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Avastin

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Avastin

Avastin

CLINICAL PHARMACOLOGY

Mechanism Of Action

Bevacizumab 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. Administration of bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression.

Pharmacokinetics

The pharmacokinetic profile of bevacizumab was assessed using an assay that measures total serum bevacizumab concentrations (i.e., the assay did not distinguish between free bevacizumab and bevacizumab bound to VEGF ligand). Based on a population pharmacokinetic analysis of 491 patients who received 1 to 20 mg/kg of Avastin weekly, every 2 weeks, or every 3 weeks, the estimated half-life of bevacizumab was approximately 20 days (range 11-50 days). The predicted time to reach steady state was 100 days. The accumulation ratio following a dose of 10 mg/kg of bevacizumab every 2 weeks was 2.8.

The clearance of bevacizumab varied by body weight, gender, and tumor burden. After correcting for body weight, males had a higher bevacizumab clearance (0.262 L/day vs. 0.207 L/day) and a larger Vc (3.25 L vs. 2.66 L) than females. Patients with higher tumor burden (at or above median value of tumor surface area) had a higher bevacizumab clearance (0.249 L/day vs. 0.199 L/day) than patients with tumor burdens below the median. In Study 1, there was no evidence of lesser efficacy (hazard ratio for overall survival) in males or patients with higher tumor burden treated with Avastin as compared to females and patients with low tumor burden. The relationship between bevacizumab exposure and clinical outcomes has not been explored.

Animal Toxicology And/Or Pharmacology

In cynomolgus monkeys, when bevacizumab was administered at doses of 0.4 to 20 times the weekly human exposure, anatomical pathology revealed several adverse effects on general growth and skeletal development, fertility and wound healing capacity. Severe physeal dysplasia was consistently reported in juvenile monkeys with open growth plates receiving 0.4 to 20 times the human dose. The physeal dysplasia was characterized by a linear cessation of growth line and chondrocyte hyperplasia which did not completely resolve after the 4 to 12 weeks recovery period without drug exposure.

Rabbits dosed with bevacizumab exhibited reduced wound healing capacity. Using full-thickness skin incision and partial thickness circular dermal wound models, bevacizumab dosing resulted in reductions in wound tensile strength, decreased granulation and re-epithelialization, and delayed time to wound closure.

Reproductive And Developmental Toxicology

Pregnant rabbits dosed with 1 to 12 times the human dose of bevacizumab every three days during the period of organogenesis (gestation day 6-18) exhibited teratogenic effects, decreases in maternal and fetal body weights, and increased number of fetal resorptions. Teratogenic effects included: reduced or irregular ossification in the skull, jaw, spine, ribs, tibia and bones of the paws; meningocele; fontanel, rib and hindlimb deformities; corneal opacity; and absent hindlimb phalanges. There are no data available regarding the level of bevacizumab exposure in the offspring.

Clinical Studies

Metastatic Colorectal Cancer (mCRC)

Study 1

In this double-blind, active-controlled study, patients were randomized (1:1:1) to IV bolus-IFL (irinotecan 125 mg/m², 5-FU 500 mg/m², and leucovorin (LV) 20 mg/m² 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). Enrollment in Arm 3 was discontinued, as pre-specified, when the toxicity of Avastin in combination with the bolus-IFL regimen was deemed acceptable. The main outcome measure was overall survival (OS).

Of the 813 patients randomized to Arms 1 and 2, the median age was 60, 40% were female, 79% were Caucasian, 57% had an ECOG performance status of 0, 21% had a rectal primary and 28% received prior adjuvant chemotherapy. In 56% of the patients, the dominant site of disease was extra-abdominal, while the liver was the dominant site in 38% of patients.

The addition of Avastin resulted in an improvement in survival across subgroups defined by age ( < 65 yrs, ≥ 65 yrs) and gender. Results are presented in Table 4 and Figure 1.

Table 4 : Study 1 Efficacy Results

  IFL+Placebo IFL + Avastin 5 mg/kg q 2 wks
Number of Patients 411 402
Overall Survivala
  Median (months) 15.6 20.3
  Hazard ratio 0.66
Profession-free Survivala
  Median (months) 6.2 10.6
  Hazard ratio 0.54
Overall Response Rateb
  Rate (percent) 35% 45%
Duration of Response
  Median (months) 7.1 10.4
a p < 0.001 by stratified log rank test.
b p < 0.01 by x2 test.

