months in 42 % of patients and >12 months in 58% of patients. The ECOG performance status was 0 or 1 for 99.8% ofpatients.
A statistically significant prolongation in PFS was demonstrated among patients receiving bevacizumab with chemotherapy compared to those receiving placebo withchemotherapy (Table 16 and Figure 8). Independent radiology review of PFS was consistent with investigator assessment [HR 0.45 (95% CI: 0.35, 0.58)]. OS was notsignificantly improved with the addition of bevacizumab to chemotherapy [HR 0.95 (95% CI: 0.77, 1.17)].
Table 16: Efficacy Results in Study AVF4095g
| Efficacy Parameter | Bevacizumab with Gemcitabine and Carboplatin (N = 242) |
Placebo with Gemcitabine and Carboplatin (N =242) |
| Progression-Free Survival | ||
| Median, in months | 12.4 | 8.4 |
| Hazard ratio | 0.46 | |
| (95% CI) | 0.37, 0.58) | |
| p-value | < 0.0001 | |
| Overall Response Rate | ||
| % patients with overall response | 78% | 57% |
| p-value | < 0.0001 | |
Figure 8: Kaplan Meier Curves for Progression-Free Survival in Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in StudyAVF4095g
 |
The safety and efficacy of bevacizumab were evaluated in a randomized, controlled, open-label study [Study GOG0213 (NCT00565851)] of bevacizumab withchemotherapy versus chemotherapy alone in the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer,who have not received more than one previous regimen of chemotherapy (N = 673). Patients were randomized (1:1) to receive carboplatin (AUC 5) and paclitaxel (175mg/mIV over 3 hours) every 3 weeks for 6 to 8 cycles (N=336) or bevacizumab (15 mg/kg) every 3 weeks with carboplatin (AUC 5) and paclitaxel (175 mg/mIVover 3 hours) for 6 to 8 cycles followed by bevacizumab (15 mg/kg every 3 weeks) as a single agent until disease progression or unacceptable toxicity. The mainoutcome measure was OS. Other outcome measures were investigator-assessed PFS, and ORR.
The median age was 60 years (23 to 85 years) and 33% of patients were ≥ 65 years. Eighty-three percent had measurable disease at baseline and 74% had abnormal CA-125 levels at baseline. Ten percent of patients had received prior bevacizumab. Twenty-six percent had a PFI of 6 months to 12 months and 74% had a PFI of >12months. GOG performance status was 0 or 1 for 99% of patients.
Results are presented in Table 17 and Figure 9.
Table 17: Efficacy Results in Study GOG-0213
| Efficacy Parameter | Bevacizumab with Carboplatin and Paclitaxel (N = 337) |
Carboplatin and Paclitaxel (N = 336) |
| Overall Survival | ||
| Median, in months | 42.6 | 37.3 |
| Hazard ratio (95% CI) (IVRS)* | 0.84 (0.69, 1.01) | |
| Hazard ratio (95% CI) (eCRF)† | 0.82 (0.68, 0.996) | |
| Progression-Free Survival | ||
| Median, in months | 13.8 | 10.4 |
| Hazard ratio (95% CI) (IVRS)* | 0.61 (0.51, 0.72) | |
| Overall Response Rate | ||
| Number of patients with measurable disease at baseline | 274 | 286 |
| Rate, % | 213 (78%) | 159 (56%) |
| *HR was estimated from Cox proportional hazards models stratified by the duration of treatment-free interval prior to enrolling onto this study per IVRS (interactive voice responsesystem) and secondary surgical debulking status. †HR was estimated from Cox proportional hazards models stratified by the duration of platinum free-interval prior to enrolling onto this study per eCRF (electronic case report form)and secondary surgical debulking status. |
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Figure 9: Kaplan Meier Curves for Overall Survival in Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Study GOG-0213
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