FDA Approves Bevacizumab Plus Chemotherapy, Followed by Bevacizumab Alone, for the Treatment of Patients with Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer

Approval is based on two large phase III studies

On 6 December 2016, Genentech, a member of the Roche Group announced that the US Food and Drug Administration (FDA) has approved bevacizumab (Avastin®), either in combination with carboplatin and paclitaxel or in combination with carboplatin and gemcitabine chemotherapy, followed by bevacizumab alone, for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. Approval is based on two large phase III trials, including GOG-0213 that showed a five month overall survival (OS) difference for women with platinum-sensitive recurrent ovarian cancer on bevacizumab plus chemotherapy compared to chemotherapy alone.

Patients have a platinum-sensitive form of the disease if a relapse occurs six months or longer following the last treatment with a platinum-based chemotherapy.

“In the United States, ovarian cancer causes more deaths annually than any other gynecologic cancer,” said David Barley, chief executive officer of the, US National Ovarian Cancer Coalition (NOCC). In women with ovarian cancer, signs and symptoms are too often unrecognised.

Bevacizumab in combination with chemotherapy for platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer was granted priority review, and this approval is based on results from two randomised, controlled phase III studies, GOG-0213 and OCEANS.

The GOG-0213 study demonstrated that adding bevacizumab to chemotherapy showed an OS difference of five months compared to chemotherapy alone (median OS: 42.6 months vs. 37.3 months; Hazard Ratio (HR)=0.84, 95% CI: 0.69-1.01 and HR=0.82, 95% CI: 0.68-0.996, depending on stratification factor). Both the GOG-0213 and OCEANS studies demonstrated a significant improvement in the progression-free survival (PFS). The GOG-0213 study showed that patients lived a median of 3.4 months longer without disease progression with the addition of bevacizumab to chemotherapy compared to chemotherapy alone (median PFS: 13.8 months vs. 10.4 months; HR=0.61, 95% CI: 0.51-0.72). The OCEANS study showed that bevacizumab in combination with chemotherapy significantly improved PFS compared to placebo plus chemotherapy (median PFS: 12.4 months vs. 8.4 months; HR=0.46, 95% CI: 0.37-0.58; p<0.0001). The OS, one of the secondary endpoints in the OCEANS study, was not significantly improved with the addition of bevacizumab to chemotherapy (HR=0.95, 95% CI: 0.77-1.17). Adverse events in both studies were consistent with those seen in previous trials of bevacizumab across tumour types for approved indications, but also included fatigue, neutropenia with fever, low sodium level in the blood, pain in extremity, thrombocytopenia, proteinuria, hypertension and headache.

In November 2014, bevacizumab was approved in the US for the treatment of women with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan chemotherapy. Women are considered to have a platinum-resistant form of the disease if a relapse occurs less than six months after the last treatment with a platinum-based chemotherapy.

GOG-0213 is an independent phase III study sponsored by the US National Cancer Institute (NCI) and conducted by the Gynecologic Oncology Group (GOG) that enrolled 673 women with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. OCEANS, a company sponsored trial, is a placebo-controlled, randomised, multicentre phase III study that evaluated the safety and efficacy of bevacizumab, administered in combination with chemotherapy (carboplatin and gemcitabine), in 484 women with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

Bevacizumab is a biologic antibody designed to specifically bind to a vascular endothelial growth factor (VEGF) that plays an important role in angiogenesis.

In the US, bevacizumab is now approved for nine distinct indications across six different types of cancer:

  • Bevacizumab is indicated for the first- or second-line treatment of patients with metastatic colorectal cancer in combination with intravenous 5-fluorouracil–based chemotherapy.
  • Bevacizumab 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 bevacizumab-containing regimen. Bevacizumab is not indicated for adjuvant treatment of colon cancer.
  • Bevacizumab in combination with carboplatin and paclitaxel chemotherapy is indicated for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer.
  • Bevacizumab is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.
  • Bevacizumab in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent or metastatic carcinoma of the cervix.
  • Bevacizumab in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan, is approved to treat platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer in women who received no more than two prior chemotherapy treatments. Bevacizumab, either in combination with carboplatin and paclitaxel or with carboplatin and gemcitabine, followed by bevacizumab alone, is approved for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

BOXED WARNINGS and additional important safety information

Patients receiving bevacizumab may experience side effects. In clinical trials, some patients treated with bevacizumab experienced serious and sometimes fatal side effects, including:

Gastrointestinal (GI) perforation:

  • Treatment with bevacizumab can result in the development of a GI perforation in the stomach, small intestine, or large intestine.
  • In clinical trials, this event occurred in more patients who received bevacizumab than in the comparison group (up to 3.2%).
  • In some cases, GI perforation resulted in fatality. Bevacizumab therapy should be permanently stopped if GI perforation occurs. 


