Avastin (bevacizumab) - 6 indications

Scroll down for information on each indication:

• Metastatic colorectal cancer; approved 02/01/2004
• Metastatic renal cell carcinoma; approved 07/01/2009
• Recurrent glioblastoma in adults; approved 05/01/2009
• Non–squamous non–small cell lung cancer; approved 10/01/2006
• Persistent, recurrent, or metastatic cervical cancer; approved 08/01/2014
• Stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer; approved 11/01/2014

General Information

Avastin is a vascular endothelial growth factor (VEGF) inhibitor.

Avastin is specifically indicated for the following indications:

• Metastatic Colorectal Cancer 1) in combination with intravenous fluorouracil-based chemotherapy for the first-or second-line treatment of patients with metastatic colorectal cancer (mCRC); 2) in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for the second-line treatment of patients with mCRC who have progressed on a first-line Avastin-containing regimen.
• First-Line Non-Squamous Non–Small Cell Lung Cancer: in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer (NSCLC).
• Recurrent Glioblastoma (GBM) in adults.
• Metastatic Renal Cell Carcinoma (mRcc) in combination with interferon alfa
• Persistent, Recurrent, or Metastatic Cervical Cancer in combination with paclitaxel and cisplatin or paclitaxel and topotecan
• Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer: 1) in combination with carboplatin and paclitaxel, followed by Avastin as a single agent, for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection; 2) in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan 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; 3) in combination with carboplatin and paclitaxel, or with carboplatin and gemcitabine, followed by Avastin as a single agent, for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Avastin is supplied as a solution for intravenous administration. Please scroll down for specific dosing recommendations for each therapeutic indication.

Mechanism of Action

Avastin (bevacizumab) is a vascular endothelial growth factor inhibitor. Avastin binds VEGF and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis.

Side Effects

Adverse effects associated with the use of Avastin may include, but are not limited to, the following:

• epistaxis
• headache
• hypertension
• rhinitis
• proteinuria
• taste alteration
• dry skin
• hemorrhage
• lacrimation disorder
• back pain
• exfoliative dermatitis

Indication 1 - metastatic colorectal cancer

approved 02/01/2004

Dosing/Administration

The recommended dosage when Avastin is administered in combination with intravenous fluorouracil-based chemotherapy is: • 5 mg/kg intravenously every 2 weeks in combination with bolus-IFL. • 10 mg/kg intravenously every 2 weeks in combination with FOLFOX4. • 5 mg/kg intravenously every 2 weeks or 7.5 mg/kg intravenously every 3 weeks in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy in patients who have progressed on a first-line Avastin-containing regimen.

Clinical Trial Results

The FDA approval of Avastin for colorectal cancer was based on two randomized, controlled trials (STUDY 1 / STUDY 2) in combination with intravenous 5-fluorouracil-based chemotherapy.

Study 1 was a double-blind trial enrolling 813 subjects with metastatic carcinoma of the colon or rectum. Subjects were randomized to bolus-IFL (irinotecan 125 mg/m2 IV, 5-fluorouracil 500 mg/m2 IV, and leucovorin 20 mg/m2 IV given once weekly for 4 weeks every 6 weeks) plus placebo (Arm 1), bolus-IFL plus Avastin (5 mg/kg every 2 weeks) (Arm 2) or 5-FU/LV plus Avastin (5 mg/kg every 2 weeks) (Arm 3). Among the subjects, 57% had an ECOG performance status of 0. The primary endpoint of this trial was overall survival. Results showed that the overall survival in Arms 1 & 2 was 20.3 months with Avastin compared with 15.6 months with placebo. The median progression-free survival was 10.6 months with Avastin compared with 6.4 months with placebo. Data showed that the median overall survival in Arm 3 was 18.3 months, median progression-free survival was 8.8 months, overall response rate was 39%, and median duration of response was 8.5 months.

Study 2 tested Avastin in combination with 5-FU/LV and enrolled as first-line treatment of metastatic colorectal cancer. Subjects were randomized to receive 5-FU/LV (5-fluorouracil 500 mg/m2, leucovorin 500 mg/m2 weekly for 6 weeks every 8 weeks) or 5-FU/LV plus Avastin (5 mg/kg every 2 weeks) or 5-FU/LV plus Avastin (10 mg/kg every 2 weeks). The primary endpoints of the trial were objective response rate and progression-free survival. Results showed that progression-free survival was significantly better in subjects receiving 5-FU/LV plus Avastin at 5 mg/kg when compared to those not receiving Avastin. However, overall survival and overall response rate were not significantly different. Results for subjects receiving 5-FU/LV plus Avastin at 10 mg/kg were not significantly different than without Avastin.

