Colorectal Cancer: Avastin Efficacy Data

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

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.

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® (bevacizumab) Overall Survival Results for Clinical Trial 2107

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

First-line Study 2107: Efficacy data overview [1,2]

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)
<0.0001
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 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

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® (bevacizumab) 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]

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

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
    • 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

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® (bevacizumab) Overall Survival 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; 52% ECOG PS of 1; 58% received irinotecan-containing therapy as first-line treatment; 55% progressed on first-line treatment within 9 months; 77% received their 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® (bevacizumab) Second-Line Study E3200 Overall Survival Results

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

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
    • 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

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% White; 49% ECOG PS of 0; 26% received prior radiation therapy; 80% received prior adjuvant chemotherapy, 99% received prior irinotecan with or without 5-fluorouracil for metastatic disease, and 1% received prior irinotecan and 5-fluorouracil as adjuvant therapy [1]

Start and continue with Avastin: A first- through second-line clinical summary

Dr. John Marshall presents the Avastin MCRC pivotal trials.

Overview

  • 1L Study 2107 trial design and results
  • TML Study trial design and results

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

Indications

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

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 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 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 fatigue (19% vs 13%), diarrhea (18% vs 13%), sensory neuropathy (17% vs 9%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), hypertension (9% vs 2%), abdominal pain (8% vs 5%), hemorrhage (5% vs 1%), other neurological (5% vs 3%), ileus (4% vs 1%), and headache (3% vs 0%). 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 MCRC5

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.