Ovarian Cancer: Avastin Efficacy Data

Stage III or IV ovarian cancer (OC) after primary surgery
Avastin, in combination with carboplatin and paclitaxel, followed by Avastin as a single agent, is indicated for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection.

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.

Patients achieved a median PFS benefit of >6 months in stage III or IV ovarian cancer after primary surgery[1]

In the GOG-0218 study, median PFS with Avastin plus chemotherapy followed by single-agent Avastin was 18.2 months vs 12.0 months with chemotherapy alone[1]

PFS=progression-free survival; GOG=Gynecologic Oncology Group; HR=hazard ratio; CI=confidence interval; CP=carboplatin + paclitaxel; PBO=placebo; AUC=area under the curve; q3w=every 3 weeks; KM=Kaplan-Meier; OS=overall survival.
CP+Avastin→Avastin=carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles, with concurrent Avastin started at cycle 2, followed by single-agent Avastin q3w for a total of up to 22 cycles of therapy.
CP+Avastin→PBO=carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles, with concurrent Avastin started at cycle 2, followed by placebo alone q3w for a total of up to 22 cycles of therapy.
CP+PBO→PBO=carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles, with concurrent placebo started at cycle 2, followed by placebo alone q3w for a total of up to 22 cycles of therapy.
*Survivor function at the far right of a KM survival curve should be interpreted cautiously since there are fewer patients remaining in the study group and the survival estimates are not as accurate.[53]

  • Median PFS: 18.2 months in the CP+Avastin→Avastin arm vs 12.0 months in the CP+PBO→PBO arm[1]
    • 38% reduction in the risk of progression in the CP+Avastin→Avastin arm as compared with the CP+PBO→PBO arm (HR=0.62 [95% CI, 0.52–0.75], P<0.0001)[1]
    • The median PFS in the CP+Avastin→PBO arm was 12.8 months vs 12.0 months in the CP+PBO→PBO arm and was not statistically significant (HR=0.83 [95% CI, 0.70–0.98])[1]
  • Median OS: 43.8 months in the CP+Avastin→Avastin arm vs 40.6 months in the CP+PBO→PBO arm (HR=0.89 [95% CI, 0.76–1.05]), and 38.8 months in the CP+Avastin→PBO arm vs 40.6 months in the CP+PBO→PBO arm (HR=1.06 [95% CI, 0.90–1.24])[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

The GOG-0218 study: Study design and patient population[1,54]

PS=performance status; FIGO=International Federation of Gynecology and Obstetrics; IV=intravenous.
Patients continued treatment for 22 cycles unless there was disease progression, unacceptable toxicity, or withdrawal.

  • GOG-0218 was a Phase III, multicenter, randomized, double-blind, placebo-controlled trial[1,54]
  • Overall, approximately 34% of patients had resected FIGO stage III with residual disease <1 cm, 40% had resected stage III with residual disease >1 cm, and 26% had resected stage IV disease[1]
  • At baseline, approximately 50% of patients had a GOG PS of 0 and 43% had a GOG PS score of 1. Patients had either epithelial ovarian cancer (83%), primary peritoneal cancer (15%), or fallopian tube cancer (2%)[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

Avastin plus chemotherapy (carboplatin and gemcitabine) resulted in significant improvement in PFS vs placebo plus chemotherapy in the OCEANS study (median 12.4 vs 8.4 months)[1]

OCEANS study: PFS results in patients with psOC who have not received prior chemotherapy in the recurrent setting or prior Avastin treatment[1]

  • Median PFS: 12.4 months with Avastin plus chemotherapy vs 8.4 months with placebo plus chemotherapy
    • Hazard ratio (HR)=0.46 (95% confidence interval [CI], 0.37–0.58), P<0.0001

PFS data are based on investigator assessment.