Indication 2 - metastatic renal cell carcinoma

approved 07/01/2009

Dosing/Administration

The recommended dosage is 10 mg/kg intravenously every 2 weeks in combination with interferon alfa.

Clinical Trial Results

The FDA approval of Avastin for renal cell carcinoma was based on a multicenter, randomized, double-blind, international study comparing Avastin plus interferon alfa 2a (IFN- a2a) versus placebo plus IFN-a2a. The trial enrolled 649 patients who had undergone a nephrectomy were randomized (1:1) to receive either Avastin (10 mg/kg IV infusion every 2 weeks; n = 327) or placebo (IV every 2 weeks; n = 322) in combination with IFN-a2a (9 MIU subcutaneously three times weekly, for a maximum of 52 weeks). The subjects were treated until disease progression or unacceptable toxicity. The main outcome measure of the study was investigator-assessed progression free survival (PFS). Secondary outcome measures were overall response rate (ORR) and overall survival (OS). PFS was statistically significantly prolonged among patients receiving Avastin plus IFN-a2a compared to those receiving IFN-a2a alone; median PFS was 10.2 months vs. 5.4 months. Among the 595 subjects with measureable disease, ORR was also significantly higher (30% vs. 12%). There was no improvement in OS based on the final analysis conducted after 444 deaths, with a median OS of 23 months in the Avastin plus IFN-a2a arm and 21 months in the IFN-a2a plus placebo arm.

Indication 3 - recurrent glioblastoma in adults

approved 05/01/2009

Dosing/Administration

The recommended dosage is 10 mg/kg intravenously every 2 weeks.

Clinical Trial Results

The FDA approval of Avastin for glioblastoma was based on a multicenter, randomized, open-label study in patients with recurrent GBM. Patients with first progression following radiotherapy and temozolomide were randomized (2:1) to receive Avastin (10 mg/kg every 2 weeks) with lomustine (90 mg/m2 every 6 weeks) or lomustine (110 mg/m2 every 6 weeks) alone until disease progression or unacceptable toxicity. Randomization was stratified by World Health Organization performance status (0 vs. >0), steroid use (yes vs. no), largest tumor diameter (≤ 40 vs. > 40 mm), and institution. The main outcome measure was OS. A total of 432 patients were randomized to receive lomustine alone (N=149) or Avastin with lomustine (N=283). No difference in OS was observed between arms; therefore, all secondary outcome measures are descriptive only. PFS was longer in the Avastin with lomustine arm with a median PFS of 4.2 months in the Avastin with lomustine arm and 1.5 months in the lomustine arm. Among the 50% of patients receiving corticosteroids at the time of randomization, a higher percentage of patients in the Avastin with lomustine arm discontinued corticosteroids (23% vs. 12%).
One single arm single center study and a randomized noncomparative multicenter study evaluated the efficacy and safety of Avastin 10 mg/kg every 2 weeks in patients with previously treated GBM. Response rates in both studies were evaluated based on modified WHO criteria that considered corticosteroid use. In study AVF3708g, the response rate was 25.9% with a median duration of response of 4.2 months. In Study NCI 06-C-0064E, the response rate was 19.6% with a median duration of response of 3.9 months.

Indication 4 - Non–squamous non–small cell lung cancer

approved 10/01/2006

Dosing/Administration

The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with carboplatin and paclitaxel.

Clinical Trial Results

The FDA approval of Avastin as first-line treatment of patients with locally advanced, metastatic, or recurrent non–squamous NSCLC was based on a single, large, randomized, active-controlled, open-label, multicenter study. A total of 878 chemotherapy-naïve patients with locally advanced, metastatic or recurrent non–squamous NSCLC were randomized (1:1) to receive six 21-day cycles of paclitaxel (200 mg/m2) and carboplatin (AUC 6) with or without Avastin 15 mg/kg. After completing or discontinuing chemotherapy, patients randomized to receive Avastin continued to receive Avastin alone until disease progression or until unacceptable toxicity. OS was statistically significantly longer for patients receiving Avastin with paclitaxel and carboplatin compared with those receiving chemotherapy alone. Median OS was 12.3 months versus 10.3 months. Based on investigator assessment which was not independently verified, patients were reported to have longer PFS with Avastin with paclitaxel and carboplatin compared to chemotherapy alone.

