SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the U.S. Food and Drug Administration (FDA) has approved Avastin® (bevacizumab), either in combination with carboplatin and paclitaxel or in combination with carboplatin and gemcitabine chemotherapy, followed by Avastin alone, for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. Women are said to 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.
“With today’s approval of Avastin plus chemotherapy, women in the U.S. with recurrent, platinum-sensitive ovarian cancer now have a treatment option that showed a survival difference of more than five months compared to chemotherapy alone in a clinical trial,” said Sandra Horning, M.D., chief medical officer and head of Global Product Development. “This approval was based in part on a Gynecologic Oncology Group cooperative clinical trial and reinforces the importance of partnerships with study groups to identify new treatment options for people in need.”
“In the United States, ovarian cancer causes more deaths annually than any other gynecologic cancer,” said David Barley, chief executive officer, National Ovarian Cancer Coalition (NOCC). “This approval demonstrates Genentech’s commitment to women with ovarian cancer, a disease with signs and symptoms that too often go unrecognized.”
Avastin in combination with chemotherapy for platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer was granted priority review, and today’s approval is based on results from two randomized, controlled Phase III studies, GOG-0213 and OCEANS. The GOG-0213 study demonstrated that adding Avastin to chemotherapy showed an overall survival 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 time women lived without their disease getting worse (progression-free survival, PFS). The GOG-0213 study showed that women lived a median of 3.4 months longer without disease progression with the addition of Avastin 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 Avastin 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). Overall survival, one of the secondary endpoints in the OCEANS study, was not significantly improved with the addition of Avastin 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 Avastin across tumor types for approved indications, but also included fatigue, low white blood cell count with fever, low sodium level in the blood, pain in extremity, low platelet count, too much protein in the urine, high blood pressure and headache. (*refer to details under GOG-0213 data table)
In November 2014, Avastin was approved in the United States 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.
About the GOG-0213 and OCEANS Studies
GOG-0213 is an independent Phase III study sponsored by the 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. The primary endpoint of the study was to assess whether the addition of Avastin to chemotherapy (carboplatin and paclitaxel) followed by continued use of Avastin alone increased overall survival (OS) compared to chemotherapy alone. Progression-free survival (PFS) and objective response rate (ORR) were secondary endpoints in the GOG-0213 study.
|GOG-0213 Study Results|
|Primary Endpoint: Overall Survival (OS)|
|Median OS||42.6 months||37.3 months|
|Hazard Ratio (95% CI) (IVRS)1||0.84 (0.69, 1.01)|
|Hazard Ratio (95% CI) (eCRF)2||0.82 (0.68, 0.996)|
|Secondary Endpoint: Progression-Free Survival (PFS)|
|Median PFS||13.8 months||10.4 months|
|Hazard Ratio (95% CI)||0.61 (0.51, 0.72)|
|Secondary Endpoint: Objective Response Rate (ORR)|
Number of patients with
|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 (8.0% vs. 0.0%), 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. 0.0%). No Grade ≥ 3 adverse events occurred with a ≥ 2% higher frequency in the chemotherapy alone arm compared to the Avastin plus chemotherapy arm. There were no Grade 5 adverse events occurring at a higher incidence (≥ 2%) in the Avastin plus chemotherapy arm compared to the chemotherapy alone arm.|
1 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.
2 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.
OCEANS, a company sponsored trial, is a placebo-controlled, randomized, multicenter Phase III study that evaluated the safety and efficacy of Avastin, administered in combination with chemotherapy (carboplatin and gemcitabine), in 484 women with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. The primary endpoint of the study was PFS, as determined by the investigator using Response Evaluation Criteria for Solid Tumors (RECIST). Secondary endpoints included ORR, OS and safety.
|AVF4095g (OCEANS) Study Results|
Avastin + chemotherapy
Placebo + chemotherapy
|Primary Endpoint: Progression-Free Survival (PFS)|
|Median PFS||12.4 months||8.4 months|
|Hazard Ratio (95% CI) p-value||
0.46 (0.37, 0.58)
|Secondary Endpoint: Objective Response Rate (ORR)|
|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%). 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. There were no Grade 5 adverse events occurring at a higher incidence (≥ 2%) for the Avastin plus chemotherapy arm compared to the placebo plus chemotherapy arm.|
About Ovarian Cancer
Ovarian cancer causes more deaths than any other gynecologic cancer in the United States. In 2016, about 22,200 women will be diagnosed with ovarian cancer in the United States and about 14,200 will die from the disease. Patients are said to have ‘platinum-sensitive’ disease if a relapse occurs six months or longer following the last cycle of platinum-based chemotherapy. About half of those who relapse after initial treatment – over 8,000 women – will have platinum-sensitive ovarian cancer.
