Antiangiogenic AntiVEGF Monoclonal Antibodies – Bevacizumab, Ziv-Aflibercept, Ramucirumab

Bevacizumab

• Recombinant humanized monoclonal IgG1 antibody which binds to and inhibit VEGF action.
• Produced in Chinese hamster ovary cells
• Molecular weight of 149kD

Pharmacokinetics

• T1/2 is around 17 -21 days
• Time to reach steady state levels – 100 days
• Minimal clearance by liver and kidney

Indications/Uses

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
Median OS	20.3m	15.6m
Median PFS	10.6m	6.2m
ORR	45%	35%

 

June 20, 2006 – FDA approval for the second-line treatment of metastatic colorectal cancer.

ECOG3200	FOLFOX + BEV	FOLFOX + PLACEBO
Median OS	13m	10.8m

 

January 23, 2013 – FDA approved for use in combination with fluoropyrimidine–irinotecan– or fluoropyrimidine–oxaliplatin-based chemotherapy in patients with mCRC progressed on 1^st line bevacizumab containing regimen.

TML TRIAL	CT + BEV	CT + PLACEBO
Median OS	11.2m	9.8m
Median PFS	5.7m	4.0m

 

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)

Maintenance Therapy

• • • 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 PFS	10.2m	5.4m
ORR	30.6%	12.4%
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
Median OS	16.8m	12.9m
ORR	45%	34%

 

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
Median PFS	6.8m	3.4m
OS	16.6m	13.3m

 

Administration

• 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)

Dosage

• 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

Temporary Discontinuation

• Severe infusion reactions.
• At least 4 weeks prior to and after elective surgery.
• Moderate-to-severe proteinuria.
• Severe hypertension not controlled with medical management.

Permanent Discontinuation

• 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
• RPLS

Ziv-Aflibercept

• 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.

Pharmacokinetics

• T1/2 – 17 days
• Metabolism and excretion not well characterized

Indication

• Metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen

VELOUR trial	FOLFIRI + Aflibercept	FOLFIRI
Median OS	13.5m	12.1m
Median PFS	6.9m	4.6m

 

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.

Dose Modification

• No dose adjustment required for mild to moderate hepatic impairment
• No dose adjustment for renal impairment

Ramucirumab

• 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

Pharmacokinetics

• Elimination t1/2 is 15-20 days
• Metabolism not well characterized
• No dose adjustment for renal impairment and mild hepatic impairment

Uses

• Advanced or metastatic gastric cancer with progression after prior 5FU or platinum containing chemotherapy
• Metastatic NSCLC  with progression after platinum based chemotherapy

Clinical Trials

REGARD TRIAL –In locally advanced or metastatic gastric cancer  who previously received platinum- or  5FU-containing chemotherapy.

REGARD TRIAL	RAM + BSC	PLACEBO + BSC
Median OS	5.2m	3.8m
PFS	2.1m	1.3m

 

RAINBOW TRIAL – Paclitaxel with or without Ramucirumab in patients with metastatic gastric or GEJ adenocarcinoma progressed on 1^st line chemotherapy

RAINBOW TRIAL	PACLI + RAM	PACLI + PLACEBO
Median OS	9.6m	7.4m
Median PFS	4.4m	2.8m
ORR	28%	16%

 

REVEL TRIAL – phase III study of ramucirumab + docetaxel vs docetaxel alone for 2^nd line treatment of stage IV NSCLC, after progression with platinum-based therapy.

REVEL TRIAL	DOCE + RAM	DOCE + PLACEBO
Median PFS	4.5m	3.0m
Median OS	10.5m	9.1m

 

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

Hypertension

• 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.

Proteinuria

• 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.

Management

• Temporary withholding of the drug if protein excretion if >2 g/day
• Permanent discontinuation for nephrotic syndrome
• ACE inhibitors/ARBs for persistent proteinuria.

Bleeding

• 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.

Arterial Thromboembolism

• 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.