Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC08 
Mechanism of action

Panitumumab is a recombinant, fully human IgG2 monoclonal antibody that binds with high-affinity and specificity to the human EGFR. EGFR is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases including EGFR (HER1/c-ErbB-1), HER2, HER3, and HER4. EGFR promotes cell growth in normal epithelial tissues, including the skin and hair follicle, and is expressed on a variety of tumor cells.

Panitumumab binds to the ligand binding domain of EGFR and inhibits receptor autophosphorylation induced by all known EGFR ligands. Binding of panitumumab to EGFR results in internalization of the receptor, inhibition of cell growth, induction of apoptosis, and decreased interleukin 8 and vascular endothelial growth factor production.

KRAS (Kirsten rat sarcoma 2 viral oncogene homologue) and NRAS (Neuroblastoma RAS viral oncogene homologue) are highly related members of the RAS oncogene family. KRAS and NRAS genes encode small, GTP-binding proteins involved in signal transduction. A variety of stimuli, including that from the EGFR activate KRAS and NRAS which in turn stimulate other intracellular proteins to promote cell proliferation, cell survival and angiogenesis.

Activating mutations in the RAS genes occur frequently in a variety of human tumors and have been implicated in both oncogenesis and tumor progression.

Pharmacodynamic effects

In vitro assays and in vivo animal studies have shown that panitumumab inhibits the growth and survival of tumor cells expressing EGFR. No anti-tumor effects of panitumumab were observed in human tumor xenografts lacking EGFR expression. The addition of panitumumab to radiation, chemotherapy or other targeted therapeutic agents, in animal studies resulted in an increase in anti-tumor effects compared to radiation, chemotherapy or targeted therapeutic agents alone.

Dermatological reactions (including nail effects), observed in patients treated with Vectibix or other EGFR inhibitors, are known to be associated with the pharmacologic effects of therapy (with cross-reference to sections 4.2 and 4.8).

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. Data on the development of anti-panitumumab antibodies has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies (an ELISA which detects high-affinity antibodies, and a Biosensor Immunoassay which detects both high and low-affinity antibodies). For patients whose sera tested positive in either screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.

As monotherapy:
•     The incidence of binding antibodies (excluding predose and transient positive patients) was < 1% as detected by the acid-dissociation ELISA and 3.8% as detected by the Biacore assay;
•     The incidence of neutralizing antibodies (excluding predose and transient positive patients) was < 1%;
•     Compared with patients who did not develop antibodies, no relationship between the presence of anti-panitumumab antibodies and pharmacokinetics, efficacy and safety has been observed.
In combination with irinotecan- or oxaliplatin-based chemotherapy:
•     The incidence of binding antibodies (excluding predose positive patients) was 1% as detected by the acid-dissociation ELISA and < 1% as detected by the Biacore assay;
•     The incidence of neutralizing antibodies (excluding predose positive patients) was < 1%;
•     No evidence of an altered safety profile was found in patients who tested positive for antibodies to Vectibix.

The detection of antibody formation is dependent on the sensitivity and specificity of the assay. The observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medicinal products and underlying disease, therefore, comparison of the incidence of antibodies to other products may be misleading.

Clinical efficacy as monotherapy

The efficacy of Vectibix as monotherapy in patients with metastatic colorectal cancer (mCRC) who had disease progression during or after prior chemotherapy was studied in open-label, single-arm trials (585 patients) and in two randomized controlled trials versus best supportive care (463 patients) and versus cetuximab (1,010 patients).

A multinational, randomized, controlled trial was conducted in 463 patients with EGFR-expressing metastatic carcinoma of the colon or rectum after confirmed failure of oxaliplatin and irinotecan-containing regimens. Patients were randomized 1:1 to receive Vectibix at a dose of 6 mg/kg given once every two weeks plus best supportive care (not including chemotherapy) (BSC) or BSC alone. Patients were treated until disease progression or unacceptable toxicity occurred. Upon disease progression BSC alone patients were eligible to crossover to a companion study and receive Vectibix at a dose of 6 mg/kg given once every two weeks.

The primary endpoint was PFS. The study was retrospectively analyzed by wild-type KRAS (exon 2) status versus mutant KRAS (exon 2) status. Tumor samples obtained from the primary resection of colorectal cancer were analyzed for the presence of the seven most common activating mutations in the codon 12 and 13 of the KRAS gene. 427 (92%) patients were evaluable for KRAS status of which 184 had mutations. The efficacy results from an analysis adjusting for potential bias from unscheduled assessments are shown in the table below. There was no difference in overall survival (OS) seen in either group.


Wild-type KRAS (exon 2)                  Mutant KRAS (exon 2) population                              population
Vectibix plus         BSC              Vectibix plus         BSC
BSC             (n = 119)              BSC             (n = 100)
(n = 124)                               (n = 84)
ORR n (%)                                17%                0%                   0%                0% Response rate (investigator                       22%                                     0% assessed)a (95% CI)                             (14, 32)                                 (0, 4) Stable disease                           34%               12%                  12%                8% PFS
Hazard ratio (95% CI)                 0.49 (0.37, 0.65), p < 0.0001           1.07 (0.77, 1.48), p = 0.6880 Median (weeks)                           16.0                 8.0                8.0                8.0 CI = confidence interval a
In patients that crossed over to panitumumab after progression on BSC alone (95% CI) 
In an exploratory analysis of banked tumor specimens from this study, 11 of 72 patients (15%) with wild-type RAS tumors receiving panitumumab had an objective response compared to only 1 of 95 patients (1%) with mutant RAS tumor status. Moreover, panitumumab treatment was associated with improved PFS compared to BSC in patients with wild-type RAS tumors (HR = 0.38 [95% CI: 0.27, 0.56]), but not in patients with tumors harboring a RAS mutation (HR = 0.98 [95% CI: 0.73, 1.31]).

