FDA Approves Genentech’s Avastin (bevacizumab) Plus Chemotherapy to Treat Women with Platinum-Resistant Recurrent Ovarian Cancer

-- Avastin Plus Chemotherapy Reduced the Risk of the Disease Worsening by 62 Percent Compared to Chemotherapy Alone in a Phase III Study --

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) approved Avastin^® in combination with chemotherapy for the treatment of women with platinum-resistant, recurrent ovarian cancer. The approval was based on results from the Phase III AURELIA study that showed Avastin plus chemotherapy reduced the risk of disease worsening or death (progression-free survival or PFS) by 62 percent compared to women who received chemotherapy alone (median PFS: 6.8 vs. 3.4 months, Hazard Ratio (HR)=0.38; p<0.0001). Adverse events were consistent with those seen in previous trials of Avastin across tumor types for approved indications, but also included high blood pressure and pain, redness or swelling of the hands or feet from the Phase III study.

“Avastin plus chemotherapy is the first new treatment option for women with this difficult-to-treat type of ovarian cancer in more than 15 years,” said Sandra Horning, M.D., chief medical officer and head of Global Product Development. “Risk of the disease worsening was reduced by 62 percent for women who received Avastin plus chemotherapy in the study, and a notable treatment effect was observed with paclitaxel, which may be important when choosing treatment.”

The new indication of Avastin is in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan chemotherapy for the treatment of women with platinum-resistant, recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received no more than two prior chemotherapy regimens. With this approval, Avastin is approved in the United States to treat six distinct tumor types.

About the AURELIA Study

AURELIA is a company-sponsored, multicenter, randomized, open-label, Phase III study in 361 women with platinum-resistant, recurrent, epithelial ovarian, primary peritoneal, or fallopian tube cancer, who had received no more than two anticancer regimens prior to enrollment in the trial. Participants were randomized to one of six treatment arms (paclitaxel, topotecan or pegylated liposomal doxorubicin with or without Avastin). The primary endpoint of the study was investigator-assessed PFS. An analysis of efficacy by chemotherapy type is shown below.

Efficacy Results in the Intent-to-Treat (ITT) Population
Chemotherapy Type	All Chemotherapies (Intent-To-Treat)
Study Group	Chemotherapy Alone			Avastin + Chemotherapy
Primary Endpoint - Progression-Free Survival (PFS)
Median PFS (months)	3.4			6.8
(95% CI)	(2.1, 3.8)			(5.6, 7.8)
HR (95% CI)	0.38 (0.30, 0.49)
p-value	<0.0001
Overall Survival (OS; Secondary Endpoint)
Median OS (months)	13.3			16.6
(95% CI)	(11.9, 16.4)			(13.7, 19.0)
HR (95% CI)	0.89 (0.69, 1.14)
Overall Response Rate (ORR; Secondary Endpoint)
ORR (%)	13%			28%
(95% CI)	(7, 18)			(21, 36)
Safety Profile (Secondary Endpoint)
Grade 3-4 adverse events occurring at a higher incidence (≥ two percent) in women receiving Avastin plus chemotherapy compared to women receiving chemotherapy alone were high blood pressure (6.7 percent vs. 1.1 percent) and hand-foot syndrome (4.5 percent vs. 1.7 percent).
Efficacy Results in Chemotherapy Cohorts
Chemotherapy Type	Paclitaxel (PAC)		Topotecan (TOP)			Pegylated Liposomal Doxorubicin (PLD)
Study Group	PAC Alone (N=55)	Avastin + PAC (N=60)	TOP (N=63)		Avastin + TOP (N=57)	PLD (N=64)	Avastin + PLD (N=62)
Median PFS (months)	3.9	9.6	2.1		6.2	3.5	5.1
(95% CI)	(3.5, 5.5)	(7.8, 11.5)	(1.9, 2.3)		(5.3, 7.6)	(1.9, 3.9)	(3.9, 6.3)
HR (95% CI)	0.47 (0.31, 0.72)		0.24 (0.15, 0.38)			0.47 (0.32, 0.71)
Median OS (months)	13.2	22.4	13.3		13.8	14.1	13.7
(95% CI)	(8.2, 19.7)	(16.7, 26.7)	(10.4, 18.3)		(11.0, 18.3)	(9.9, 17.8)	(11.0, 18.3)
HR (95% CI)	0.64 (0.41, 1.01)		1.12 (0.73, 1.73)			0.94 (0.63, 1.42)
ORR (%)	30%	53%	2%		17%	8%	16%
(95% CI)	(17, 44)	(39, 68)	(0, 6)		(6, 28)	(0, 15)	(6, 26)

About Ovarian Cancer

Ovarian cancer causes more deaths than any other gynecologic cancer in the United States. In 2014, nearly 22,000 women will be diagnosed with ovarian cancer in the United States and more than 14,000 will die from the disease. Patients are said to have ‘platinum-resistant’ disease if the disease worsens within six months of completing platinum-based chemotherapy. One quarter of those who relapse after initial treatment, more than 4,300 women, will have platinum-resistant cancer, the most difficult-to-treat form of the disease.

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About Avastin

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 U.S. Indications:

Colon Cancer

• Avastin is approved 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 approved for the second line treatment of patients with metastatic colorectal cancer who have progressed on a first line Avastin-containing regimen.
• Avastin is not approved for adjuvant treatment of colon cancer.

Lung Cancer

• Avastin, in combination with carboplatin and paclitaxel chemotherapy, is approved for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic nonsquamous, non-small cell lung cancer.

Kidney Cancer

• Avastin is approved for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Cervical Cancer

• Avastin is approved in combination with paclitaxel and cisplatin or paclitaxel and topotecan for treatment of women with persistent, recurrent or metastatic carcinoma of the cervix.

Ovarian Cancer

• Avastin is approved in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan for the treatment of women with platinum-resistant, recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer, who received no more than two prior chemotherapy regimens.

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 percent).
• 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 percent for patients who received Avastin and four percent 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.

Severe bleeding:

• 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 percent to 6.9 percent 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 patients, but less commonly in other cancer types. 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 percent 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 three percent of people, and severe reactions occurred in 0.2 percent of people.
• Avastin can cause fertility issues for women. 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.

Common side effects that occurred in more than 10 percent 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 percent to 21 percent of people because of side effects.

Patients who 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 at least six months following the last dose of Avastin.

Women should be advised to discontinue nursing or discontinue treatment with Avastin, taking into account the importance of Avastin to the mother.

Report side effects to the FDA at (800) FDA-1088 or http://www.fda.gov/medwatch.
Patients and caregivers may also report side effects to Genentech at [phone].

For full Prescribing Information and Boxed WARNINGS on Avastin, please visit http://www.avastin.com.

About Genentech

Founded more than 35 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.