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Colorectal Cancer: Avastin Efficacy Data

Metastatic colorectal cancer (MCRC)
Avastin, in combination with intravenous 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 bevacizumab product-containing regimen.

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

1L Study 2107 Results 2L TML Study Results 2L Study E3200 Results 
1L Study 2107 Results

Start Avastin first line for proven overall survival (OS)[1]

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

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.

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

Endpoint   Avastin + IFL
 FOLFOX4 alone HR (95% CI) Pvalue
  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

1L=first line; HR=hazard ratio; CI=confidence interval; PFS=progression-free survival; ORR=overall response rate.

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) 0–2; adequate renal, hepatic, and hematologic function; prior chemotherapy with an irinotecan- and fluoropyrimidine-containing regimen for advanced disease[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] 
2L TML Study Results

Continue Avastin beyond first progression for proven overall survival (OS)[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]

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.

First- through second-line TML study*: Efficacy data overview[1,4]

Endpoint   Avastin + fluoropyrimidine-based chemotherapy† Fluoropyrimidine-based chemotherapy† alone HR (95% CI) Pvalue
  Number of patients 409
 411
    
Primary OS (median) 11.2 months 9.8 months 0.81 (0.69–0.94) 0.057
Secondary PFS (median) 5.7 months 4.0 months 0.68 (0.59–0.78)
 <0.0001

2L=second line; HR=hazard ratio; CI=confidence interval; PFS=progression-free survival.

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

Overall survival results by chemotherapy backbone[1,5]

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*[4]

“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.”[4]

— 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[1,4]

  • 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[4]
    • 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)[4]
    • 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] 
2L Study E3200 Results 

Avastin is the first FDA-approved biologic with proven overall survival (OS) benefits in second-line Avastin-naive patients with MCRC[1,6]

Significant increase in OS achieved in second-line Study E3200[1,3,6]

  • 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

2L=second line; HR=hazard ratio; CI=confidence interval.

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.

Second-line Study E3200: Efficacy data overview[1,3,6] 

Endpoint   Avastin + FOLFOX4 FOLFOX4 alone HR (95% CI) Pvalue
  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 PFS (median) 23%
 9%
   <0.0001

PFS=progression-free survival; ORR=overall response rate.
*n=280.[6]
†n=279.[6]

Second-line Study E3200: Study design and patient population[1,3,6]

  • 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[1,6]
    • 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[3,6]
    • 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[3,6]
    • 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]
View the 1L MCRC (Study 2107) publication by Hurwitz et al
View the 2L MCRC (Study E3200) publication by Giantonio et al

Overview

  • First-line Study 2107 trial design and results
  • TML Study trial design and results

Important Safety Information & Indication

Indication

Metastatic colorectal cancer (MCRC)

Avastin, in combination with intravenous 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 bevacizumab product-containing regimen.

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

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 first-line MCRC, the most common Grade 3–4 reactions 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) reactions 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 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 for additional important safety information.

    • Avastin Prescribing Information. Genentech, Inc. 2022.

      Avastin Prescribing Information. Genentech, Inc. 2022.

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