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

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Bevacizumab

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 fluoropyrimidineirinotecan– or fluoropyrimidine–oxaliplatin-based chemotherapy in patients with mCRC progressed on 1st 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

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 1st 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 2nd 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.

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