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Avastin (Bevacizumab) - Description and Clinical Pharmacology

 
 



DESCRIPTION

AVASTIN® (Bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in in vitro and in vivo assay systems. Bevacizumab contains human framework regions and the complementarity‑determining regions of a murine antibody that binds to VEGF (1). Bevacizumab is produced in a Chinese Hamster Ovary mammalian cell expression system in a nutrient medium containing the antibiotic gentamicin and has a molecular weight of approximately 149 kilodaltons. AVASTIN is a clear to slightly opalescent, colorless to pale brown, sterile, pH 6.2 solution for intravenous (IV) infusion. AVASTIN is supplied in 100 mg and 400 mg preservative‑free, single‑use vials to deliver 4 mL or 16 mL of AVASTIN (25 mg/mL). The 100 mg product is formulated in 240 mg α,α‑trehalose dihydrate, 23.2 mg sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg polysorbate 20, and Water for Injection, USP. The 400 mg product is formulated in 960 mg α,α‑trehalose dihydrate, 92.8 mg sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate (dibasic, anhydrous), 6.4 mg polysorbate 20, and Water for Injection, USP.

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, by gender, and by 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 a randomized study of 813 patients (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.

SPECIAL POPULATIONS

Analyses of demographic data suggest that no dose adjustments are necessary for age or sex.

Patients with renal impairment. No studies have been conducted to examine the pharmacokinetics of Bevacizumab in patients with renal impairment.

Patients with hepatic dysfunction. No studies have been conducted to examine the pharmacokinetics of Bevacizumab in patients with hepatic impairment.

CLINICAL STUDIES

AVASTIN® In Metastatic Colorectal Cancer (mCRC)

The safety and efficacy of AVASTIN in the treatment of patients with metastatic carcinoma of the colon or rectum were studied in three randomized, controlled clinical trials in combination with intravenous 5‑fluorouracil‑based chemotherapy. The activity of AVASTIN in patients with metastatic colorectal cancer that progressed on or after receiving both irinotecan based- and oxaliplatin based‑chemotherapy regimens was evaluated in an open‑access trial in combination with intravenous 5‑fluorouracil‑based chemotherapy.

AVASTIN in Combination with Bolus‑IFL

Study 1 was a randomized, double‑blind, active‑controlled clinical trial evaluating AVASTIN as first‑line treatment of metastatic carcinoma of the colon or rectum. Patients 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). Enrollment in Arm 3 was discontinued, as pre specified, when the toxicity of AVASTIN in combination with the bolus‑IFL regimen was deemed acceptable.

Of the 813 patients randomized to Arms 1 and 2, the median age was 60, 40% were female, and 79% were Caucasian. Fifty‑seven percent had an ECOG performance status of 0. Twenty‑one percent had a rectal primary and 28% received prior adjuvant chemotherapy. In the majority of patients, 56%, the dominant site of disease was extra abdominal, while the liver was the dominant site in 38% of patients. Results are presented in Table 1 and Figure 1.

Table 1: Study 1 Efficacy Results
IFL + PlaceboIFL + AVASTIN
5 mg/kg q 2 wks
Number of Patients411402
Overall Survival 1
 Median (months)15.620.3
 Hazard ratio0.66
Progression‑free Survival
Median (months)6.210.6
 Hazard ratio0.54
Overall Response Rate p < 0.01 by χ2 test
 Rate (percent)35%45%
Duration of Response
 Median (months)7.110.4

1 p < 0.001 by stratified logrank test.

Figure 1: Duration of Survival in Study 1
Error bars represent 95% confidence intervals.

The clinical benefit of AVASTIN, as measured by survival in the two principal arms, was seen in subgroups defined by age (<65 yrs, ≥65 yrs) and gender.

Among the 110 patients enrolled in Arm 3, median overall survival 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.

AVASTIN in Combination with 5‑FU/LV Chemotherapy

Study 2 was a randomized, active‑controlled clinical trial testing AVASTIN in combination with 5‑FU/LV as first‑line treatment of metastatic colorectal cancer. Patients 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 are presented in Table 2.

Table 2: Study 2 Efficacy Result
5-FU/LV 5‑FU/LV + AVASTIN 5 mg/kg 5‑FU/LV + AVASTIN 10 mg/kg
Number of Patients363533
Overall Survival
 Median (months)13.617.715.2
Progression‑free Survival
 Median (months)5.29.07.2
Overall Response Rate
 Rate (percent)174024

Progression‑free survival was significantly longer in patients 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. Outcomes for patients receiving 5‑FU/LV plus AVASTIN at 10 mg/kg were not significantly different than for patients who did not receive AVASTIN.

