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
    • 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

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

Study E4599: Avastin plus paclitaxel/carboplatin (PC) in first-line advanced 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 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
  • 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

Persistent, recurrent, or metastatic cervical cancer (CC)

GOG-0240 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-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (psOC)

OCEANS study: Avastin plus chemotherapy in psOC

Endpoint   Avastin + chemotherapy Placebo + chemotherapy HR
(95% Cl)
P
value
  Number of patients 242 242    
Main efficacy outcome measure PFS (median) 12.4 months 8.4 months

0.46

(0.37–0.58)

<0.0001
Secondary outcome measure ORR 78%

57%

  <0.0001

Chemotherapy included carboplatin and gemcitabine.
PFS data are based on investigator assessment.
 

  • OS: OS was not significantly improved with the addition of Avastin to chemotherapy (HR=0.95 [95% CI, 0.77–1.17])

GOG-0213 study: Avastin plus chemotherapy in psOC

Endpoint   Avastin + Chemotherapy Chemotherapy alone HR (95% Cl)
  Number of patients 337 336  
Main efficacy outcome measure OS (median) 42.6 months 37.3 months

0.84

(0.69–1.01 [IVRS])

 

0.82

(0.68–0.996 [eCRF])

Additional efficacy outcome measure PFS (median) 13.8 months 10.2 months

0.61

(0.51–0.72 [IVRS])

Exploratory efficacy outcome measure ORR

78%

(n=274)

56%

(n=286)

 

IVRS=interactive voice response system; eCRF=electronic case report form.
Chemotherapy included carboplatin and paclitaxel.

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

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    
Main outcome measure PFS (median) 6.8 months 3.4 months 0.38
(0.30–0.49)
<0.0001
Secondary outcome measure OS (median) 16.6 months 13.3 months 0.89
(0.69–1.14)
 
Secondary outcome measure  ORR 28%
(n=142)
(95% Cl, 21–36)
13%
(n=144)
(95% Cl, 7–18)
   

Chemotherapy included paclitaxel, pegylated liposomal doxorubicin, or topotecan.

  • Median of response duration: 9.4 months with Avastin plus chemotherapy vs 5.4 months with chemotherapy alone

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 was exploratory. 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 was exploratory. 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 was exploratory. Analysis not designed to evaluate statistical significance between treatment arms or compare among the 3 chemotherapy cohorts. 

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

Recurrent glioblastoma (rGBM)

Glioblastoma (GBM)
Avastin is indicated for the treatment of recurrent glioblastoma in adults.

EORTC study: Avastin plus chemotherapy in previously-treated GBM [1,49]

Endpoint   Avastin + chemotherapy Chemotherapy alone HR
(95% Cl)
P value
  Number of patients 283 149    
Primary OS
(median)
There was no difference in median OS between study arms 0.91 0.4578
Secondary PFS
(median)
4.2 months 1.5 months 0.52
(0.41–0.64)
 

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

Recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (rOC)
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.

Avastin, in combination with carboplatin and paclitaxel, or with carboplatin and gemcitabine, followed by Avastin as a single agent, is indicated for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

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

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

Glioblastoma (GBM)
Avastin is indicated for the treatment of recurrent glioblastoma in adults.

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

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
  • 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

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 psOC, grade 3 or 4 adverse reactions in the OCEANS study occurring at a higher incidence (≥2%) in 247 patients receiving Avastin plus carboplatin and gemcitabine (chemotherapy), compared to 233 patients receiving placebo plus chemotherapy, were thrombocytopenia (40% vs 34%), nausea (4% vs 1.3%), fatigue (6% vs 4%), headache (4% vs 0.9%), proteinuria (10% vs 0.4%), dyspnea (4% vs 1.7%), epistaxis (5% vs 0.4%), and hypertension (17% vs 0.9%)
  • In psOC, grade 3 or 4 adverse reactions in the GOG-0213 study occurring at a higher incidence (≥2%) in 325 patients receiving Avastin plus carboplatin and paclitaxel (chemotherapy), compared to 332 patients receiving chemotherapy alone, were hypertension (11% vs 0.6%), fatigue (8% vs 3%), febrile neutropenia (6% vs 3%), proteinuria (8% vs 0%), abdominal pain (6% vs 0.9%), hyponatremia (4% vs 0.9%), headache (3% vs 0.9%), and pain in extremity (3.4% vs 0%)
  • In prOC, grade 3-4 adverse reactions in AURELIA 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%)
  • In CC, grade 3 or 4 adverse reactions in Study GOG-0240, occurring at a higher incidence (≥2%) in 218 patients receiving Avastin plus chemotherapy compared to 222 patients receiving chemotherapy alone, were abdominal pain (12% vs 10%), diarrhea (6% vs 3%), anal fistula (4% vs 0%), proctalgia (3% vs 0%), urinary tract infection (8% vs 6%), cellulitis (3% vs 0.5%), fatigue (14% vs 10%), hypertension (11% vs 0.5%), thrombosis (8% vs 3%), hypokalemia (7% vs 4%), hyponatremia (4% vs 1%), dehydration (4% vs 0.5%), neutropenia (8 vs 4%), lymphopenia (6% vs 3%), back pain (6% vs 3%), and pelvic pain (6% vs 1%)
  • 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)
  • In rGBM Study EORTC 26101, 22% of patients discontinued treatment in the Avastin with lomustine arm due to adverse reactions compared with 10% of patients in the lomustine arm. In patients receiving Avastin with lomustine, the adverse reaction profile was similar to that observed in other approved indications
  • 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 thromboembolism (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 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.