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Kidney Cancer: Avastin Efficacy Data

Metastatic renal cell carcinoma (mRCC)
Avastin, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell carcinoma.

AVOREN study results: Avastin plus interferon alfa (IFN) improved median progression-free survival (PFS) by 4.8 months and more than doubled objective response rate (ORR) vs placebo plus IFN[1]

AVOREN study: PFS results[1,13]

  • 4.8-month increase in median PFS: 10.2 months with Avastin plus IFN vs 5.4 months with placebo plus IFN
    • Hazard ratio (HR)=0.60 (95% confidence interval [CI], 0.49–0.72); P<0.0001
  • There was no improvement in median overall survival (OS) with Avastin plus IFN (23 months) vs placebo plus IFN (21 months, HR=0.86 [95% CI, 0.72–1.04] based on the final analysis conducted after 444 deaths[1]

Avastin® (bevacizumab) AVOREN Study Progression-Free Survival Results Chart
  • The PFS benefit of Avastin plus IFN was observed as early as 2 months and was sustained through the duration of the study[1,14]

PFS was investigator-assessed in the AVOREN trial.[1]

Select Important Safety Information

The Warnings and Precautions for Avastin include gastrointestinal perforation and fistulae, surgery and wound healing complications, hemorrhage, arterial thromboembolic events, venous thromboembolic events, hypertension, posterior reversible encephalopathy syndrome, renal injury and proteinuria, infusion-related reactions, embryo-fetal toxicity, ovarian failure, and congestive heart failure.

AVOREN study: Efficacy data overview[1,3,13,14] 

Endpoint   Avastin + IFN Placebo + IFN HR (95% CI) P value
  Number of patients 327 322    
Primary PFS (median) 10.2 months 5.4 months 0.60 (0.49–0.72) <0.0001
Initial primary* OS (median) 23 months 21 months 0.86 (0.72–1.04)  
Secondary ORR 30% (n=306) 12% (n=289)   <0.0001

*The initial primary endpoint was OS, with secondary endpoints including PFS and safety. Based on the approval of new active therapies during the conduct of the trial, which could have confounded OS analyses, it was agreed with regulatory agencies that PFS would become the main outcome measure. There was no improvement in OS.[14]

PFS and ORR were investigator-assessed in the AVOREN trial.[1,13]

AVOREN study: A large, multicenter, randomized, double-blind, placebo-controlled Phase III trial[1,14] 

Avastin® (bevacizumab) Avoren Study Trial Design

IV=intravenous; q2w=every 2 weeks; MIU=million international units; sc=subcutaneous.
Patients in AVOREN were stratified by Memorial Sloan-Kettering Cancer Center score and by country.[14]

  • The initial primary endpoint was OS, with secondary endpoints including PFS and safety[14]
  • Based on the approval of new active therapies during the conduct of the trial, which could have confounded OS analyses, it was agreed with regulatory agencies that PFS would become the main outcome measure[14]

In AVOREN, per protocol[1,14]

  • Avastin was continued until disease progression or unacceptable toxicity even if IFN was reduced or discontinued to manage IFN toxicities
  • IFN was discontinued after a maximum of 52 weeks, but Avastin was continued until disease progression or unacceptable toxicity 

Indication

Metastatic renal cell carcinoma (mRCC)

Avastin, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell carcinoma.

Serious adverse reactions (Warnings and Precautions)

  • Serious and sometimes fatal adverse reactions with increased incidence in the Avastin-treated arm vs chemotherapy arm included:
    • Gastrointestinal (GI) perforation ranged from 0.3% to 3% of patients across clinical studies
    • Non-GI fistulae (<1% to 1.8%, highest in patients with cervical cancer)
    • Arterial thromboembolic events (Grade ≥3, 5%, highest in patients with GBM)
    • The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients
    • Hemorrhage (Grade 3–5) ranged from 0.4% to 7% of patients across clinical studies
    • Renal injury and proteinuria
      • Grade 3–4 proteinuria ranged from 0.7% to 7% in clinical studies
      • Nephrotic syndrome (<1%)
  • Additional serious adverse reactions with increased incidence in the Avastin-treated arm vs chemotherapy arm included:
    • Venous thromboembolism (Grade ≥3, 11% seen in GOG-0240)
    • Hypertension (Grade 3–4, 5%–18%)
    • Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
    • Congestive heart failure (CHF): Grade ≥3 left ventricular dysfunction (1%)
  • Infusion-related reactions with the first dose of Avastin occurred in <3% of patients, and severe reactions occurred in 0.4% of patients
  • Avoid use 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
  • Inform females of reproductive potential of the risk of ovarian failure prior to initiating treatment with Avastin
  • An evaluation for the presence of varices is recommended within 6 months of initiation of Avastin in patients with HCC

Pregnancy warning

  • Based on the mechanism of action and animal studies, Avastin may cause fetal harm
  • Advise female patients that Avastin may cause fetal harm, and to inform their healthcare provider of a known or suspected pregnancy
  • Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose of Avastin
  • Advise nursing women not to breastfeed during treatment with Avastin and for 6 months following their last dose of treatment
  • Avastin may impair fertility

Most common adverse reactions

  • Across studies, the most common adverse reactions observed in Avastin patients at a rate >10% were:
    • Epistaxis
    • Headache
    • Hypertension
    • Rhinitis
    • Proteinuria
    • Taste alteration
    • Dry skin
    • Hemorrhage
    • Lacrimation disorder
    • Back pain
    • Exfoliative dermatitis

  • Across all studies, Avastin was discontinued in 8% to 22% of patients because of adverse reactions

Indication-specific adverse reactions

  • In mRCC, the most common Grade 3–5 adverse reactions in AVOREN, occurring at a >2% higher incidence in Avastin-treated patients vs controls, 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 ulcer hemorrhage, gingival bleeding, hemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma)

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.
You may also report side effects to Genentech at (888) 835-2555.

Please see full Prescribing Information for additional important safety information.

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