Figure 1: Duration of Survival in Study 1

Duration of Survival in Study 1 - Illustration

Among the 110 patients enrolled in Arm 3, median OS was 18.3 months, median progression-free survival (PFS) was 8.8 months, objective response rate (ORR) was 39%, and median duration of response was 8.5 months.

Study 2

Study 2 was a randomized, open-label, active-controlled trial in patients who were previously treated with irinotecan ± 5-FU for initial therapy for metastatic disease or as adjuvant therapy. Patients were randomized (1:1:1) to IV FOLFOX4 (Day 1: oxaliplatin 85 mg/m² and LV 200 mg/m² concurrently, then 5-FU 400 mg/m b2o lus followed by 600 mg/m continuously; Day 2: LV 2 200 mg/m², then 5-FU 400 mg/m² bolus followed by 600 mg/m² continuously; repeated every 2 weeks), FOLFOX4 plus Avastin (10 mg/kg every 2 weeks prior to FOLFOX4 on Day 1), or Avastin monotherapy(10 mg/kg every 2 weeks). The main outcome measure was OS.

The Avastin monotherapy arm was closed to accrual after enrollment of 244 of the planned 290 patients following a planned interim analysis by the data monitoring committee based on evidence of decreased survival compared to FOLFOX4 alone.

Of the 829 patients randomized to the three arms, the median age was 61 years, 40% were female, 87% were Caucasian, 49% had an ECOG performance status of 0, 26% received prior radiation therapy, and 80% received prior adjuvant chemotherapy, 99% received prior irinotecan, with or without 5-FU as therapy for metastatic disease, and 1% received prior irinotecan and 5-FU as adjuvant therapy.

The addition of Avastin to FOLFOX4 resulted in significantly longer survival as compared to FOLFOX4 alone (median OS 13.0 months vs. 10.8 months; hazard ratio 0.75 [95% CI 0.63, 0.89], p = 0.001 stratified log rank test) with clinical benefit seen in subgroups defined by age ( < 65 yrs, ≥ 65 yrs) and gender. PFS and ORR based on investigator assessment were higher in the Avastin plus FOLFOX4 arm.

Study 3

The activity of Avastin in combination with bolus or infusional 5-FU/LV was evaluated in a single arm study enrolling 339 patients with mCRC with disease progression following both irinotecan- and oxaliplatin-containing chemotherapy regimens. Seventy-three percent of patients received concurrent bolus 5-FU/LV. One objective partial response was verified in the first 100 evaluable patients for an overall response rate of 1% (95% CI 0-5.5%).

Study 4

Study 4 was a prospective, randomized, open-label, multinational, controlled trial in patients with histologically confirmed metastatic colorectal cancer who had progressed on a first-line Avastin containing regimen. Patients were excluded if they progressed within 3 months of initiating firstline chemotherapy and if they received Avastin for less than 3 consecutive months in the first-line setting.

Patients were randomized (1:1) within 3 months after discontinuation of Avastin as first-line therapy to receive fluoropyrimidine/oxaliplatin- or fluoropyrimidine/irinotecan-based chemotherapy with or without Avastin administered at 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks. The choice of second line therapy was contingent upon first-line chemotherapy treatment. Second-line treatment was administered until progressive disease or unacceptable toxicity. The main outcome measure was OS defined as the time from randomization until death from any cause.

Of the 820 patients randomized, the majority of patients were male (64%) and the median age was 63.0 years (range 21 to 84 years). At baseline, 52% of patients were ECOG performance status (PS) 1, 44% were ECOG PS 0, 58% received irinotecan-based therapy as first-line treatment, 55% progressed on first-line treatment within 9 months, and 77% received their last dose of Avastin as first-line treatment within 42 days of being randomized. Second-line chemotherapy regimens were generally balanced between each treatment arm.

The addition of Avastin to fluoropyrimidine-based chemotherapy resulted in a statistically significant prolongation of survival and PFS; there was no significant difference in overall response rate, a key secondary outcome measure. Results are presented in Table 5 and Figure 2.

Table 5: Study 4 Efficacy Results

  Chemotherapy Avastin + Chemotherapy
Number of Patients 411 409
Overall Survivala
  Median (months) 9.8 11.2
  Hazard ratio (95% CI) 0.81 (0.69, 0.94)
Progression-Free Survivalb
  Median (months) 4.0 5.7
  Hazard ratio (95% CI) 0.68 (0.59, 0.78)
a p = 0.0057 by unstratified log rank test.
b p-value < 0.0001 by unstratified log rank test.

