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Mechanism Of Action

The EGFR is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases, including EGFR, HER2, HER3, and HER4. EGFR is constitutively expressed in normal epithelial tissues, including the skin and hair follicle. EGFR is overexpressed in certain human cancers, including colon and rectum cancers. Interaction of EGFR with its normal ligands (eg, EGF, transforming growth factor-alpha) leads to phosphorylation and activation of a series of intracellular proteins, which in turn regulate transcription of genes involved with cellular growth and survival, motility, and proliferation. Signal transduction through the EGFR results in activation of the wild-type KRAS protein. However, in cells with activating KRAS somatic mutations, the KRAS-mutant protein is continuously active and appears independent of EGFR regulation.

Panitumumab binds specifically to EGFR on both normal and tumor cells, and competitively inhibits the binding of ligands for EGFR. Nonclinical studies show that binding of panitumumab to the EGFR prevents ligand-induced receptor autophosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, decreased proinflammatory cytokine and vascular growth factor production, and internalization of the EGFR. In vitro assays and in vivo animal studies demonstrate that panitumumab inhibits the growth and survival of selected human tumor cell lines expressing EGFR.


Panitumumab administered as a single agent exhibits nonlinear pharmacokinetics.

Following single-dose administrations of panitumumab as 1-hour infusions, the area under the concentration-time curve (AUC) increased in a greater than dose-proportional manner, and clearance (CL) of panitumumab decreased from 30.6 to 4.6 mL/day/kg as the dose increased from 0.75 to 9 mg/kg. However, at doses above 2 mg/kg, the AUC of panitumumab increased in an approximately dose-proportional manner.

Following the recommended dose regimen (6 mg/kg given once every 2 weeks as a 1-hour infusion), panitumumab concentrations reached steady-state levels by the third infusion with mean (± SD) peak and trough concentrations of 213 ± 59 and 39 ± 14 mcg/mL, respectively. The mean (± SD) AUC0-tau and CL were 1306 ± 374 mcg•day/mL and 4.9 ± 1.4 mL/kg/day, respectively. The elimination half-life was approximately 7.5 days (range: 3.6 to 10.9 days).

A population pharmacokinetic analysis was performed to explore the potential effects of selected covariates on panitumumab pharmacokinetics. Results suggest that age (21-88 years), gender, race (15% nonwhite), mild-tomoderate renal dysfunction, mild-to-moderate hepatic dysfunction, and EGFR membrane-staining intensity (1+, 2+, and 3+) in tumor cells had no apparent impact on the pharmacokinetics of panitumumab.

No formal pharmacokinetic studies of panitumumab have been conducted in patients with renal or hepatic impairment.

Animal Toxicology And/Or Pharmacology

Weekly administration of panitumumab to cynomolgus monkeys for 4 to 26 weeks resulted in dermatologic findings, including dermatitis, pustule formation and exfoliative rash, and deaths secondary to bacterial infection and sepsis at doses of 1.25 to 5-fold higher (based on body weight) than the recommended human dose.

Reproductive And Developmental Toxicology

Pregnant cynomolgus monkeys were treated weekly with panitumumab during the period of organogenesis (gestation day [GD] 20-50). While no panitumumab was detected in serum of neonates from panitumumab-treated dams, anti-panitumumab antibody titers were present in 14 of 27 offspring delivered at GD 100. There were no fetal malformations or other evidence of teratogenesis noted in the offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight).

Clinical Studies

Recurrent Or Refractory mCRC

The safety and efficacy of Vectibix was demonstrated in Study 1, an open-label, multinational, randomized, controlled trial of 463 patients with EGFR-expressing, metastatic carcinoma of the colon or rectum, and in Study 2, an open-label, multicenter, multinational, randomized trial of 1010 patients with wild-type KRAS mCRC.

