"Oct. 24, 2012 -- One of the oldest and cheapest drugs around may be highly effective against colon cancer, a new study shows.
Some of the most cutting-edge cancer therapies involve targeted treatments used in patients with specific gene mut"...
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 over-expressed in certain human cancers, including colon and rectum cancers. Interaction of EGFR with its normal ligands (e.g. 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 mutant KRAS 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% non-white), mild-tomoderate renal dysfunction, mild-to-moderate hepatic dysfunction, and EGFR membrane-staining intensity (1+, 2+, 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).
The safety and efficacy of Vectibix were studied in Study 1, an open-label, multinational, randomized, controlled trial of 463 patients with EGFR-expressing, metastatic carcinoma of the colon or rectum (mCRC). Patients 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) for 75% of the patients. All patients were required to have EGFR expression defined as at least 1+ membrane staining in ≥ 1% of tumor cells by the Dako EGFR pharmDx® test kit. 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 (0–1 vs 2) and geographic region (western Europe, eastern/central Europe, or other). Upon investigatordetermined disease progression, patients in the BSC-alone arm were eligible to receive panitumumab and were followed until disease progression was confirmed by the IRC. The analyses of progression-free survival (PFS), objective response, and response duration were based on events confirmed by the IRC that was masked to treatment assignment.
Among the 463 patients, 63% were male, the median age was 62 years, 40% were 65 years or older, 99% were white, 86% had a baseline ECOG performance status of 0 or 1, and 67% had colon cancer. The median number of prior therapies for metastatic disease was 2.4. The membrane-staining intensity for EGFR was 3+ in 19%, 2+ in 51%, and 1+ in 30% of patients' tumors. The percentage of tumor cells with EGFR membrane staining in the following categories of > 35%, > 20%-35%, 10%-20%, and 1%- < 10% was 38%, 8%, 31%, and 22%, respectively.
Based upon IRC determination of disease progression, a statistically significant prolongation in PFS was observed in patients receiving Vectibix compared to those receiving BSC alone. The mean PFS was 96 days in the Vectibix arm and 60 days in the BSC-alone arm. Results are presented in Figure 1.
Figure 1: Kaplan-Meier Plot of Progression-Free
Survival Time as Determined by the IRC
In a series of sensitivity analyses, including one adjusting for potential ascertainment bias, i.e., assessment for progressive disease at a nonstudy specified time point, PFS was still significantly prolonged among patients receiving Vectibix as compared to patients receiving BSC alone.
Of the 232 patients randomized to BSC alone, 75% of patients crossed over to receive Vectibix following investigator determination of disease progression; the median time to cross over was 8.4 weeks (0.3–26.4 weeks). Partial responses were identified by the IRC in 19 patients randomized to Vectibix, for an overall response of 8% (95% CI: 5.0%, 12.6%). No patient in the control arm had an objective response identified by the IRC. The median duration of response was 17 weeks (95% CI: 16 weeks, 25 weeks). There was no difference in overall survival between the study arms.
Vectibix in Combination with Bevacizumab and Chemotherapy
Vectibix shortened PFS, decreased survival time, and increased toxicity when given in combination with bevacizumab and chemotherapy in Study 2, a randomized, open-label, multicenter trial in the first-line treatment of mCRC. Patients (n = 1053) were randomized 1:1 to Vectibix at a dose of 6 mg/kg given once every 2 weeks, in combination with bevacizumab and an oxaliplatin- or irinotecan-based 5-fluorouracil-containing chemotherapy regimen, or to bevacizumab and chemotherapy alone. Randomization was stratified by type of regimen (oxaliplatin- or irinotecan-based); 86% of patients received an oxaliplatin-based regimen and 14% received an irinotecan-based regimen.
The major study objective was comparison of PFS in the oxaliplatin stratum as determined by an independent central review. An interim analysis based on 257 PFS events in the oxaliplatin stratum demonstrated shorter PFS in patients receiving Vectibix, bevacizumab, and chemotherapy compared to those receiving bevacizumab and chemotherapy alone (median PFS was 8.8 months and 10.5 months; hazard ratio 1.44 [95% CI: 1.12, 1.85], p-value = 0.0024, Cox model with randomization factors as covariates). An unplanned analysis of overall survival after 155 deaths (both strata combined), conducted at the time of the interim analysis of PFS, yielded an adjusted hazard ratio of 1.55 [95% CI: 1.12, 2.14], comparing patients receiving Vectibix, bevacizumab, and chemotherapy (92 deaths) to those receiving bevacizumab and chemotherapy alone (63 deaths) [see WARNINGS AND PRECAUTIONS].
Lack of Efficacy of Anti-EGFR Monoclonal Antibodies in Patients with mCRC Containing KRAS Mutations
Retrospective analyses as presented in Table 2 across seven randomized clinical trials suggest that anti-EGFR-directed monoclonal antibodies are not effective for the treatment of patients with mCRC containing KRAS mutations. In these trials, patients received standard of care (i.e., BSC or chemotherapy) and were randomized to receive either an anti-EGFR antibody (cetuximab or panitumumab) or no additional therapy. In all studies, investigational tests were used to detect KRAS mutations in codon 12 or 13. The percentage of study populations for which KRAS status was assessed ranged from 23% to 92% [see INDICATIONS AND USAGE, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].
Table 2: Retrospective Analyses of Treatment Effect in
the Subset of Patients with mCRC Containing KRAS Mutations Enrolled in
Randomized Clinical Trials
|Population (n: ITT1)||Treatment||Number of Patients with KRAS Results (% ITT)||Number of Patients with KRAS mutant (mAb2/ control)||Effect of mAb on Endpoints: KRAS mutant3|
|1st line treatment mCRC (n = 1198)||FOLFIRI ± cetuximab||540 (45%)||105/87||PFS2: no difference OS2: no difference ORR2: decreased|
|1st line treatment mCRC (n =337)||FOLFOX-4 ± cetuximab||233 (69%)||52/47||ORR: decreased PFS: decreased OS: no difference|
|Study 2: 1st line treatment mCRC (n= 1053 )||oxaliplatin or irinotecan- based chemotherapy, bevacizumab ± Vectibix||oxaliplatin 664 (81%)||135/125||PFS: decreased OS: no difference ORR: increased|
|irinotecan 201 (87%)||47/39||ORR: decreased PFS: decreased OS: decreased|
|1st line treatment mCRC (n = 736)||bevacizumab, capecitabine, oxaliplatin ± cetuximab||528 (72%)||98/108||PFS: decreased OS: decreased ORR: decreased|
|2nd line treatment mCRC (n = 1298)||irinotecan ± cetuximab||300 (23%)||49/59||OS: decreased PFS: no difference ORR: increased|
|3rd line treatment mCRC (n = 572)||BSC ± cetuximab||394 (69%)||81/83||OS: no difference PFS: no difference ORR: increased|
|Study 1: 3rd line treatment mCRC (n = 463)||BSC ± Vectibix||427 (92%)||84/100||PFS: no difference OS: no difference ORR: no difference|
|1 ITT: intent-to-treat
2 mAb: EGFR monoclonal antibody; PFS: progression-free-survival; ORR: overall response rate; OS: overall survival
3 Results from the primary efficacy endpoint are in bold. A given endpoint is designated as ”decreased“ if there was a numerically smaller result and as ”increased“ if there was a numerically higher result in the mAb group than in the control group.
Last reviewed on RxList: 4/15/2013
This monograph has been modified to include the generic and brand name in many instances.
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