Figure 2 : Duration of Survival in Study 4

Duration of Survival in Study 4 - Illustration

Lack Of Efficacy In Adjuvant Treatment Of Colon Cancer

Lack of efficacy of Avastin as an adjunct to standard chemotherapy for the adjuvant treatment of colon cancer was determined in two randomized, open-label, multicenter clinical trials.

The first study conducted in 3451 patients with high risk stage II and III colon cancer, who had undergone surgery for colon cancer with curative intent, was a 3-arm study of Avastin administered at a dose equivalent to 2.5 mg/kg/week on either a 2-weekly schedule in combination with FOLFOX4, or on a 3-weekly schedule in combination with XELOX and FOLFOX4 alone. Patients were randomized as follows: 1151 patients to FOLFOX4 arm, 1155 to FOLFOX4 plus Avastin arm, and 1145 to XELOX plus Avastin arm. The median age was 58 years, 54% were male, 84% were Caucasian and 29% were ≥ age 65. Eighty-three percent had stage III disease.

The main efficacy outcome of the study was disease free survival (DFS) in patients with stage III colon cancer. Addition of Avastin to chemotherapy did not improve DFS. As compared to the control arm, the proportion of stage III patients with disease recurrence or with death due to disease progression were numerically higher in the FOLFOX4 plus Avastin and in the XELOX plus Avastin arms. The hazard ratios for DFS were 1.17 (95% CI: 0.98-1.39) for the FOLFOX4 plus Avastin versus FOLFOX4 and 1.07 (95% CI: 0.90-1.28) for the XELOX plus Avastin versus FOLFOX4. The hazard ratios for overall survival were 1.31 (95% CI=1.03, 1.67) and 1.27 (95% CI=1.00, 1.62) for the comparison of Avastin plus FOLFOX4 versus FOLFOX4 and Avastin plus XELOX versus FOLFOX4, respectively. Similar lack of efficacy for DFS were observed in the Avastin-containing arms compared to control in the high-risk stage II cohort.

In a second study, 2710 patients with stage II and III colon cancer who had undergone surgery with curative intent, were randomized to receive either Avastin administered at a dose equivalent to 2.5 mg/kg/week in combination with mFOLFOX6 (N=1354) or mFOLFOX6 alone (N=1356). The median age was 57 years, 50% were male and 87% Caucasian. Seventy-five percent had stage III disease. The main efficacy outcome was DFS among stage III patients. The hazard ratio for DFS was 0.92 (95% CI: 0.77, 1.10). Overall survival, an additional efficacy outcome, was not significantly improved with the addition of Avastin to mFOLFOX6 (HR=0.96, 95% CI=[0.75,1.22].

Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

Study 5

The safety and efficacy of Avastin as first-line treatment of patients with locally advanced, metastatic, or recurrent non-squamous NSCLC was studied in a single, large, randomized, active-controlled, open-label, multicenter study.

Chemotherapy-naive 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 = 6.0, by IV on day 1 (PC) or PC in combination with Avastin 15 mg/kg by IV on day 1 (PC plus Avastin). After completion or upon discontinuation of chemotherapy, patients in the PC plus Avastin arm continued to receive Avastin alone until disease progression or until unacceptable toxicity. Patients with predominant squamous histology (mixed cell type tumors only), central nervous system (CNS) metastasis, gross hemoptysis ( ≥ 1/2 tsp of red blood), unstable angina, or receiving therapeutic anticoagulation were excluded. The main outcome measure was duration of survival.

Of the 878 patients randomized, the median age was 63, 46% were female, 43% were > age 65, and 28% had ≥ 5% weight loss at study entry. Eleven percent had recurrent disease and of the 89% with newly diagnosed NSCLC, 12% had Stage IIIB with malignant pleural effusion and 76% had Stage IV disease.

The results are presented in Figure 3. OS was statistically significantly higher among patients receiving PC plus Avastin compared with those receiving PC alone; median OS was 12.3 months vs. 10.3 months [hazard ratio 0.80 (repeated 95% CI 0.68, 0.94), final p- value 0.013, stratified log-rank test]. Based on investigator assessment which was not independently verified, patients were reported to have longer PFS with Avastin in combination with PC compared to PC alone.

Figure 3 : Duration of Survival in Study 5

Duration of Survival in Study 5 - Illustration

In an exploratory analyses across patient subgroups, the impact of Avastin on OS was less robust in the following: women [HR=0.99 (95% CI: 0.79, 1.25)], age ≥ 65 years [HR=0.91 (95% CI: 0.72, 1.14)] and patients with ≥ 5% weight loss at study entry [HR=0.96 (95% CI: 0.73, 1.26)].