Study 1

Patients in Study 1 were required to have progressed on or following treatment with a regimen(s) containing a fluoropyrimidine, oxaliplatin, and irinotecan; progression was confirmed by an independent review committee (IRC) masked to treatment assignment for 76% of the patients. Patients were randomized (1:1) to receive panitumumab at a dose of 6 mg/kg given once every 2 weeks plus BSC (N = 231) or BSC alone (N = 232) until investigator-determined disease progression. Randomization was stratified based on Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0 and 1 vs 2) and geographic region (Western Europe, Eastern/Central Europe, or other). Upon investigator-determined disease progression, patients in the BSC-alone arm were eligible to receive panitumumab and were followed until disease progression was confirmed by the IRC.

Based upon IRC determination of disease progression, a statistically significant prolongation in PFS was observed in patients receiving panitumumab compared to those receiving BSC alone. The mean PFS was 96 days in the panitumumab arm and 60 days in the BSC-alone arm.

The study results were analyzed in the wild-type KRAS subgroup where KRAS status was retrospectively determined using archived paraffin-embedded tumor tissue. KRAS mutation status was determined in 427 patients (92%); of these, 243 (57%) had no detectable KRAS mutations in either codons 12 or 13. The hazard ratio for PFS in patients with wild-type KRAS mCRC was 0.45 (95% CI: 0.34-0.59) favoring the panitumumab arm. The response rate was 17% for the panitumumab arm and 0% for BSC. There were no differences in OS; 77% of patients in the BSC arm received panitumumab at the time of disease progression.

Study 2

Study 2 was an open-label, multicenter, multinational, randomized (1:1) clinical trial, stratified by region (North America, Western Europe, and Australia versus rest of the world) and ECOG PS (0 and 1 vs 2) in patients with wild-type KRAS mCRC. A total of 1010 patients who received prior treatment with irinotecan, oxaliplatin, and a thymidylate synthase inhibitor were randomized to receive Vectibix 6 mg/kg intravenously over 60 minutes every 14 days or cetuximab 400 mg/m² intravenously over 120 minutes on day 1 followed by 250 mg/m² intravenously over 60 minutes every 7 days. The trial excluded patients with clinically significant cardiac disease and interstitial lung disease. The major efficacy analysis tested whether the OS of Vectibix was noninferior to cetuximab. Data for investigator-assessed PFS and objective response rate (ORR) were also collected. The criteria for noninferiority was for Vectibix to retain at least 50% of the OS benefit of cetuximab based on an OS hazard ratio of 0.55 from the NCIC CTG CO.17 study relative to BSC.

In Study 2, 37% of patients were women, 52% were white, 45% were Asian, and 1.3% were Hispanic or Latino. Thirty-one percent of patients were enrolled at sites in North America, Western Europe, or Australia. ECOG performance was 0 in 32% of patients, 1 in 60% of patients, and 2 in 8% of patients. Median age was 61 years. More patients (62%) had colon cancer than rectal cancer (38%). Most patients (74%) had not received prior bevacizumab.

The key efficacy analysis for Study 2 demonstrated that Vectibix was statistically significantly noninferior to cetuximab for OS.

The efficacy results for Study 2 are presented in Table 3 and Figure 1.

Table 3: Results in Previously Treated Wild-type KRAS mCRC (Study 2)

Wild-type KRAS Population Vectibix
(n = 499)a
(n = 500)a
Number of OS events (%) 383 (76.8) 392 (78.4)
Median (months) (95% CI) 10.4 (9.4, 11.6) 10.0 (9.3, 11.0)
Hazard ratio (95% CI) 0.97 (0.84, 1.11)
Median (months) (95% CI) 4.1 (3.2, 4.8) 4.4 (3.2, 4.8)
Hazard ratio (95% CI) 1.00 (0.88, 1.14)
% (95% CI) 22% (18%, 26%) 19% (16%, 23%)
aModified intent-to-treat population that included all patients who received at least one dose of therapy

Figure 1 : Kaplan - Meier Plot of Overall Survival in Patients with Wild-type KRAS mCRC (Study 2)

