Clinically meaningful activity in 6 distinct tumor types [1]

Metastatic colorectal cancer (MCRC)

First-line MCRC Study 2107: Avastin plus 5-fluorouracil (5-FU)/leucovorin (LV)/irinotecan (IFL) [1-3]

Endpoint   Avastin + IFL Placebo + IFL HR 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

HR=hazard ratio; CI=confidence interval; OS=overall survival; PFS=progression-free survival; ORR=overall response rate.

Second-line MCRC Study E3200: Avastin plus 5-FU/LV/oxaliplatin (FOLFOX4) in Avastin-naive patients [1,3,4]

Endpoint   Avastin + FOLFOX4 FOLFOX4 alone HR
(95% Cl)
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

Second-line TML study*: Avastin plus fluoropyrimidine-based chemotherapy in MCRC patients who progressed on a first-line Avastin-containing regimen [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

*TML=Treatment through Multiple Lines (first and second line).
Chemotherapy combinations included either an irinotecan- or oxaliplatin-containing regimen. After first progression, chemotherapy was switched: oxaliplatin → irinotecan or irinotecan → oxaliplatin.
[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

Non-squamous non-small cell lung cancer (NSCLC)

Study E4599: Avastin plus paclitaxel/carboplatin (PC) in first-line metastatic non-squamous NSCLC [1,3,6]

Endpoint   Avastin + PC PC alone  HR (95% Cl) P value
  Number of patients 434 444    
Primary OS (median) 12.3 months 10.3 months 0.80
(0.68–0.94)
0.013
Secondary

PFS (median)

6.2 months

4.5 months

0.66
(0.57–0.77)

<0.001

Secondary

Objective response rate

35%

15%

 

<0.001

Based on investigator assessment (not independently verified).

Metastatic renal cell carcinoma (mRCC)

AVOREN study: Avastin plus interferon alfa (IFN) in mRCC [1,7,8]

Endpoint   Avastin + IFN Placebo + IFN HR (95% Cl) 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)

0.1291

Secondary

Objective response rate

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. [7]

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
    • Venous thromboembolism (grade 3–4, up to 10.6%) in patients with persistent, recurrent, or metastatic cervical cancer treated with Avastin
    • 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 
  • 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

Persistent, recurrent, or metastatic cervical cancer (CC)

GOG 240 study: Avastin plus chemotherapy in CC [1]

Endpoint   Avastin + chemotherapy Chemotherapy alone HR
(95% Cl)
P
value
  Number of patients 227 225    
Primary OS (median) 16.8 months 12.9 months 0.74
(0.58–0.94)
0.0132
Secondary ORR 45%
(95% Cl, 39–52)

34%
(95% CI, 28–40)

   

Chemotherapy included either cisplatin/paclitaxel or topotecan/paclitaxel.

Platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (prOC)

AURELIA ITT: Avastin plus chemotherapy in prOC [1]

Endpoint   Avastin + Chemotherapy Chemotherapy alone HR (95% Cl) P value
  Number of patients 179 182    
Primary PFS (median) 6.8 months 3.4 months 0.38
(0.30–0.49)
<0.0001
Secondary OS (median) 16.6 months 13.3 months 0.89
(0.69–1.14)
 
Secondary ORR 28%
(n=142)
(95% Cl, 21–36)
13%
(n=144)
(95% Cl, 7–18)
   

Chemotherapy included paclitaxel, pegylated liposomal doxorubicin, or topotecan.

Median PFS by chemotherapy cohort [1]

Chemotherapy cohort

Avastin + chemotherapy

Chemotherapy alone

HR
(95% CI)

Avastin + paclitaxel

9.6 months
(n=60)

3.9 months
(n=55)

0.47
(0.31–0.72)

Avastin + topotecan

6.2 months
(n=57)

2.1 months
(n=63)

0.24
(0.15–0.38)

Avastin + PLD

5.1 months
(n=62)

3.5 months
(n=64)

0.47
(0.32–0.71)

PLD=pegylated liposomal doxorubicin.

Cohort analysis based on prespecified endpoint (PFS). Analysis not designed to evaluate statistical significance between treatment arms or compare among the 3 chemotherapy cohorts.