The safety and efficacy of Avastin in patients with locally advanced, metastatic or recurrent non-squamous NSCLC, who had not received prior chemotherapy was studied in another randomized, double-blind, placebo controlled, three-arm study of Avastin in combination with cisplatin and gemcitabine (CG) versus placebo and CG. A total of 1043 patients were randomized 1:1:1 to receive placebo plus CG, Avastin 7.5 mg/kg plus CG or Avastin 15.0 mg/kg plus CG. The median age was 58 years, 36% were female, and 29% were ≥ age 65. Eight percent had recurrent disease and 77% had Stage IV disease. Progression-free survival, the main efficacy outcome measure, was significantly higher in both Avastin containing arms compared to the placebo arm [HR 0.75 (95% CI 0.62, 0.91), p = 0.0026 for the Avastin 7.5 mg/kg plus CG arm and HR 0.82 (95% CI 0.68; 0.98), p = 0.0301 for the Avastin 15.0 mg/kg plus CG arm]. The addition of Avastin to CG chemotherapy failed to demonstrate an improvement in the duration of overall survival, an additional efficacy outcome measure, [HR 0.93 (95% CI 0.78; 1.11), p = 0.4203 for the Avastin 7.5 mg/kg plus CG arm and HR 1.03 (95% CI 0.86; 1.23), p = 0.7613 for the Avastin 15.0 mg/kg plus CG arm].

Glioblastoma

Study 6

The efficacy and safety of Avastin was evaluated in Study 6, an open-label, multicenter, randomized, non-comparative study of patients with previously treated glioblastoma. Patients received Avastin (10 mg/kg IV) alone or Avastin plus irinotecan every 2 weeks until disease progression or until unacceptable toxicity. All patients received prior radiotherapy (completed at least 8 weeks prior to receiving Avastin) and temozolomide. Patients with active brain hemorrhage were excluded.

Of the 85 patients randomized to the Avastin arm, the median age was 54 years, 32% were female, 81% were in first relapse, Karnofsky performance status was 90-100 for 45% and 70-80 for 55%.

The efficacy of Avastin was demonstrated using response assessment based on both WHO radiographic criteria and by stable or decreasing corticosteroid use, which occurred in 25.9% (95% CI 17.0%, 36.1%) of the patients. Median duration of response was 4.2 months (95% CI 3.0, 5.7).

Radiologic assessment was based on MRI imaging (using T1 and T2/FLAIR). MRI does not necessarily distinguish between tumor, edema, and radiation necrosis.

Study 7

Study 7, was a single-arm, single institution trial with 56 patients with glioblastoma. All patients had documented disease progression after receiving temozolomide and radiation therapy. Patients received Avastin 10 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity.

The median age was 54, 54% were male, 98% Caucasian, and 68% had a Karnofsky Performance Status of 90-100.

The efficacy of Avastin was supported by an objective response rate of 19.6% (95% CI 10.9%, 31.3%) using the same response criteria as in Study 6. Median duration of response was 3.9 months (95% CI 2.4, 17.4).

Metastatic Renal Cell Carcinoma (mRCC)

Study 8

Patients with treatment-naive mRCC were evaluated in a multicenter, randomized, double-blind, international study comparing Avastin plus interferon alfa 2a (IFN-a2a) versus placebo plus IFN-α2a. A total of 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-α2a (9 MIU subcutaneously three times weekly, for a maximum of 52 weeks). Patients were treated until disease progression or unacceptable toxicity. The main outcome measure of the study was investigator-assessed PFS. Secondary outcome measures were ORR and OS.

The median age was 60 years (range 18-82), 96% were white, and 70% were male. The study population was characterized by Motzer scores as follows: 28% favorable (0), 56% intermediate (1-2), 8% poor (3-5), and 7% missing.

The results are presented in Figure 4. PFS was statistically significantly prolonged among patients receiving Avastin plus IFN-α2a compared to those receiving IFN-α2a alone; median PFS was 10.2 months vs. 5.4 months [HR 0.60 (95% CI 0.49, 0.72), p-value < 0.0001, stratified log-rank test]. Among the 595 patients with measurable disease, ORR was also significantly higher (30% vs. 12%, p < 0.0001, stratified CMH test). 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-α2a arm and 21 months in the IFN-a2a plus placebo arm [HR 0.86, (95% CI 0.72, 1.04)].

Figure 4: Progression-Free Survival in Study 8

Progression-Free Survival in Study 8 - Illustration

Last reviewed on RxList: 12/30/2013
This monograph has been modified to include the generic and brand name in many instances.

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