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Avastin is a prescription-only medicine that is a solution for intravenous infusion. It is a biologic antibody designed to specifically bind to a protein called vascular endothelial growth factor (VEGF) that plays an important role throughout the lifecycle of the tumor to develop and maintain blood vessels, a process known as angiogenesis. Avastin is designed to interfere with the tumor blood supply by directly binding to the VEGF protein to prevent interactions with receptors on blood vessel cells. The tumor blood supply is thought to be critical to a tumor's ability to grow and spread in the body (metastasize).
- Avastin is indicated for the first or second line treatment of patients with metastatic colorectal cancer in combination with intravenous 5 fluorouracil–based chemotherapy.
- 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. Avastin is not indicated for adjuvant treatment of colon cancer.
- Avastin in combination with carboplatin and paclitaxel chemotherapy is indicated for first line treatment of patients with unresectable, locally advanced, recurrent or metastatic nonsquamous, non-small cell lung cancer.
- Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.
- Avastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent or metastatic carcinoma of the cervix.
- Avastin in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan, is approved to treat platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (prOC) in women who received no more than two prior chemotherapy treatments. Avastin, either in combination with carboplatin and paclitaxel or with carboplatin and gemcitabine, followed by Avastin alone, is approved for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (psOC).
BOXED WARNINGS and Additional Important Safety Information
People receiving Avastin may experience side effects. In clinical trials, some people treated with Avastin experienced serious and sometimes fatal side effects, including:
Gastrointestinal (GI) perforation:
- Treatment with Avastin can result in the development of a serious side effect called GI perforation, which is the development of a hole in the stomach, small intestine, or large intestine.
- In clinical trials, this event occurred in more people who received Avastin than in the comparison group (up to 3.2%).
- In some cases, GI perforation resulted in fatality. Avastin therapy should be permanently stopped if GI perforation occurs.
Surgery and wound healing problems:
- Treatment with Avastin can lead to slow or incomplete wound healing (for example, when a surgical incision has trouble healing or staying closed). In some cases, this event resulted in fatality.
- Surgery and wound healing problems occurred more often in people who received Avastin 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 Avastin and 4% for patients who did not receive Avastin.
- Avastin 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 Avastin and having voluntary surgery without the risk of wound healing problems following surgery has not been determined.
- Treatment with Avastin 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 Avastin should be stopped in patients with slow or incomplete wound healing.
- Treatment with Avastin 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 people who received Avastin compared to patients who received only chemotherapy.
- Across cancer types, 0.4% to 6.9% of people who received Avastin experienced severe to fatal bleeding. People who have recently coughed up blood (greater than or equal to a half teaspoon of red blood) or have serious bleeding should not receive Avastin. Treatment with Avastin 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 Avastin than in those in the comparison group.
- The formation of an abnormal passage in the body (GI and non-GI fistula formation) was seen in up to 2% of people in metastatic colorectal cancer and ovarian cancer patients. In a study of patients with cervical cancer, formation of an abnormal passage between the vagina and GI tract was seen in 8.3% of people.
- Severe to life-threatening stroke or heart problems were seen in 2.6% of people.
- Too much protein in the urine that led to kidney problems was seen in ≤1% of people.
Additional serious side effects that occurred in more people who
received Avastin than those in the comparison group included
- Severe to life-threatening blood clots (VTE), up to 10.6%
- Severe to life-threatening high blood pressure, which was seen in 5% to 18% of people
- Nervous system and vision disturbances (Posterior Reversible Encephalopathy Syndrome), which was seen in less than 0.5% of people.
- Infusion reactions with the first dose of Avastin were uncommon and occurred in less than 3% of people, and severe reactions occurred in 0.2% of people.
- Avastin could cause a woman’s ovaries to stop working and may impair her ability to have children. Avastin 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 Avastin to the fetus during and following Avastin therapy, and the need to continue an effective birth control method for six months following the last dose of Avastin. Avastin can cause fertility issues for women.
Women should be advised that breastfeeding while on Avastin may harm the baby and is therefore not recommended.
Common side effects that occurred in more than 10% of people who received Avastin for different cancer types, and at least twice the rate of the comparison group, were nosebleeds, headache, high blood pressure, inflammation of the nose, too much protein in the urine, taste change, dry skin, rectal bleeding, tear production disorder, back pain and inflammation of the skin (exfoliative dermatitis).
Across all trials, treatment with Avastin was permanently stopped in 8.4% to 21% of people because of side effects.
Report side effects to the FDA at (800) FDA-1088 or http://www.fda.gov/medwatch. Report side effects to Genentech at (888) 835-2555.
For full Prescribing Information and Boxed WARNINGS on Avastin please visit http://www.avastin.com.
Founded 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious or life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.