- Recombinant humanized monoclonal IgG1 antibody which binds to and inhibit VEGF action.
- Produced in Chinese hamster ovary cells
- Molecular weight of 149kD
- T1/2 is around 17 -21 days
- Time to reach steady state levels – 100 days
- Minimal clearance by liver and kidney
First and second-line treatment of metastatic colorectal cancer
February 26, 2004 – FDA approved bevacizumab as a first-line treatment for metastatic colorectal cancer
|AVF2107g||IFL + BEV||IFL + PLACEBO|
June 20, 2006 – FDA approval for the second-line treatment of metastatic colorectal cancer.
|ECOG3200||FOLFOX + BEV||FOLFOX + PLACEBO|
January 23, 2013 – FDA approved for use in combination with fluoropyrimidine–irinotecan– or fluoropyrimidine–oxaliplatin-based chemotherapy in patients with mCRC progressed on 1st line bevacizumab containing regimen.
|TML TRIAL||CT + BEV||CT + PLACEBO|
First-line treatment of Non-Small non squamous Lung Cancer
First Line Therapy
- October 11, 2006 – FDA approved bevacizumab in combination with carboplatin and paclitaxel, for locally advanced, recurrent, or metastatic, non-squamous, NSCLC.
- Median OS 3 vs 10.3 months(ECOG 4599)
- Continuation maintenance therapy with bevacizumab and pemetrexed showed PFS advantage (6 mths vs 5.6 mths) (POINTBREAK STUDY).
First line treatment of renal cell carcinoma
- July 31, 2009 – FDA approved Bevacizumab in combination with INF-α for mRCC.
|AVOREN trial||INF-α + BEV||INF-α + PLACEBO|
|Median OS||No OS benefit|
Recurrent GBM (Glioblastoma Multiformae)
On May 5, 2009, FDA approved for patients with glioblastoma, with progressive disease following prior therapy with radiation and temozolamide.
AVF3708g – Patients received bevacizumab alone or with irinotecan every 2 weeks until disease progression.
- Responses were observed in 25.9% and 38%
- Median survival was 9 months.
NCI 06-C-0064E – continuation of bevacizumab in the patients who have previously received bevacizumab.
- Prevents rapid neurological deterioration
- ORR – 19.6 %
- Median survival of 32 weeks
Persistent, recurrent, or metastatic cervical cancer
August 14, 2014 – FDA approved in combination with paclitaxel and either cisplatin or topotecan for the treatment of persistent, recurrent, or metastatic cervical cancer.
|GOG240||CT + BEV||CT + PLACEBO|
Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
November 14, 2014, FDA approved bevacizumab in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan, for platinum-resistant recurrent or advanced epithelial ovarian cancer.
|AURELIA trial||CT + BEV||CT + PLACEBO|
- Infuse the initial dose over 90 minutes.
- The second infusion may be shortened to 60 minutes if the initial infusion is well tolerated.
- The third and subsequent infusions may be shortened to 30 minutes if the 60-minute infusion is well tolerated.
- Monitor closely during the infusion for signs/symptoms of an infusion reaction.
- Do not administer I.V. push.
- Do not administer with dextrose solutions.
- Available as 100mg and 400mg vial (25 mg/mL)
- mCRC, in combination with fluorouracil-based chemotherapy:
- 5 mg/kg every 2 weeks (in combination with IFL reg) or
- 10 mg/kg every 2 weeks (in combination with FOLFOX4)
- mCRC, following first-line therapy containing bevacizumab:
- 5 mg/kg every 2 weeks or 5 mg/kg every 3 weeks
- NSCLC (non-squamous cell histology):
- 15 mg/kg every 3 wks for 4-6 cycles followed by maintenance treatment (unlabeled use) of bevacizumab 15 mg/kg every 3 weeks as monotherapy until disease progression or unacceptable toxicity (Sandler, 2006)
- Renal cell cancer, metastatic:
- 10 mg/kg every 2 weeks (in combination with interferon alfa)
- Glioblastoma: 10 mg/kg every 2 weeks
- Ovarian cancer : 10mg/kg every 2 weeks
- Cervical cancer : 15mg/kg every 3 weeks
When to discontinue Bevacizumab
- Severe infusion reactions.
- At least 4 weeks prior to and after elective surgery.
- Moderate-to-severe proteinuria.
- Severe hypertension not controlled with medical management.
- Wound dehiscence and wound healing complications requiring intervention
- Fistula and gastrointestinal perforation
- Hypertensive crisis or encephalopathy
- Serious bleeding/hemorrhage
- Severe arterial thromboembolic event
- Nephrotic syndrome
- Dimeric glycoprotein with a molecular weight of 115 kDa
- Designed to function as VEGF trap to prevent activation of VEGF receptors and thus inhibit angiogenesis.
- T1/2 – 17 days
- Metabolism and excretion not well characterized
- Metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen
|VELOUR trial||FOLFIRI + Aflibercept||FOLFIRI|
Dosing and Administration
- Available as 100mg/4mL and 200mg/8mL (25 mg per mL) vials.