Indication 5 - persistent, recurrent, or metastatic cervical cancer

approved 08/01/2014

Dosing/Administration

The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with paclitaxel and cisplatin or in combination with paclitaxel and topotecan.

Clinical Trial Results

The FDA approval of Avastin for persistent, recurrent, or metastatic cervical cancer was based on a randomized, four-arm, multi-center study comparing Avastin with chemotherapy versus chemotherapy alone. A total of 452 patients were randomized (1:1:1:1) to receive paclitaxel and cisplatin with or without Avastin, or paclitaxel and topotecan with or without Avastin. The dosing regimens for Avastin, paclitaxel, cisplatin and topotecan were as follows:

Day 1: Paclitaxel 135 mg/m2 over 24 hours, Day 2: cisplatin 50 mg/m2 with Avastin;

Day 1: Paclitaxel 175 mg/m2 over 3 hours, Day 2: cisplatin 50 mg/m2 with Avastin;

Day 1: Paclitaxel 175 mg/m2 over 3 hours with cisplatin 50 mg/m2 with Avastin;

Day 1: Paclitaxel 175 mg/m2 over 3 hours with Avastin, Days 1-3: topotecan IV 0.75 mg/m2 over 30 minutes

Patients were treated until disease progression or unacceptable adverse reactions. The main outcome measure was OS. Results showed an increase in overall survival to 16.8 months in patients who received chemotherapy in combination with Avastin as compared to 12.9 months for those receiving chemotherapy alone.

Indication 6 - Stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer

approved 11/01/2014

Dosing/Administration

Stage III or IV Disease Following Initial Surgical Resection

• The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with carboplatin and paclitaxel for up to 6 cycles, followed by Avastin 15 mg/kg every 3 weeks as a single agent for a total of up to 22 cycles or until disease progression, whichever occurs earlier.

Recurrent Disease

• Platinum Resistant The recommended dosage is 10 mg/kg intravenously every 2 weeks in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan (every week). The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with topotecan (every 3 weeks).
• Platinum Sensitive The recommended dosage is 15 mg/kg intravenously every 3 weeks, in combination with carboplatin and paclitaxel for 6 to 8 cycles, followed by Avastin 15 mg/kg every 3 weeks as a single agent until disease progression. The recommended dosage is 15 mg/kg intravenously every 3 weeks, in combination with carboplatin and gemcitabine for 6 to 10 cycles, followed by Avastin 15 mg/kg every 3 weeks as a single agent until disease progression

Clinical Trial Results

The FDA approval of Avastin for epithelial ovarian, fallopian tube, or primary peritoneal cancer was based on the following trials:

Study MO22224: a multicenter, open-label, randomized study comparing Avastin with chemotherapy versus chemotherapy alone in patients with platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within <6 months from the most recent platinum-based therapy (N=361). Patients had received no more than 2 prior chemotherapy regimens. Patients received one of the following chemotherapy regimens at the discretion of the investigator: paclitaxel (80 mg/m2 on days 1, 8, 15 and 22 every 4 weeks; pegylated liposomal doxorubicin 40 mg/m2 on day 1 every 4 weeks; or topotecan 4 mg/m2 on days 1, 8 and 15 every 4 weeks or 1.25 mg/m2 on days 1-5 every 3 weeks). Patients were treated until disease progression, unacceptable toxicity, or withdrawal. Forty percent of patients on the chemotherapy alone arm received Avastin alone upon progression. The main outcome measure was investigator-assessed PFS. The addition of Avastin to chemotherapy demonstrated a statistically significant improvement in investigator-assessed PFS. The median PFS was 6.8 months for the Avastin/chemo arm and 3.4 months for the chemo monotherapy arm.

Study AVF4095g: a randomized, double-blind, placebo-controlled study studying Avastin with chemotherapy versus chemotherapy alone in the treatment of patients with platinum sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have not received prior chemotherapy in the recurrent setting or prior bevacizumab treatment (N=484). Patients were randomized (1:1) to receive Avastin (15 mg/kg day 1) or placebo every 3 weeks with carboplatin (AUC 4, day 1) and gemcitabine (1000 mg/m2 on days 1 and 8) a for 6 to 10 cycles followed by Avastin or placebo alone until disease progression or unacceptable toxicity. The main outcome measures was investigator-assessed PFS.  A statistically significant prolongation in PFS was demonstrated among patients receiving Avastin with chemotherapy compared to those receiving placebo with chemotherapy: median 12.4 months versus 8.4 months, respectively.