Friday, May 29, 2009

Avastin Plus Commonly Used Chemotherapies Improved Progression-Free Survival in Advanced Breast Cancer

Data From RIBBON 1 Study Provides Efficacy and Safety Information With Different Types of Chemotherapy

Orlando, Fla. -- May 29, 2009 --

Genentech, Inc. today announced results of a Phase III study (RIBBON 1) that showed Avastin® (bevacizumab) plus commonly used chemotherapies, including capecitabine and anthracycline-based therapies, increased the time women receiving first-line therapy for advanced HER2-negative breast cancer lived without the disease worsening (progression-free survival or PFS), compared to the chemotherapies alone. The safety profile of Avastin was consistent with previous experience, and no new safety signals for Avastin were observed in the study. The data will be presented on June 1, 2009, during the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Orlando, Florida.


"There are multiple chemotherapy medicines for women with advanced breast cancer, so it is important to understand Avastin's efficacy and safety in combination with these different treatments," said Dr. Nicholas Robert, M.D., co-chair of the Breast Cancer Research Committee, U.S. Oncology, Inc., and physician investigator of the RIBBON 1 study. "The growing body of evidence about combining Avastin with commonly used chemotherapies may give physicians more flexibility to tailor the most appropriate course of Avastin-based therapy for patients."


RIBBON 1 comprised two independently powered study groups. Group One evaluated capecitabine plus Avastin versus capecitabine plus placebo. Group Two evaluated a taxane or anthracycline-based chemotherapy plus Avastin versus the chemotherapy plus placebo. The taxanes in the study were protein-bound paclitaxel or docetaxel. The anthracycline-based chemotherapies were doxorubicin- or epirubicin-based regimens.


Patients receiving Avastin plus capecitabine (Group One) had a 45 percent improvement in the time they lived without their disease worsening or death compared to those who received the chemotherapy alone (hazard ratio=0.69; p=0.0002, 31 percent risk reduction). Patients receiving Avastin plus taxane or anthracycline-based chemotherapies (Group Two) had a 55 percent improvement in the time they lived without their disease worsening or death compared to those who received chemotherapy alone (hazard ratio=0.64; p0.0001, 36 percent risk reduction).


"Avastin has been studied as a first-line treatment in more than 2,600 women with advanced breast cancer in three Phase III trials, and we have confidence in its ability to help delay breast cancer progression," said Hal Barron, M.D., executive vice president, Global Development and chief medical officer, Genentech. "We plan to submit data from the RIBBON 1 and AVADO studies to the FDA in the second half of 2009."


Avastin was approved for advanced breast cancer in February 2008 under the U.S. Food and Drug Administration's (FDA) accelerated approval program, which allows provisional approval of medicines for cancer or other life-threatening diseases. Avastin, in combination with paclitaxel, is indicated for the treatment of patients who have not received chemotherapy for advanced HER2-negative breast cancer. The effectiveness of Avastin in metastatic breast cancer is based on an improvement in PFS. Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Avastin in breast cancer.


FDA review of data from the positive RIBBON 1 and AVADO studies is required for the accelerated approval to be converted into a full approval. Genentech will also provide data from three additional ongoing or planned randomized trials.


RIBBON 1 Study Results
RIBBON 1: Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Chemotherapy With or Without Bevacizumab for First-Line Treatment of HER2-Negative Locally-Recurrent or Metastatic Breast Cancer (Abstract #1005) - Monday, June 1, 2009, 11:15 a.m. - 11:30 a.m. EDT, West Hall D2


RIBBON 1 was an international, multicenter, randomized, double-blind, placebo-controlled clinical study of 1,237 patients with locally recurrent or metastatic HER2-negative breast cancer who had not received chemotherapy for their metastatic disease. Avastin was administered every three weeks until disease progression. Secondary endpoints included objective response rate, one-year survival rate and overall survival at the time of PFS analysis.


Primary Efficacy Results
Progression-Free Survival



Avastin Plus Capecitabine Vs. Placebo Plus Capecitabine
(Group One)

Avastin Plus Taxane or Anthracycline-Based Chemotherapies Vs. Placebo Plus Chemotherapies
(Group Two)

Overall PFS Improvement (%)
Risk Reduction (%)
Hazard Ratio
(95% Confidence Intervals)
p-value

45
31
0.69
(0.56, 0.84)
p=0.0002

55
36
0.64
(0.52, 0.80)
p<0.0001

Avastin Plus Capecitabine

(409 patients)

Capecitabine
Alone

(206 patients)

Avastin Plus Taxane or Anthracycline-Based Chemotherapies
(415 patients)

Taxane or Anthracycline-Based Chemotherapies Alone
(207 patients)

Median PFS (months)

8.6

5.7

9.2

8.0

95% Confidence Intervals (months)

(8.1, 9.5)

(4.3, 6.2)

(8.6, 10.1)

(6.7, 8.4)

Secondary Endpoints

Overall Response Rate (%)
95% Confidence Intervals (%)
p-value

35

24

51

38

(30, 41)

(18, 31)

(46, 57)

(31, 45)

p=0.0097

p=0.0054

1-Year Survival Rate (%)
(not statistically significant)
95% Confidence Intervals (%)
p-value

81

74

81

83

(77, 85)

(68, 81)

(77,85)

(78, 88)

p=0.076

p=0.44

Overall Survival
33% of events had occurred when overall survival was calculated; data are still immature.
Hazard Ratio
95% Confidence Intervals
p-value
(not statistically significant)

0.85
(0.63, 1.14)

p=0.27

1.03
(0.77, 1.38)

p=0.83

The majority of patients in both study groups who received chemotherapy alone went on to receive second-line therapies, including Avastin, after disease progression.