 

  • Objective response rate (ORR): 78% with Avastin plus chemotherapy vs 57% with placebo plus chemotherapy (P<0.0001)
  • OS: OS was not significantly improved with the addition of Avastin to chemotherapy (HR=0.95 [95% CI, 0.77–1.17])

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

OCEANS study: Efficacy data overview[1]

Endpoints

Avastin + 
chemotherapy

Placebo +
chemotherapy

HR
(95% CI)

P value

PFS
(Main efficacy outcome measure)

12.4 months
(n=242)

8.4 months
(n=242)

0.46
(0.37–0.58)

<0.0001

ORR
(Secondary outcome measure)

78%
(n=242)

57%
(n=242)

 

<0.0001

PFS data are based on investigator assessment.

Stage III or IV ovarian cancer (OC) after primary surgery
Avastin, in combination with carboplatin and paclitaxel, followed by Avastin as a single agent, is indicated for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection.

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.

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

The OCEANS study evaluated Avastin plus chemotherapy vs placebo plus chemotherapy in platinum-sensitive ovarian cancer[1,47]

ECOG=Eastern Cooperative Oncology Group; PS=performance status; IV=Intravenous; q3w=every 3 weeks; AUC=area under the curve.

  • OCEANS was a Phase III, randomized, double-blind, placebo-controlled study
  • Eligibility criteria included: measurable disease at baseline
  • Ineligibility criteria included: prior chemotherapy in the recurrent setting or prior Avastin treatment 
  • Stratification factors included: platinum-free interval of 6–12 months, >12 months

The OCEANS study included a diverse population of women[1]

Baseline patient characteristics

Age

Median age
Range
≥65 years
<65 years

61 years
28–87 years
37%
63%

ECOG PS [47]

0
1
2

75%
24%
<1%

Measurable disease

Measurable disease at baseline
Baseline CA-125 levels above ULN (>35 U/mL)

100%
74%

Platinum-free interval

6–12 months
>12 months

42%
58%

CA=cancer antigen; ULN=upper limit of normal.

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

Avastin plus chemotherapy (carboplatin and paclitaxel) demonstrated a 5.3-month increase in median OS compared with chemotherapy alone in the GOG-0213 study (42.6 vs 37.3 months)[1]

GOG-0213 study: OS results in patients with psOC who have not received more than 1 prior chemotherapy regimen[1]

  • Median overall survival (OS): 42.6 months with Avastin plus chemotherapy vs 37.3 months with chemotherapy alone
    • Hazard ratio (HR)=0.84 (95% confidence interval [CI], 0.69–1.01 [IVRS]); HR=0.82 (95% CI, 0.68–0.996 [eCRF])
Avastin® (bevacizumab) GOG 213 Study KM Curve

GOG=Gynecologic Oncology Group; psOC=platinum-sensitive ovarian cancer; IVRS=interactive voice response system; eCRF=electronic case report form.

  • Median progression-free survival (PFS): 13.8 months with Avastin plus chemotherapy vs 10.4 months with chemotherapy alone (HR=0.61 [95% CI, 0.51–0.72] [IVRS])
  • Objective response rate (ORR): 78% with Avastin plus chemotherapy vs 56% with chemotherapy alone

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

GOG-0213 study: Efficacy data overview[1]

Endpoints

Avastin +
chemotherapy

Chemotherapy alone

HR
(95% CI)

OS
(Main efficacy outcome measure)

42.6 months
(n=337)

37.3 months
(n=336)

0.84

(0.69–1.01 [IVRS])
0.82
(0.68–0.996 [eCRF])

PFS
(Additional efficacy outcome measure)

13.8 months
(n=337)

10.4 months
(n=336)

0.61
(0.51–0.72 [IVRS])

ORR
(Exploratory efficacy outcome measure)

78% 
(n=274)*

56% 
(n=286)*

 

*Number of patients with measurable disease at baseline.

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

The GOG-0213 study evaluated Avastin plus chemotherapy vs chemotherapy alone in platinum-sensitive ovarian cancer[1,3]

PS=performance status; IV=intravenous; q3w=every 3 weeks; ORR=objective response rate; AUC=area under the curve.

