Recurrent Platinum-Treated Ovarian Cancer: Avastin Safety Profile


The Avastin® (bevacizumab) side effect and toxicity profile in platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (psOC) was evaluated in the Gynecologic Oncology Group (GOG) 213 study and the OCEANS study.

The Avastin side effect and toxicity profile in platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (prOC) was evaluated in the large Eastern Cooperative Oncology Group (ECOG) AURELIA study.

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

Safety profile of Avastin in psOC was evaluated in the GOG 213 study: Avastin plus chemotherapy vs chemotherapy alone [1]

Grade 1–5 adverse events in GOG 213
(occurring at higher incidence (≥5%) in Avastin plus chemo vs chemo alone)

Adverse events Avastin + chemotherapy
(n=325) (%)
Chemotherapy alone
(n=332) (%)
Adverse events Avastin + chemotherapy
(n=325) (%)
Chemotherapy alone
(n=332) (%)
Gastrointestinal disorders   Nervous system disorders  
Diarrhea 39 32 Headache 38 20
Abdominal pain 33 28 Dysarthria 14 2
Vomiting 33 25 Dizziness 13 8
Stomatitis 33 16 Investigations  
Aspartate aminotransferase increased 15 9
Metabolism and nutrition disorders   Weight decreased 15 4
Decreased appetite 35 25
Hyperglycemia 31 24 Blood creatinine
increased
13 5
Hypomagnesemia 27 17 Skin and subcutaneous tissue disorders  
Exfoliative rash 23 16
Hyponatremia 17 6 Nail disorder 10 2
Hypocalcemia 12 5 Dry skin 7 2
Hypoalbuminemia 11 6 Vascular disorders  
Hypertension 42 3
Hyperkalemia 9 3 Renal and urinary disorders  
Proteinuria 17 1
Musculoskeletal and connective tissue disorders   General disorders and administration site conditions  
Arthralgia 45 30 Chest pain 8 2
Myalgia 29 18 Infections and infestations  
Sinusitis 7 2
Pain in extremity 25 14      
Back pain 17 10      
Muscular weakness 13 8      
Neck pain 9 0      
Respiratory, thoracic, and mediastinal disorders        
Epistaxis 33 2
Dyspnea 30 25      
Cough 30 17      
Rhinitis allergic 17 4      
Nasal mucosal
disorder
14 3      
  • There were no grade 5 events occurring at a higher incidence (≥2%) in patients receiving Avastin plus chemotherapy vs chemotherapy alone [1]
  • Grade 3 or 4 adverse events occurring at a higher incidence (≥2%) in 325 patients treated with Avastin plus chemotherapy compared to 332 patients treated with 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%) [1]

Safety profile of Avastin in psOC was evaluated in the OCEANS study: Avastin plus chemotherapy vs placebo plus chemotherapy [1]

Grade 1−5 adverse events in OCEANS
(occurring at higher incidence (≥5%) in Avastin plus chemo vs placebo + chemo)

Adverse events Avastin + chemotherapy
(n=247) (%)
Placebo + chemotherapy
(n=233) (%)
Adverse events Avastin + chemotherapy
(n=247) (%)
Placebo + chemotherapy
(n=233) (%)
Blood and lymphatic system disorders   Psychiatric disorders  
Thrombocytopenia 58 51 Insomnia 21 15
Gastrointestinal disorders   Renal and urinary disorders  
Nausea 72 66 Proteinuria 20 3
Diarrhea 38 29 Respiratory, thoracic, and mediastinal disorders  
Epistaxis 55 14
Stomatitis 15 7 Dyspnea 30 24
Hemorrhoids 8 3 Cough 26 18
Gingival bleeding 7 0 Oropharyngeal pain 16 10
General disorders and administration site conditions   Dysphonia 13 3
Fatigue 82 75
Mucosal inflammation 15 10 Rhinorrhea 10 4
Infections and infestations   Sinus congestion 8 2
Sinusitis 15 9
Injury, poisoning, and procedural complications   Vascular disorders  
Contusion 17 9 Hypertension 42 9
Musculoskeletal and connective tissue disorders        
Arthralgia 28 19      
Back pain 21 13      
Nervous system disorders        
Headache 49 30      
Dizziness 23 17      
  • There were no grade 5 events occurring at a higher incidence (≥2%) in patients receiving Avastin plus chemotherapy vs placebo plus chemotherapy [1]
  • Grade 3 or 4 adverse events occurring at a higher incidence (≥2%) in 247 patients treated with Avastin plus chemotherapy compared to 233 patients treated with placebo plus chemotherapy 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%) [1]
  • 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 [1]

Safety profile of Avastin in prOC was evaluated in the AURELIA study: Avastin plus chemotherapy vs chemotherapy alone

Grade 3–4 adverse events observed in the AURELIA study (with ≥2% higher incidence in the Avastin plus chemotherapy arm) [1]

Adverse events

Avastin + chemotherapy
(n=179) (%)

Chemotherapy alone
(n=181) (%)

Hyper­tension

6.7

1.1

Palmar-plantar erythrody­saesthesia syndrome

4.5

1.7

There were no grade 5 events occurring at a higher incidence (≥2%) in patients receiving Avastin plus chemotherapy vs chemotherapy alone

Grade 2–4 adverse events observed in the AURELIA study (with ≥5% higher incidence in the Avastin plus chemotherapy arm) [1]

Adverse events

Avastin + chemotherapy (n=179) (%)

Chemotherapy alone (n=181) (%)

Blood and lymphatic system disorders

 

Neutropenia

30.7

25.4

General disorders and administration site conditions

 

Mucosal inflammation

12.8

5.5

Infections and infestations

 

Infection

10.6

4.4

Nervous system disorders

 

Peripheral sensory neuropathy

17.9

7.2

Renal and urinary disorders

 

Proteinuria

12.3

0.6

Respiratory, thoracic, and mediastinal disorders

 

Epistaxis

5.0

0

Skin and subcutaneous tissue disorders

 

Palmar−plantar erythrodysaesthesia syndrome

10.6

5.0

Vascular disorders

 

Hypertension

19.0

5.5

Chemotherapy included paclitaxel, pegylated liposomal doxorubicin, or topotecan. 

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.