Vectibix (Page 5 of 7)
12 CLINICAL PHARMACOLOGY
12.1 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 (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. KRAS (Kirsten rat sarcoma 2 viral oncogene homologue) and NRAS (Neuroblastoma RAS viral oncogene homologue) are highly related members of the RAS oncogene family. Signal transduction through the EGFR can result in activation of the wild-type KRAS and NRAS proteins; however, in cells with activating RAS somatic mutations, the RAS-mutant proteins are continuously active and appear 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.
12.3 Pharmacokinetics
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-to-moderate 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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity or mutagenicity studies of panitumumab have been conducted. It is not known if panitumumab can impair fertility in humans. Prolonged menstrual cycles and/or amenorrhea occurred in normally cycling, female cynomolgus monkeys treated weekly with 1.25 to 5 times the recommended human dose of panitumumab (based on body weight). Menstrual cycle irregularities in panitumumab-treated female monkeys were accompanied by both a decrease and delay in peak progesterone and 17β-estradiol levels. Normal menstrual cycling resumed in most animals after discontinuation of panitumumab treatment. A no-effect level for menstrual cycle irregularities and serum hormone levels was not identified. The effects of panitumumab on male fertility have not been studied; however, no adverse effects were observed microscopically in reproductive organs from male cynomolgus monkeys treated for 26 weeks with panitumumab at doses of up to approximately 5-fold the recommended human dose (based on body weight).
14 CLINICAL STUDIES
Figure 1: Kaplan Meier Plot of Overall Survival in Patients with Wild type KRAS mCRC (Study 20080763)Figure 2: Kaplan Meier Plot of Overall Survival in Patients with Wild type RAS mCRC (Study 20100007)Figure 3: Kaplan Meier Plot of Overall Survival in Patients with Wild type KRAS mCRC (Study 20050203)Figure 4: Kaplan Meier Plot of Overall Survival in Patients with Wild Type RAS mCRC (Study 20050203)14.1 Recurrent or Refractory mCRC
The safety and efficacy of Vectibix was demonstrated in Study 20020408, an open-label, multinational, randomized, controlled trial of 463 patients with EGFR-expressing, metastatic carcinoma of the colon or rectum, in Study 20080763, an open-label, multicenter, multinational, randomized trial of 1010 patients with wild-type KRAS mCRC, and in Study 20100007, an open-label, multicenter, multinational, randomized trial of 377 patients with wild-type KRAS mCRC.
Study20020408(NCT00113763)
Patients in Study 20020408 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.
Study20080763 (NCT01001377)
Study 20080763 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 20080763, 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 20080763 demonstrated that Vectibix was statistically significantly noninferior to cetuximab for OS.
The efficacy results for Study 20080763 are presented in Table 3 and Figure 1.
Table 3 : Results in Previously Treated Wild –type KRAS mCRC ( Study 20080763 )
| Wild – type KRAS Population | Vectibix (n = 499) a | Cetuximab (n = 500) a |
| OS | ||
| 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) | |
| PFS | ||
| 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) | |
| ORR | ||
| % (95% CI) | 22% (18%, 26%) | 19% (16%, 23%) |
a Modified 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 20080763 )
Study20100007 (NCT01412957)
Study 20100007 was an open-label, multicenter, randomized (1:1) clinical study stratified by ECOG performance status (0 or 1 vs 2) and region (sites in Europe versus Asia versus rest of world) in patients with wild-type KRAS mCRC. Eligible patients were required to have received prior therapy with irinotecan, oxaliplatin, and a thymidylate synthase inhibitor, and have wild-type KRAS exon 2 mCRC as determined by a clinical trial assay. An assessment for RAS status (defined as KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4) using Sanger sequencing was conducted in patients for whom tumor tissue was available.
Patients were randomized to receive Vectibix (6 mg/kg intravenously every 14 days) plus BSC or BSC alone. Patients received Vectibix and BSC or BSC until disease progression, withdrawal of consent, unacceptable toxicity, or death. Patients randomized to BSC were not offered Vectibix at the time of disease progression. The major efficacy outcome measure was OS in patients with wild-type KRAS mCRC. Secondary efficacy outcome measures included OS in the subgroup of patients with wild-type RAS mCRC; PFS and ORR in patients with wild-type KRAS ; and PFS and ORR in the subgroup of patients with wild-type RAS mCRC.
A total of 377 patients were randomized, 189 to the Vectibix plus BSC arm and 188 to the BSC alone arm. Baseline demographics and disease characteristics were: median age of 61 years (range 19, 82); 57% male; 55% White, 43% Asian; 36% ECOG PS-0, 55% ECOG PS-1; 57% had a primary colon tumor and 43% had a primary rectal tumor; and 32% had prior bevacizumab exposure.
KRAS tumor mutation status was available for all patients and RAS tumor mutation status was available for 86% of the 377 patients. Among the 377 patients, 270 (72%) patients had wild-type RAS tumors, 54 (14%) had mutant RAS tumors, and 54 (14%) had unknown RAS tumor status.
The results of the study demonstrated a statistically significant improvement in overall survival. The efficacy results for Study 20100007 are presented in Table 4 and Figure 2.
Table 4 : Results in Previously Treated Wild –type KRAS and Wild –type RAS mCRC ( Study 20100007 )
| Wild-type KRASPopulation (n = 377) | Wild-type RASPopulation (n = 270) | |||
| Vectibix Plus BSC (n = 189) | BSC (n = 188) | Vectibix Plus BSC (n = 142) | BSC (n = 128) | |
| OS | ||||
| Number of deaths (%) | 136 (72) | 135 (72) | 104 (73) | 95 (74) |
| Median (months) (95% CI) | 10.0 (8.7, 11.4) | 7.4 (5.8, 9.3) | 10.0 (8.7, 11.6) | 6.9 (5.2, 7.9) |
| HR (95% CI) | 0.73 (0.57, 0.93) | 0.70 (0.53, 0.93) | ||
| p-value | 0.0096 | 0.0135 | ||
| PFS | ||||
| Number of events (%) | 182 (96) | 162 (86) | 137 (97) | 113 (88) |
| Median (months) (95% CI) | 3.6 (3.4, 5.3) | 1.7 (1.6, 1.9) | 5.2 (3.5, 5.3) | 1.7 (1.6, 2.2) |
| HR (95% CI) | 0.51 (0.41, 0.64) | 0.46 (0.35. 0.59) | ||
| p-value | < 0.0001 | < 0.0001 | ||
| ORR % (95% CI ) | 27(20.8, 33.9) | 1.6(0.3, 4.6) | 31(23.5, 39.3) | 2.3(0.5, 6.7) |
Figure 2 : Kaplan –Meier Plot of Overall Survival in Patients with Wild –type RAS mCRC ( Study 20100007 )
All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.