  • GOG-0213 was a Phase III, randomized, controlled, open-label study[1,3]
  • Eligibility criteria included: prior Avastin allowed
  • Ineligibility criteria included: symptoms or diagnosis of bowel obstruction 
  • Stratification factors included: participation in surgical randomization (yes or no), and treatment-free interval prior to study enrollment (6-12 or >12 months)[1,3]
  • 10.3% of platinum-sensitive patients enrolled in GOG-0213 received prior bevacizumab 

Patients who progress after 6 months with platinum therapy are considered platinum sensitive[1]

GOG 213 Clinical Study Patient Disease Progression Timeline
  • Upon completion of indicated cycles of combination therapy, Avastin is indicated for continued use as a single agent until disease progression in patients with platinum-sensitive recurrent ovarian cancer

The GOG-0213 study included a diverse population of women[1]

Baseline patient characteristics

Age

Median age
Range
≥65 years
<65 years

60 years
23–85 years
33%
67%

GOG PS [3]

0
1
2

82%
17%
1%

Measurable disease

Measurable disease at baseline
Baseline CA-125 levels above ULN (>35 U/mL)

83%
74%

Platinum-free interval

6–12 months
>12 months

26%
74%

CA=cancer antigen; ULN=upper limit of normal.

Avastin plus chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan) significantly increased PFS over chemotherapy alone in the AURELIA study (HR=0.38 [95% CI, 0.30–0.49], P<0.0001)[1]

AURELIA study: PFS results in patients with prOC who received no more than 2 prior chemotherapy regimens[1]

  • Median PFS: 6.8 months (95% CI, 5.6–7.8) with Avastin plus chemotherapy vs 3.4 months (95% CI, 2.1–3.8) with chemotherapy alone 
    • Hazard ratio (HR)=0.38 (95% confidence interval [CI], 0.30–0.49), P<0.0001
Avastin® (bevacizumab) AURELIA Study KM Curve

PFS data are based on investigator assessment.

  • ORR: 28% (n=142 [95% CI, 21%–36%]) with Avastin plus chemotherapy vs 13% (n=144 [95% CI, 7%–18%]) with chemotherapy alone. The number of patients with measurable disease at baseline was 142 in the Avastin plus chemotherapy arm and 144 in the chemotherapy alone arm
  • Avastin plus chemotherapy demonstrated
    • A 62% reduction in the risk of disease progression vs chemotherapy alone
    • Doubled median PFS vs chemotherapy alone (6.8 vs 3.4 months)

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

AURELIA study: Efficacy data overview in ITT population[1]

Endpoint

Avastin + chemotherapy

Chemotherapy alone

HR
(95% CI)

P value

PFS
(Main outcome measure)

6.8 months
(n=179)

3.4 months
(n=182)

0.38
(0.30–0.49)

<0.0001

OS
(Secondary outcome measure)

16.6 months
(n=179)
(95% CI, 13.7–19.0)

13.3 months
(n=182)
(95% CI, 11.9–16.4)

0.89
(0.69–1.14)

 

ORR
(Secondary outcome measure)

28%
(n=142)
(95% CI, 21–36)

13%
(n=144)
(95% CI, 7–18)

 

 

PFS=progression-free survival; prOC=platinum-resistant ovarian cancer; ORR=objective response rate; ITT=intent-to-treat; OS=overall survival.

The first biologic regimen to show a benefit in PFS, OS, and ORR in prOC[1]:

  • Median PFS: 6.8 months (95% CI, 5.6–7.8) with Avastin plus chemotherapy vs 3.4 months (95% CI, 2.1–3.8) with chemotherapy alone (HR=0.38 [95% CI, 0.30–0.49], P<0.0001)
  • ORR: 28% (n=142 [95% CI, 21%–36%]) with Avastin plus chemotherapy vs 13% (n=144 [95% CI, 7%–18%]) with chemotherapy alone. The number of patients with measurable disease at baseline was 142 in the Avastin plus chemotherapy arm and 144 in the chemotherapy alone arm
  • Median OS: 16.6 months (95% CI, 13.7–19.0) with Avastin plus chemotherapy vs 13.3 months (95% CI, 11.9–16.4) with chemotherapy alone (HR=0.89 [95% CI, 0.69–1.14])
  • Median duration of response: 9.4 months with Avastin plus chemotherapy vs 5.4 months with chemotherapy alone

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

PFS benefit was achieved in all 3 chemotherapy cohorts[1]

Median PFS by chemotherapy cohort

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

Chemotherapy cohorts

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.