- Dose – 4 mg/kg every two weeks
- Administer the diluted solution (in NS or 5%D) as an intravenous infusion over 1 hour through a 0.2 micron polyethersulfone filter.
- Do not administer as an intravenous (IV) bolus.
- No dose adjustment required for mild to moderate hepatic impairment
- No dose adjustment for renal impairment
- Recombinant human IgG1 monoclonal antibody
- Binds to VEGF receptor 2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D.
- Molecular weight – 147 kDa
- Elimination t1/2 is 15-20 days
- Metabolism not well characterized
- No dose adjustment for renal impairment and mild hepatic impairment
- Advanced or metastatic gastric cancer with progression after prior 5FU or platinum containing chemotherapy
- Metastatic NSCLC with progression after platinum based chemotherapy
REGARD TRIAL –In locally advanced or metastatic gastric cancer who previously received platinum- or 5FU-containing chemotherapy.
|REGARD TRIAL||RAM + BSC||PLACEBO + BSC|
RAINBOW TRIAL – Paclitaxel with or without Ramucirumab in patients with metastatic gastric or GEJ adenocarcinoma progressed on 1st line chemotherapy
|RAINBOW TRIAL||PACLI + RAM||PACLI + PLACEBO|
REVEL TRIAL – phase III study of ramucirumab + docetaxel vs docetaxel alone for 2nd line treatment of stage IV NSCLC, after progression with platinum-based therapy.
|REVEL TRIAL||DOCE + RAM||DOCE + PLACEBO|
Dosage and Administration
- 8 mg/kg every 2 weeks – gastric cancer
- 10mg/kg every 3 weeks – NSCLC
- Given by IV infusion over 60min in 250mL of 9%NaCl
- Do not use dextrose containing solution
- Do not freeze or shake
- Available as 100mg/10mL and 500mg/50mL vials
Dose modification in Infusion related reaction(IRR)
- Reduce the infusion rate by 50% for Grade 1 or 2 IRRs.
- Permanently discontinue for Grade 3 or 4 IRRs.
Class Side Effects of Anti-VEGF Therapy
- VEGF decreases vascular resistance by release of nitric oxide and prostacyclines ; inhibition of which causes hypertension.
- Incidence – 9% and 67% (all grades)
- Incidence of severe hypertension (Grade 3 or Grade 4) – 3% and 18%.
- Sorafenib, Bevacizumab< Axitinib < Sunitinib, Pazopanib, Regorafenib, Cabozantinib, Vandetanib < Aflibercept
- Dose -dependent.
- Observed within the first few weeks of treatment
- Regular BP monitoring is recommended, more frequently during initial weeks.
- Target BP is <140/90 mm Hg.
- Treatment should be interrupted for severe hypertension (>200 mm Hg systolic or >110 mm Hg diastolic), hypertensive urgency or persistent hypertension despite anti-hypertensive medications.
- Mild proteinuria – 21 to 63 %
- Grade 3 proteinuria (defined as 3+ on dipstick, >3.5 g of protein/24 hours, or nephrotic syndrome) – 2 %
- Cause not understood – Renal thrombotic microangiopathy leading to glomerular capillary endothelial injury.
- Temporary withholding of the drug if protein excretion if >2 g/day
- Permanent discontinuation for nephrotic syndrome
- ACE inhibitors/ARBs for persistent proteinuria.
- Incidence (all grades) – 30 %
- Risk of major bleeding – 2.8%
- Most common – epistaxis; although hemoptysis, GI bleeding, intracerebral hemorrhage, and intratumoral hemorrhage may also occur.
- Decreased regenerating capacity and endothelial cell defect leading to weakening of walls of blood vessels.
- Incidence of arterial TE is 4-5 %, i.e., 2-3 fold higher than controls.
- Anti VEGF agents cause defects that exposes pro-coagulant phospholipids on the luminal plasma membrane or underlying matrix, leading to platelet aggregation and thrombosis.
- Past h/o of TE event not an absolute CI.
- Continuation with concurrent anticoagulation is recommended for patients benefitting from therapy.
- Discontinuation recommended in severe TE events.
Intestinal perforation/fistula formation
- Incidence 1-4%
- Risk factors – abdominal carcinomatosis, acute diverticulitis, bowel obstruction, recent h/o sigmoidoscopy or colonoscopy and h/o pelvic or abdominal irradiation.
- Prevention – Gap of at least 4 weeks (preferably 6 – 8 weeks) from surgery
- For TKIs 2 weeks gap should be given
- Management – appropriate surgical intervention and permanent discontinuation of VEGF-targeted therapy.
Reversible posterior leukoencephalopathy
- Serious but reversible condition
- Headache, altered mental function, seizure and visual disturbances.
- Associated with hypertension, cerebral edema and vasospasm.
- Endothelial cell damage and breakdown of BBB implicated in pathophysiology.
Prevention and management –
- Control of blood pressure
- In suspected cases of RPLS, discontinue the agent
- Plasmapheresis may be considered.