Kaplan - Meier Plot of Overall Survival in Patients with Wild-type KRAS mCRC (Study 2) - Illustration

First-line in Combination with FOLFOX Chemotherapy

Study 3

Study 3 was a multicenter, open-label trial that randomized (1:1) patients with mCRC who were previously untreated in the metastatic setting and who had received no prior oxaliplatin to receive Vectibix every 14 days in combination with FOLFOX or to FOLFOX alone every 14 days. Vectibix was administered at 6 mg/kg over 60 minutes prior to administration of chemotherapy. The FOLFOX regimen consisted of oxaliplatin 85 mg per m² IV infusion over 120 minutes and leucovorin (dl-racemic) 200 mg per m² intravenous infusion over 120 minutes at the same time on day 1 using a Y-line, followed on day 1 by 5-FU 400 mg per m² intravenous bolus. The 5FU bolus was followed by a continuous infusion of 5-FU 600 mg per m² over 22 hours. On day 2, patients received leucovorin 200 mg per m² followed by the bolus dose (400 mg per m²) and continuous infusion of 5FU (600 mg per m²) over 22 hours. Study 3 excluded patients with known central nervous system metastases, clinically significant cardiac disease, interstitial lung disease, or active inflammatory bowel disease. The prespecified major efficacy measure was PFS in patients (n = 656) with wild-type KRAS mCRC as assessed by a blinded independent central review of imaging. Other key efficacy measures included OS and ORR.

In Study 3, in the wild-type KRAS group, 64% of patients were men, 92% white, 2% black, and 4% Hispanic or Latino. Sixty-six percent of patients had colon cancer and 34% had rectal cancer. ECOG performance was 0 in 56% of patients, 1 in 38% of patients, and 2 in 6% of patients. Median age was 61.5 years.

The efficacy results in Study 3 in patients with wild-type KRAS mCRC are presented in Table 4 below.

Table 4: Results in Patients with Wild-type KRAS mCRC and KRAS-Mutant mCRC (Study 3)

Wild-type KRAS population Primary Analysis
Vectibix plus FOLFOX
(n = 325)a
(n = 331)a
Median (months) (95% CI) 9.6 (9.2, 11.1) 8.0 (7.5, 9.3)
Hazard ratio (95% CI)
0.80 (0.66, 0.97)
p =0.02
% (95% CI) 54% (48%, 59%) 47% (41%, 52%)
aIntent-to-treat population

KRAS-Mutant Subgroup

In Study 3, among patients with KRAS-mutant tumors, median PFS was 7.3 months (95% CI: 6.3, 8.0) among 221 patients receiving Vectibix plus FOLFOX versus 8.8 months (95% CI: 7.7, 9.4) among patients who received FOLFOX alone (HR = 1.29, 95% CI: 1.04, 1.62). Median OS was 15.5 months (95% CI: 13.1, 17.6) among patients receiving Vectibix plus FOLFOX versus 19.3 months (95% CI: 16.5, 21.8) among patients who received FOLFOX alone (HR = 1.24, 95% CI: 0.98, 1.57).

Exploratory Analysis of OS

An exploratory analysis of OS with updated information based on events in 82% of patients with wild-type KRAS mCRC estimated the treatment effect of Vectibix plus FOLFOX compared with FOLFOX alone on OS (Figure 2). Median OS among 325 patients with wild-type KRAS mCRC who received Vectibix plus FOLFOX was 23.8 months (95% CI: 20.0, 27.7) versus 19.4 months (95% CI: 17.4, 22.6) among 331 patients who received FOLFOX alone (HR = 0.83, 95% CI: 0.70, 0.98).

Figure 2 : Kaplan - Meier Plot of Overall Survival in Patients with Wild-type KRAS mCRC (Study 3)

Kaplan - Meier Plot of Overall Survival in Patients with Wild-type KRAS mCRC (Study 3) - Illustration

Last reviewed on RxList: 6/9/2014
This monograph has been modified to include the generic and brand name in many instances.

Vectibix - User Reviews

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