ORR by chemotherapy cohort

Chemotherapy cohorts

Avastin + chemotherapy

Chemotherapy alone

Avastin + paclitaxel

53%
(95% CI, 39–68)
(n=45)

30%
(95% CI, 17–44)
(n=43)

Avastin + topotecan

17%
(95% CI, 6–28)
(n=46)

2%
(95% CI, 0–6)
(n=50)

Avastin + PLD

16%
(95% CI, 6–26)
(n=51)

8%
(95% CI, 0–15)
(n=51)

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

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

The AURELIA study evaluated Avastin plus chemotherapy vs chemotherapy alone in platinum-resistant ovarian cancer[1]

Aurelia Study Platinum Resistant Ovarian Cancer Progression with Avastin versus Chemotherapy Chart

ECOG PS=Eastern Cooperative Oncology Group performance status; CT=computerized tomography; IV=intravenous;  q2w=every 2 weeks; q3w=every 3 weeks; q4w=every 4 weeks; PD=progressive disease.
*Avastin used in combination with paclitaxel, PLD, or weekly topotecan was dosed at 10 mg/kg q2w. Avastin used in combination with topotecan q3w was dosed at 15 mg/kg q3w.

  • AURELIA was a multicenter, randomized, open-label clinical trial in patients with prOC that recurred within <6 months from the most recent platinum-based therapy
  • Patients were treated until disease progression or unacceptable toxicity or withdrawal
  • 40% of patients in the chemotherapy alone arm received Avastin monotherapy upon progression

Patients who progress within <6 months after platinum therapy cessation are considered platinum resistant

Aurelia Clinical Study Patient Disease Progression Timeline

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

Patients in the AURELIA study received no more than 2 prior chemotherapy regimens across all lines of therapy[1]

AURELIA patient eligibility graphic

Chemotherapy included paclitaxel, PLD, or topotecan.

The AURELIA study included a diverse population of women[1]

Baseline patient characteristics

Age

Median age

61 years

Range

25–84 years

≥65 years

37%

<65 years

63%

ECOG PS

PS 0

59%

PS 1

34%

PS 2

7%

Baseline characteristics

Measurable disease at baseline

79%

Baseline CA-125 levels ≥2 x ULN

87%

Ascites at baseline

31%

Platinum-free interval (PFI)

3–6 months

73%

<3 months

27%

Indications

Stage III or IV ovarian cancer (OC) after primary surgery
Avastin, in combination with carboplatin and paclitaxel, followed by Avastin as a single agent, is indicated for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection.

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.

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 Stage III or IV OC after primary surgery, 608 patients received CP+Avastin→Avastin, 607 patients received CP+Avastin→PBO, and 602 patients received CP+PBO→PBO. Grade 3–4 adverse reactions occurring at a higher incidence (≥2%) in either of the Avastin arms vs the chemotherapy only arm were fatigue (CP+Avastin→Avastin, 9%; CP+Avastin→PBO, 6%; CP+PBO→PBO, 6%), hypertension (CP+Avastin→Avastin, 10%; CP+Avastin→PBO, 6%; CP+PBO→PBO, 2%), platelet count decreased (CP+Avastin→Avastin, 21%; CP+Avastin→PBO, 20%; CP+PBO→PBO, 15%), and white blood cell count decreased (CP+Avastin→Avastin, 51%; CP+Avastin→PBO, 53%; CP+PBO→PBO, 50%)
  • 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%)

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.