Recurrent Platinum-Treated Ovarian Cancer: Avastin Efficacy Data


Avastin® (bevacizumab) plus chemotherapy (carboplatin and paclitaxel) is the first and only biologic regimen to demonstrate a 5.3-month difference in overall survival (OS) vs chemotherapy alone in platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (psOC).

Avastin plus chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan) is the first biologic regimen to demonstrate a significant increase in progression-free survival (PFS) vs chemotherapy alone in platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (prOC).

Avastin plus chemotherapy (carboplatin and paclitaxel) demonstrated a 5.3-month difference in median OS compared with chemotherapy alone in the GOG 213 study (42.6 vs 37.3 months) [1]

GOG 213 study: OS results in patients with psOC who have not received more than 1 prior chemotherapy regimen [1]

  • Main efficacy outcome measure: Overall survival (OS)—Median OS of 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 GOG 213 Clinical Study Overall Survival Results in Ovarian Cancer Patients

*Hazard ratio was estimated from Cox proportional hazards models stratified by the duration of treatment free-interval prior to enrolling onto this study per IVRS (interactive voice response system) and secondary surgical debulking status.
Hazard ratio was estimated from Cox proportional hazards models stratified by the duration of platinum free-interval prior to enrolling onto this study per eCRF (electronic case report form) and secondary surgical debulking status.
GOG=Gynecologic Oncology Group.

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

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

GOG 213 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
(Additional efficacy outcome measure)

78% 
(n=274)

56% 
(n=286)

 

*Hazard ratio was estimated from Cox proportional hazards models stratified by the duration of treatment free-interval prior to enrolling onto this study per IVRS (interactive voice response system) and secondary surgical debulking status.
Hazard ratio was estimated from Cox proportional hazards models stratified by the duration of platinum free-interval prior to enrolling onto this study per eCRF (electronic case report form) and secondary surgical debulking status.
Number of patients with measurable disease at baseline.

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

  • Main efficacy outcome measure: Significant increase in PFS—Median PFS of 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; independent radiology review of PFS was consistent with investigator assessment (HR=0.45 [95% CI, 0.35–0.58])
Avastin OCEANS Clinical Study Progression Free Survival Results in Ovarian Cancer Patients

Efficacy endpoints were investigator assessed.

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

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

Efficacy endpoints were investigator assessed.

Avastin plus chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan) significantly increased median PFS over chemotherapy alone in the AURELIA study (6.8 vs 3.4 months) [1]

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

  • Main outcome measure: Significantly increased PFS—6.8 months with Avastin plus chemotherapy vs 3.4 months with chemotherapy alone 
    • Hazard ratio (HR)=0.38 (95% confidence interval [CI], 0.30–0.49), P<0.0001
Avastin Aurelia Study Proportion Progression Free Results Graph

PFS was investigator assessed.

  • Avastin plus chemotherapy demonstrated
    • A 62% reduction in the risk of progression vs chemotherapy alone
    • Doubled median PFS vs chemotherapy alone (6.8 vs 3.4 months)
  • Statistically significant improvement in investigator assessed PFS was supported by a retrospective independent review analysis

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)

13.3 months
(n=182)

0.89
(0.69–1.14)

 

ORR
(Secondary outcome measure)

28%
(n=142)
(95% CI, 21–36)

13%
(n=144)
(95% CI, 7–18)

 

 

ORR=objective response rate.

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

  • Avastin plus chemotherapy demonstrated 
    • A 3.4-month increase in median PFS vs chemotherapy alone (6.8 vs 3.4 months)
    • A 3.3-month difference in median OS vs chemotherapy alone (16.6 vs 13.3 months)
    • A 28% ORR (vs 13% with chemotherapy alone)

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

Median PFS benefit was observed in all 3 chemotherapy cohorts [1]

Median PFS by chemotherapy cohort 

PFS by chemotherapy cohort

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

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

The GOG 213 study evaluated Avastin plus chemotherapy vs chemotherapy alone in platinum-sensitive ovarian cancer [1,3]

GOG 213 Study Platinum-Sensitive Ovarian Cancer Overall Survival with Avastin vs Chemotherapy Chart

GOG=Gynecologic Oncology Group; PS=performance status; IV=solution for intravenous infusion; q3w=every three weeks; ORR=objective response rate; AUC=area under the curve.

  • The GOG 213 study was a Phase III randomized, controlled, open-label trial evaluating Avastin plus chemotherapy vs chemotherapy alone in patients with recurrent psOC who have not received more than 1 previous regimen of chemotherapy [1]
  • 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 platinum-free interval prior to study enrollment (6–12 or ≥12 months) [3]

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 or unacceptable toxicity in patients with platinum-sensitive recurrent ovarian cancer

The GOG 213 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.

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

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

OCEANS Study Platinum-Sensitive Ovarian Cancer Progression Free Survival with Avastin vs Chemotherapy Chart

ECOG=Eastern Cooperative Oncology Group; PS=performance status.

  • The OCEANS study was a Phase III randomized, double-blind, placebo-controlled study comparing Avastin plus chemotherapy vs placebo plus chemotherapy in patients with recurrent psOC who have not received prior chemotherapy in the recurrent setting or prior bevacizumab treatment 
  • 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%

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

CT=computerized tomography; PLD=pegylated liposomal doxorubicin; q2w=every 2 weeks; q3w=every 3 weeks; q4w=every 4 weeks; PD=progressive disease.

  • The AURELIA study was a multicenter, open-label, randomized, 2-arm study comparing Avastin plus chemotherapy vs chemotherapy alone 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
  • 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

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

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, pegylated liposomal doxorubicin, 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

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, either in combination with carboplatin and paclitaxel or in combination 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 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
    • 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 psOC, grade 3 or 4 adverse events in the GOG 213 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 (11.1% vs 0.6%), fatigue (7.7% vs 2.7%), febrile neutropenia (6.2% vs 2.7%), proteinuria (8% vs 0%), abdominal pain (5.8% vs 0.9%), hyponatremia (3.7% vs 0.9%), headache (3.1% vs 0.9%), and pain in extremity (3.4% vs 0%). No grade 5 AE occurred with a ≥2% higher frequency in the Avastin plus chemotherapy arm compared to the chemotherapy alone arm
  • In psOC, grade 3 or 4 adverse events 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 chemotherapy alone were thrombocytopenia (40.1% vs 33.9%), nausea (4.5% vs 1.3%), fatigue (6.5% vs 4.3%), headache (3.6% vs 0.9%), proteinuria (9.7% vs 0.4%), dyspnea (4.5% vs 1.7%), epistaxis (4.9% vs 0.4%), and hypertension (17.0% vs 0.9%). Grade ≥3 anemia (16.2% vs 18.9%) and decreased white blood cell count (1.6% vs 4.3%) occurred with a ≥2% higher frequency in the chemotherapy alone arm compared to the Avastin plus chemotherapy arm. No grade 5 AE occurred with a ≥2% higher frequency in the Avastin plus chemotherapy arm compared to the chemotherapy alone arm
  • 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.