The RIBBON 1 study assessed select adverse events based on the type of chemotherapy. Specific severe (Grade 3 or 4) adverse events (AEs) that occurred at a rate of at least 2 percent more often in patients who received Avastin plus chemotherapy versus chemotherapy alone were:


 

Avastin Plus Capecitabine

Capecitabine Alone

≥Grade 3 Hypertension

9% (38/404)

1% (2/201)

≥Grade 3 Proteinuria

2% (9/404)

0% (0/201)

≥Grade 3 Sensory neuropathy

3% (12/404)

<1% (1/201)

Grade 5 AEs (Deaths during study not due to breast cancer did not occur 2 percent more often)

 

3% (10/404)

 

4% (7/201)


 

Avastin Plus Taxane
Chemotherapy

Taxane Chemotherapy Alone

≥Grade 3 Bleeding

5% (11/203)

0% (0/102)

≥Grade 3 Febrile neutropenia

8% (16/203)

2% (2/102)

≥Grade 3 Hypertension

9% (18/203)

2% (2/102)

Any Grade left ventricular systolic dysfunction

3% (5/203)

0% (0/102)

≥Grade 3 Neutropenia

9% (19/203)

5% (5/102)

≥Grade 3 Proteinuria

3% (7/203)

0% (0/102)

Grade 5 AEs (Deaths during study not due to breast cancer)

 

5% (11/203)

 

3% (3/102)


 

Avastin Plus Anthracycline-Based Chemotherapy

Anthracycline-Based Chemotherapy Alone

≥Grade 3 Hypertension

11% (22/210)

0% (0/100)

≥Grade 3 Proteinuria

3% (6/210)

0% (0/100)

≥Grade 3 Venous thromboembolism

3% (6/210)

1% (1/100)

Grade 5 AEs (Deaths during study not due to breast cancer did not occur 2 percent more often)

 

2% (5/210)

 

3% (3/100)


About Avastin
Avastin was the first anti-angiogenesis therapy approved by the FDA and is approved for the treatment of four tumor types. Avastin is indicated for the first- and second-line treatment of metastatic colorectal cancer in combination with intravenous 5-FU-based chemotherapy; for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel; for previously untreated, metastatic HER2-negative breast cancer in combination with paclitaxel; and for glioblastoma that has progressed following prior therapy.


The effectiveness of Avastin in metastatic breast cancer is based on an improvement in PFS. Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Avastin in breast cancer.


The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate as assessed by magnetic resonance imaging (MRI) and measured using World Health Organization radiographic criteria along with decreased or stable corticosteroid use. MRI does not necessarily distinguish between the tumor, swelling (edema) or tissue death (necrosis) caused by prior radiation therapy. Currently, no data are available from randomized controlled trials demonstrating an improvement in disease-related symptoms or increased survival with Avastin in glioblastoma.


BOXED WARNINGS and Additional Important Safety Information
Patients treated with Avastin may experience side effects. In clinical trials, some patients treated with Avastin experienced serious 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 side effect occurred in 0.3 to 2.4 percent of patients and in some cases resulted in fatality. Avastin therapy should be permanently stopped in people with GI perforation.


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. In a clinical trial, 15 percent of patients with metastatic colorectal cancer who had surgery while receiving Avastin treatment had serious and fatal complications compared to 4 percent of patients who did not receive Avastin. Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Avastin therapy should be permanently stopped in patients with wound healing problems that require medical treatment. The appropriate waiting time between stopping treatment with Avastin and having surgery has not been determined.


Severe bleeding:
Severe or fatal bleeding, including hemoptysis (coughing up of blood), GI bleeding, hematemesis (bloody vomit), central nervous system (CNS) hemorrhage (bleeding in the brain), epistaxis (nose bleeds), and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, Grade 3 or higher (severe or fatal) bleeding events have occurred in 1.2 to 4.6 percent of patients receiving Avastin. In patients with previously treated glioblastoma, intracranial hemorrhage (bleeding within the brain) occurred in eight of 163 patients and two people had Grade 3 to 4 (severe) bleeding. In patients treated with Avastin and chemotherapy for lung cancer, serious and sometimes fatal pulmonary hemorrhage (bleeding in the lungs) occurred in four of 13 (31 percent) patients with squamous cell histology and two of 53 (4 percent) patients with non-squamous NSCLC, compared to none of 32 (0 percent) patients treated with chemotherapy. People with serious bleeding or recent hemoptysis should not receive Avastin.


In clinical trials, additional serious side effects seen across different cancer types, in some cases resulting in fatality, included the following: formation of an abnormal passage from parts of the body to another part (non-GI fistula formation - less than 0.3 percent); stroke or heart problems (arterial thromboembolic events - 2.6 percent); high blood pressure (5 to 18 percent); nervous system and vision disturbances known as RPLS (reversible posterior leukoencephalopathy syndrome - less than 0.1 percent); severe infusion reactions (0.2 percent of people), too much protein in the urine and kidney damage (nephrotic syndrome - less than 1 percent).


The most common adverse reactions observed in Avastin patients at a rate of more than 10 percent and at least twice the control arm rate were nose bleeds, headache, high blood pressure, irritation of the nose (rhinitis), protein in the urine, taste alteration, dry skin, rectal bleeding, tear production disorder (lacrimation) and inflammation of the skin (exfoliative dermatitis).


Avastin may cause problems getting pregnant. People who are pregnant or thinking of becoming pregnant should talk with their doctor about the potential risks of loss of pregnancy or the potential risk of Avastin to the fetus. Nursing mothers should not breast-feed while receiving Avastin or for a short period of time after treatment is finished.


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


About Genentech
Founded more than 30 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 wholly-owned member of the Roche Group, has headquarters in South San Francisco, Calif. For additional information about the company, please visit http://www.gene.com.

# # #