AVASTIN in Combination with 5‑FU/LV and Oxaliplatin Chemotherapy

Study 3 was an open label, randomized, 3‑arm, active‑controlled, multicenter clinical trial evaluating AVASTIN alone, AVASTIN in combination with 5‑FU/LV and oxaliplatin (FOLFOX4), and FOLFOX4 alone in the second line treatment of metastatic carcinoma of the colon or rectum. Patients were previously treated with irinotecan and 5‑FU for initial therapy for metastatic disease or as adjuvant therapy. Patients were randomized to FOLFOX4 (Day 1: oxaliplatin 85 mg/m2 and leucovorin 200 mg/m2 concurrently IV, then 5‑FU 400 mg/m2 IV bolus followed by 600 mg/m2 continuously IV; Day 2: leucovorin 200 mg/m2 IV, then 5‑FU 400 mg/m2 IV bolus followed by 600 mg/m2 continuously IV; repeated every 2 weeks), FOLFOX4 plus AVASTIN, or AVASTIN monotherapy. AVASTIN was administered at a dose of 10 mg/kg every 2 weeks and for patients in the FOLFOX4 plus AVASTIN arm, prior to the FOLFOX4 chemotherapy on Day 1.

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

The AVASTIN monotherapy arm of Study 3 was closed to accrual after enrollment of 244 of the planned 290 patients following a planned interim analysis by the data monitoring committee (DMC), based on evidence of decreased survival in the AVASTIN alone arm as compared to the FOLFOX4 alone arm. In the two remaining study arms, overall survival (OS) was significantly longer in patients receiving AVASTIN in combination with FOLFOX4 as compared to those receiving FOLFOX4 alone (median OS 13.0 mos vs. 10.8 mos; hazard ratio 0.75 [95% CI 0.63, 0.89], p=0.001 stratified logrank test). In addition, patients treated with AVASTIN in combination with FOLFOX4 were reported to have significantly longer progression-free survival and a higher overall response rate based on investigator assessment. The clinical benefit of AVASTIN, as measured by survival, was seen in the subgroups defined by age (<65 yrs, ≥65 yrs) and gender.

AVASTIN in Third‑Line Metastatic Colorectal Cancer

Study 4 was an open access, multicenter, single arm study that evaluated the activity of AVASTIN in combination with bolus or infusional 5‑FU/LV in 339 patients with metastatic colorectal cancer with disease progression following both irinotecan and oxaliplatin containing chemotherapy regimens. The majority (73%) of patients received concurrent 5‑FU/LV according to a bolus regimen.

There was one objective partial response in the first 100 evaluable patients for an overall response rate of 1% (95% CI 0–5.5%).

AVASTIN® In Unresectable Non‑Squamous, Non‑Small Cell Lung Cancer (NSCLC)

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 (Study 5, n=878), supported by a randomized, dose ranging, active controlled Phase 2 study (Study 6, n=98).

In Study 5, chemotherapy‑naïve patients with locally advanced, metastatic or recurrent non‑squamous NSCLC were randomized (1:1) to receive six cycles of paclitaxel 200 mg⁄m2 and carboplatin AUC=6.0, both by IV infusion on day 1 (PC) or PC in combination with AVASTIN at a dose of 15  mg⁄kg by IV infusion 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. Cycles were repeated every 21 days. Patients with predominant squamous histology (mixed cell type tumors only), central nervous system (CNS) metastasis, gross hemoptysis (≥1⁄2 tsp of red blood), or unstable angina and those receiving therapeutic anticoagulation were excluded. The main outcome measure of the study was duration of survival.

Among the 878 patients randomized to the two treatment arms, 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 remaining 89% with newly diagnosed NSCLC, 12% had Stage IIIB with malignant pleural effusion and 76% had Stage IV disease. The survival curves are presented in Figure 2. Overall survival was statistically significantly higher among patients receiving PC plus AVASTIN compared with those receiving PC alone; median OS was 12.3 mos vs. 10.3 mos (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 progression‑free survival with AVASTIN in combination with PC compared to PC alone.

Figure 1: Duration of Survival in Study 5

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