Colorectal Cancer: Avastin Efficacy Data


Avastin® (bevacizumab) is the only available biologic cancer treatment proven to increase overall survival (OS) in 3 large Phase III trials in first- and second-line metastatic colorectal cancer (MCRC). [1,2,4]

Start Avastin first line for proven overall survival [1]

Avastin is the only available biologic cancer therapy with an FDA-approved label that includes prospectively demonstrated OS in a Phase III first-line MCRC trial. [1,2]

First-line Study 2107: Significant increase in OS achieved in first-line Study 2107 [1-3]

  • 4.7-month increase in median OS: 20.3 months with Avastin plus 5-fluorouracil/leucovorin/irinotecan (IFL) vs 15.6 months with placebo plus IFL
Avastin Overall Survival Results for Clinical Trial 2107

First-line Study 2107: Efficacy data overview [1-3]

Endpoint

 

Avastin + IFL

Placebo + IFL

HR (95% CI)

P value

  Number of patients 402 411    
Primary OS (median) 20.3 months 15.6 months 0.66
(0.54–0.81)
<0.001
Secondary PFS (median) 10.6 months 6.2 months 0.54
(0.45–0.66)
<0.001
Secondary ORR 45% 35%  

<0.01

PFS=progression-free survival; ORR=overall response rate.

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence (up to 3.2%) in Avastin-treated patients compared to controls. Discontinue Avastin for 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 
    • Discontinue in patients with wound dehiscence. Discontinue at least 28 days prior to elective surgery. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined
    • Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed
  • Hemorrhage
    • Severe or fatal hemorrhage, hemoptysis, GI bleeding, CNS hemorrhage, epistaxis, and vaginal bleeding are increased in Avastin-treated patients. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis

First-line Study 2107: Study design and patient population [1,2]

  • Study AVF2107g was a randomized, double-blind, active-controlled clinical trial evaluating the efficacy and safety of Avastin plus IFL vs placebo plus IFL in patients with first-line MCRC [1,2]
    • Inclusion criteria: included Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1; adequate renal, hepatic, and hematologic function [2]
    • Exclusion criteria: included prior chemotherapy for metastasis (prior adjuvant treatment >12 months before study entry was allowed); radiotherapy within 14 days; major surgery within 28 days; clinically significant cardiovascular disease; clinically detectable ascites; central nervous system metastases; ongoing therapeutic anticoagulation; regular use of aspirin (>325 mg/day) or other nonsteroidal anti-inflammatory drugs [2]
    • Patient characteristics: median age, 60 years; 40% female; 79% Caucasian; 57% ECOG PS of 0; 21% with a primary rectal tumor; 28% received prior adjuvant chemotherapy; 56% with extra-abdominal dominant disease site; 38% with liver as the dominant disease site; patients were studied regardless of biomarker status [1]

Continue Avastin beyond first progression for proven overall survival [1]

Avastin is the only available biologic cancer therapy to demonstrate significant OS when continued after a first-line Avastin-containing regimen in MCRC. [1]

Significant increase in OS achieved after first progression in the first- through second-line TML study‡[1]

  • 1.4-month increase in median OS: 11.2 months with Avastin plus fluoropyrimidine-based chemotherapy§ vs 9.8 months with fluoropyrimidine-based chemotherapy§ alone
Avastin Median Overall Survival Rate for First through Second-Line TML Study

TML=Treatment through Multiple Lines (first and second line).
§Chemotherapy combinations included either an irinotecan- or oxaliplatin-containing regimen. [1]

First- through second-line TML study: Efficacy data overview [1,5]

Endpoint   Avastin + fluoropyrimidine-based chemotherapy§ Fluoropyrimidine-based chemotherapy§ alone HR (95% CI) P value
  Number of patients 409 411    
Primary OS (median) 11.2 months 9.8 months 0.81 (0.69–0.94) 0.0057
Secondary PFS (median) 5.7 months 4.0 months 0.68 (0.59–0.78) <0.0001

PFS=progression-free survival.

There was no significant difference in response rate. [1]

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence (up to 3.2%) in Avastin-treated patients compared to controls. Discontinue Avastin for 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 
    • Discontinue in patients with wound dehiscence. Discontinue at least 28 days prior to elective surgery. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined
    • Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed
  • Hemorrhage
    • Severe or fatal hemorrhage, hemoptysis, GI bleeding, CNS hemorrhage, epistaxis, and vaginal bleeding are increased in Avastin-treated patients. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis

Overall survival results by chemotherapy backbone [1,35]

When continued through first- and second-line MCRC, Avastin demonstrated OS benefits in combination with both oxaliplatin- and irinotecan-containing chemotherapy that were consistent with the intent-to-treat population. 

Avastin Demonstrated Overall Survival Benefits when Continued through First and Second-Line MCRC

||Chemotherapy combinations included either an irinotecan- or oxaliplatin-containing regimen.[1]

  • More than 8 variations of fluoropyrimidine-based chemotherapy were received by patients enrolled in the TML study[5]‡

“Our results show that bevacizumab continued beyond disease progression, while switching chemotherapy, is beneficial for patients with metastatic colorectal cancer who were previously treated with bevacizumab in the first-line setting.”[5]

— Bennouna J, Sastre J, Arnold D, et al. Lancet Oncol. 2013;14:29-37.