Surgery and wound healing problems:

  • Treatment with bevacizumab can lead to slow or incomplete wound healing. In some cases, this event resulted in fatality.
  • Surgery and wound healing problems occurred more often in patients who received bevacizumab than in the comparison group. In a controlled clinical trial, in patients with metastatic colorectal cancer who had surgery during the course of treatment, the incidence of wound healing complications, including serious and fatal complications, was 15% for patients who received bevacizumab and 4% for patients who did not receive bevacizumab.
  • Bevacizumab therapy should not be started for at least 28 days after surgery and until the surgical wound is fully healed. The length of time between stopping bevacizumab and having voluntary surgery without the risk of wound healing problems following surgery has not been determined.
  • Treatment with bevacizumab should be stopped at least 28 days before voluntary surgery and in people with wound healing problems following surgery that require medical treatment. Treatment with bevacizumab should be stopped in patients with slow or incomplete wound healing.

Severe bleeding:

  • Treatment with bevacizumab can result in serious or fatal bleeding, including coughing up blood, bleeding in the stomach, vomiting of blood, bleeding in the brain, nosebleeds and vaginal bleeding. These events occurred up to five times more often in patients who received bevacizumab compared to patients who received only chemotherapy.
  • Across cancer types, 0.4% to 6.9% of patients who received bevacizumab experienced severe to fatal bleeding. Patients who have recently coughed up blood or have serious bleeding should not receive bevacizumab. Treatment with bevacizumab should be permanently stopped if serious bleeding occurs. 


Additional serious adverse events

In clinical trials for different cancer types, there were additional serious and sometimes fatal side effects that occurred in more people who received bevacizumab than in those in the comparison group.

  • The formation of a GI and non-GI fistula was seen in up to 2% of patients in metastatic colorectal cancer and ovarian cancer patients. In a study of patients with cervical cancer, formation of fistula between the vagina and GI tract was seen in 8.3% of patients.
  • Severe to life-threatening stroke or heart problems were seen in 2.6% of patients.
  • Proteinuria that led to kidney problems was seen in ≤1% of patients.
  • Additional serious side effects that occurred in more patients who received bevacizumab than those in the comparison group included
    • Severe to life-threatening VTE, up to 10.6%

    • Severe to life-threatening hypertension, which was seen in 5% to 18% of patients
    • Nervous system and vision disturbances (Posterior Reversible Encephalopathy Syndrome), which was seen in less than 0.5% of patients.
    • Infusion reactions with the first dose of bevacizumab were uncommon and occurred in less than 3% of patients, and severe reactions occurred in 0.2% of patients.
  • Bevacizumab could cause a woman’s ovaries to stop working and may impair her ability to have children. Bevacizumab should not be used in ovarian cancer patients who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. 


Patients who are pregnant, think they are pregnant, or thinking of becoming pregnant should talk with their doctor about the potential risk of loss of the pregnancy or the potential risk of bevacizumab to the foetus during and following bevacizumab therapy, and the need to continue an effective birth control method for six months following the last dose of bevacizumab. Bevacizumab can cause fertility issues for women.

Women should be advised that breastfeeding while on bevacizumab may harm the baby and is therefore not recommended.

Common side effects that occurred in more than 10% of patients who received bevacizumab for different cancer types, and at least twice the rate of the comparison group, were nosebleeds, headache, hypertension, inflammation of the nose, proteinuria, taste change, dry skin, rectal bleeding, tear production disorder, back pain and exfoliative dermatitis.

Across all trials, treatment with bevacizumab was permanently stopped in 8.4% to 21% of patients because of side effects.