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.

Avastin plus 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 [1,8]

  • 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]); p<0.0001
  • Median overall survival (OS) with Avastin plus IFN was 23 months, no improvement in OS 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 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 [1,7]

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

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Discontinue for gastrointestinal perforation
  • Surgery and wound healing complications
    • Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed
    • Discontinue in patients with wound healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage have occurred
    • Do not administer Avastin to patients with serious hemorrhage or recent history of hemoptysis
    • Discontinue for Grade 3-4 hemorrhage

AVOREN study: Efficacy data overview [1,3,7,8]

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. [7]

PFS and ORR were investigator-assessed in the AVOREN trial. [1,8]

AVOREN study: A large, multicenter, randomized, double-blind, placebo-controlled Phase III trial [1,7] 

Avastin Avoren Study Trial Design

RCC=renal cell carcinoma; IV=intravenous; q2w=every 2 weeks; MIU=million international units; sc=subcutaneous.
Patients in AVOREN were stratified by Memorial Sloan-Kettering Cancer Center (MSKCC) score and by country.
[7]

  • The initial primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS) and safety [7]
  • 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 [7]

 

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Discontinue for gastrointestinal perforation
  • Surgery and wound healing complications
    • Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed
    • Discontinue in patients with wound healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage have occurred
    • Do not administer Avastin to patients with serious hemorrhage or recent history of hemoptysis
    • Discontinue for Grade 3-4 hemorrhage

In AVOREN, per protocol [1,7]

  • 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

Indications

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

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to patients treated with chemotherapy
    • The incidence of GI perforation ranged from 0.3% to 3% across clinical studies
    • Discontinue Avastin in patients with GI perforation
  • Surgery and wound healing complications
    • The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients
    • Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed
    • Discontinue in patients with wound healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. In clinical studies, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 7%
    • Do not administer Avastin to patients with serious hemorrhage or a recent history of hemoptysis (≥1/2 tsp of red blood)
    • Discontinue Avastin in patients who develop grade 3-4 hemorrhage

Additional serious adverse events

  • Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs chemotherapy arm included:
    • Non-GI fistulae (<1% to 1.8%, highest in patients with cervical cancer)
    • Arterial thromboembolic events (grade ≥3, 5%, highest in patients with GBM)
    • Renal injury and proteinuria
      • Grade 3–4 proteinuria ranged from 0.7% to 7% in clinical studies
      • Nephrotic syndrome (<1%)
  • Additional serious adverse events 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) (1%)
  • Infusion reactions with the first dose of Avastin occurred in <3% of patients, and severe reactions occurred in 0.2% of patients
  • Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

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 that breastfeeding is not recommended during treatment with Avastin and for 6 months following their last dose of treatment
  • Avastin may impair fertility

Most common adverse events

  • 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
— Rectal 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 events

  • In mRCC, the most common grade 3–5 adverse events 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, including Boxed WARNINGS, for additional important safety information.