Median OS by chemotherapy cohort [1]

Chemotherapy cohort Avastin + chemotherapy Chemotherapy alone HR
(95% CI)
Avastin + paclitaxel 22.4 months
(n=60)
13.2 months
(n=55)
0.64
(0.41–1.01)
Avastin + topotecan 13.8 months
(n=57)
13.3 months
(n=63)
1.12
(0.73–1.73)
Avastin + PLD 13.7 months
(n=62)
14.1 months
(n=64)
0.94
(0.63–1.42)

Cohort analysis based on non-prespecified endpoint (OS). Analysis not designed to evaluate statistical significance between treatment arms or compare among the 3 chemotherapy cohorts.

Median ORR by chemotherapy cohort [1]

Chemotherapy cohort

Avastin + chemotherapy

Chemotherapy alone

Avastin + paclitaxel

53%
(n=45)
(95% CI, 39–68)

30%
(n=43)
(95% CI, 17–44)

Avastin + topotecan

17%
(n=46)
(95% CI, 6–28)

2%
(n=50)
(95% CI, 0–6)

Avastin + PLD

16%
(n=51)
(95% CI, 6–26)

8%
(n=51)
(95% CI, 0–15)

Cohort analysis based on non-prespecified endpoint (ORR). Analysis not designed to evaluate statistical significance between treatment arms or compare among the 3 chemotherapy cohorts. 

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

Recurrent glioblastoma (rGBM)

Glioblastoma (GBM)
Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin.

BRAIN study (AVF3708g): Single-agent Avastin in previously treated GBM [1,9]

Endpoint

 

Single-agent Avastin

95% CI

 

Number of patients

85

 

Primary

Objective response rate§

25.9%

17.0–36.1

Secondary

Median duration of response§

4.2 months

3.0–5.7

§Objective response rate and median duration of response were measured by a blinded independent review facility.

National Cancer Institute (NCI) study: Single-agent Avastin in previously treated GBM [1,3]

Endpoint  

Single-agent Avastin

95% CI

 

Number of patients

56

 

Primary

Objective response rate§

19.6%

10.9–31.3

Secondary

Median duration of response§

3.9 months

2.4–17.4

Indications

Glioblastoma (GBM)
Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin.

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.

Non-squamous non-small cell lung cancer (NSCLC)
Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

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

Persistent, recurrent, or metastatic cervical cancer (CC)
Avastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix.

Platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (prOC)
Avastin in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan is indicated for the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens.

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
    • Venous thromboembolism (grade 3–4, up to 10.6%) in patients with persistent, recurrent, or metastatic cervical cancer treated with Avastin
    • 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 
  • 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

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 GBM Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%), and diarrhea (21%). Of these, the incidence of grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%), and diarrhea (1%). Two deaths were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection 
  • In GBM patients receiving Avastin alone or Avastin plus irinotecan,a the incidences of Avastin-related adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and PRES (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage

aAvastin is not approved for use in combination with irinotecan or any other combination regimens.

  • 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
  • In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)
  • 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%), and hemorrhage (3% vs 0.3%)
  • In CC, grade 3 or 4 adverse reactions in Study GOG 240, occurring at a higher incidence (≥2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone, were abdominal pain (11.9% vs 9.9%), diarrhea (5.5% vs 2.7%), anal fistula (3.7% vs 0%), proctalgia (2.8% vs 0%), urinary tract infection (8.3% vs 6.3%), cellulitis (3.2% vs 0.5%), fatigue (14.2% vs 9.9%), hypertension (11.5% vs 0.5%), thrombosis (8.3% vs 2.7%), hypokalemia (7.3% vs 4.5%), hyponatremia (3.7% vs 1.4%), dehydration (4.1% vs 0.5%), neutropenia (7.8% vs 4.1%), lymphopenia (6.0% vs 3.2%), back pain (5.5% vs 3.2%), and pelvic pain (5.5% vs 1.4%). There were no grade 5 adverse reactions occurring at a higher incidence (≥2%) in patients receiving chemotherapy plus Avastin compared to patients receiving chemotherapy alone
  • In prOC, grade 3–4 adverse events occurring at a higher incidence (≥2%) in 179 patients receiving Avastin plus chemotherapy compared to 181 patients receiving chemotherapy alone were hypertension (6.7% vs 1.1%) and palmar-plantar erythrodysaesthesia syndrome (4.5% vs 1.7%). There were no grade 5 events occurring at a higher incidence (≥2%) in patients receiving Avastin plus chemotherapy compared to patients receiving chemotherapy alone

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.