First- through second-line TML study: Study design and patient population [1,5]

  • The TML study was a prospective, randomized, open-label, multinational, controlled, Phase III clinical trial evaluating the use of Avastin following MCRC disease progression on a first-line Avastin-containing regimen [1]
    • Inclusion criteria: included Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2; evidence of tumor according to Response Evaluation Criteria in Solid Tumors (RECIST) up to 4 weeks prior to start of study treatment; previous treatment with Avastin plus a fluoropyrimidine and either oxaliplatin or irinotecan; not being a candidate for primary metastasectomy [5]
    • Exclusion criteria: included diagnosis of progressive disease >3 months after the last Avastin administration; first-line progression-free survival <3 months; first-line Avastin therapy duration <3 months (consecutive) [5]
    • Patient characteristics: median age, 63 years; 36% female; 44% ECOG PS of 0; 58% received irinotecan-containing therapy as first-line treatment; 55% progressed on first-line treatment within 9 months; 77% received the last dose of Avastin as a first-line treatment within 42 days of randomization [1]

Avastin is the first FDA-approved biologic with proven OS benefits in second-line Avastin-naive patients with MCRC [1,4]

Significant increase in OS achieved in second-line Study E3200 [1,3,4]

  • 2.2-month increase in median OS: 13.0 months with Avastin plus 5-fluorouracil (5-FU)/leucovorin/oxaliplatin (FOLFOX4) vs 10.8 months with FOLFOX4 alone
Avastin Second-Line Study E3200 Overall Survival Results Graph

Second-line Study E3200: Efficacy data overview [1,3,4]

Endpoint   Avastin + FOLFOX4 FOLFOX4 alone HR (95% CI) P value
  Number of patients 286 291    
Primary OS (median) 13.0 months 10.8 months 0.75 (0.63–0.89) 0.001
Secondary PFS (median) 7.3 months* 4.7 months 0.61 <0.0001
Secondary ORR 23% 9%   <0.0001

PFS=progression-free survival; ORR=overall response rate.
*n=280.
[4]
n=279. [4]

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence (up to 3.2%) in Avastin-treated patients compared to controls. Discontinue Avastin for 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 
    • Discontinue in patients with wound dehiscence. Discontinue at least 28 days prior to elective surgery. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined
    • Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed
  • Hemorrhage
    • Severe or fatal hemorrhage, hemoptysis, GI bleeding, CNS hemorrhage, epistaxis, and vaginal bleeding are increased in Avastin-treated patients. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis

Second-line Study E3200: Study design and patient population [1,3,4]

  • Study E3200 was an open-label, randomized, active-controlled, multicenter clinical trial evaluating Avastin plus FOLFOX4 vs FOLFOX4 alone as a second-line MCRC treatment [1,4]
    • Inclusion criteria: included Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2; adequate renal, hepatic, and hematologic function; prior chemotherapy with an irinotecan- and fluoropyrimidine-containing regimen for advanced disease [3,4]
    • Exclusion criteria: included previous use of oxaliplatin or Avastin; history of hypertension (unless blood pressure was well controlled); proteinuria (≥500 mg/24 hours); radiotherapy within 14 days; major surgery within 28 days; ongoing therapeutic anticoagulation; regular use of aspirin (>325 mg/day) or other platelet inhibitors [3,4]
    • Patient characteristics: median age, 61 years; 40% female; 87% Caucasian; 49% ECOG PS of 0; 26% received prior radiation therapy; 80% received prior adjuvant chemotherapy [1]

Start and continue with Avastin: a hypothetical patient’s journey

Dr. John Marshall presents the Avastin MCRC pivotal trials. Follow a hypothetical patient through first- and second-line treatment with Avastin.

Overview

  • Hypothetical patient profile
  • 1L Study 2107 trial design and results
  • Hypothetical patient: 1L treatment
  • TML Study trial design and results
  • Hypothetical patient: 2L treatment
  • First- through second-line clinical summary

Dr. John Marshall received a consultation fee for sharing his opinion and treatment practices with Avastin.

Indications

Metastatic colorectal cancer (MCRC)
Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls
    • The incidences of GI perforation ranged from 0.3% to 3.2% 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
    • Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined
    • Discontinue Avastin at least 28 days prior to elective surgery and 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. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 6.9% 
    • Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) 
    • Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

  • Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included
    • GI fistulae (up to 2% in metastatic colorectal cancer and ovarian cancer patients)
    • Non-GI fistulae (<1% in trials across various indications; 1.8% in a cervical cancer trial) 
    • Arterial thromboembolic events (grade ≥3, 2.6%)
    • Proteinuria (nephrotic syndrome, <1%)
  • Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included 
    • GI-vaginal fistulae occurred in 8.3% of patients in a cervical cancer trial
    • Hypertension (grade 3–4, 5%–18%)
    • Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
  • Infusion reactions with the first dose of Avastin were uncommon (<3%), 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
  • Avastin may impair fertility

Most common adverse events

  • Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate 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 8.4% to 21% of patients because of adverse reactions

Indication-specific adverse events

  • In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)
  • In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study
  • When continued beyond first progression in MCRC, no new safety signals were observed in the TML study (ML18147) when Avastin was administered in second-line MCRC patients who progressed on an Avastin containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC

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.