The efficacy of Vectibix was also evaluated in an open-label trial in patients with wild-type KRAS (exon 2) mCRC. A total of 1,010 patients refractory to chemotherapy were randomized 1:1 to receive Vectibix or cetuximab to test whether Vectibix is non-inferior to cetuximab. The primary endpoint was OS. Secondary endpoints included PFS and objective response rate (ORR).

The efficacy results for the study are presented in the table below.

Wild-type KRAS (exon 2)                     Vectibix                             Cetuximab population                           (n = 499)                             (n = 500) OS
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 n (%) (95% CI)                            22% (18%, 26%)               20% (16%, 24%) Odds ratio (95% CI)                                    1.15 (0.83, 1.58) 
Overall, the safety profile of panitumumab was similar to that of cetuximab, in particular regarding skin toxicity. However, infusion reactions were more frequent with cetuximab (13% versus 3%) but electrolyte disturbances were more frequent with panitumumab, especially hypomagnesemia (29% versus 19%).

Clinical efficacy in combination with chemotherapy

Among patients with wild-type RAS mCRC, PFS, OS, and ORR were improved for subjects receiving panitumumab plus chemotherapy (FOLFOX or FOLFIRI) compared with those receiving chemotherapy alone. Patients with additional RAS mutations beyond KRAS exon 2 were unlikely to benefit from the addition of panitumumab to FOLFIRI and a detrimental effect was seen with the addition of panitumumab to FOLFOX in these patients. BRAF mutations in exon 15 were found to be prognostic of worse outcome. BRAF mutations were not predictive of the outcome for panitumumab treatment in combination with FOLFOX or FOLFIRI.

First-line combination with FOLFOX

The efficacy of Vectibix in combination with oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (FOLFOX) was evaluated in a randomized, controlled trial of 1,183 patients with mCRC with the primary endpoint of PFS. Other key endpoints included the OS, ORR, time to response, time to progression (TTP), and duration of response. The study was prospectively analyzed by tumor KRAS (exon 2) status which was evaluable in 93% of the patients.

A predefined retrospective subset analysis of 641 patients of the 656 patients with wild-type KRAS (exon 2) mCRC was performed. Patient tumor samples with wild-type KRAS exon 2 (codons 12/13) status were tested for additional RAS mutations in KRAS exon 3 (codons 61) and exon 4 (codons 117/146) and NRAS exon 2 (codons 12/13), exon 3 (codon 61), and exon 4 (codons 117/146) and BRAF exon 15 (codon 600). The incidence of these additional RAS mutations in the wild-type KRAS exon 2 population was approximately 16%.

Results in patients with wild-type RAS mCRC and mutant RAS mCRC are presented in the table below.

Vectibix plus         FOLFOX                Difference         Hazard ratio FOLFOX              (months)              (months)            (95% CI) (months)        Median (95% CI)
Median (95% CI)
Wild-type RAS population
PFS                    10.1                 7.9                                      0.72 2.2
(9.3, 12.0)          (7.2, 9.3)                               (0.58, 0.90) OS                     26.0                20.2                                      0.78 5.8
(21.7, 30.4)         (17.7, 23.1)                              (0.62, 0.99) Mutant RAS population
PFS                     7.3                 8.7                                      1.31 -1.4
(6.3, 7.9)          (7.6, 9.4)                               (1.07, 1.60) OS                     15.6                19.2                                      1.25 -3.6
(13.4, 17.9)         (16.7, 21.8)                              (1.02, 1.55) 
Additional mutations in KRAS and NRAS at exon 3 (codon 59) were subsequently identified (n = 7).
An exploratory analysis showed similar results to those in the previous table.

Combination with FOLFIRI
The efficacy of Vectibix in second-line in combination with irinotecan, 5-fluorouracil (5-FU) and leucovorin (FOLFIRI) was evaluated in a randomized, controlled trial of 1,186 patients with mCRC with the primary endpoints of OS and PFS. Other key endpoints included the ORR, time to response, TTP, and duration of response. The study was prospectively analyzed by tumor KRAS (exon 2) status which was evaluable in 91% of the patients.

A predefined retrospective subset analysis of 586 patients of the 597 patients with wild-type KRAS (exon 2) mCRC was performed, where tumor samples from these patients were tested for additional RAS and BRAF mutations as previously described. The RAS/BRAF ascertainment was 85% (1,014 of 1,186 randomized patients). The incidence of these additional RAS mutations (KRAS exons 3, 4 and NRAS exons 2, 3, 4) in the wild-type KRAS (exon 2) population was approximately 19%. The incidence of BRAF exon 15 mutation in the wild-type KRAS (exon 2) population was approximately 8%. Efficacy results in patients with wild-type RAS mCRC and mutant RAS mCRC are shown in the below table.



Vectibix plus                  FOLFIRI                   Hazard ratio FOLFIRI                      (months)                   (95% CI)
(months)                  Median (95% CI)
Median (95% CI)
Wild-type RAS population
PFS                          6.4                            4.6                       0.70 (5.5, 7.4)                     (3.7, 5.6)               (0.54, 0.91)
OS                          16.2                           13.9                       0.81 (14.5, 19.7)                   (11.9, 16.0)              (0.63, 1.02) Mutant RAS population
PFS                          4.8                            4.0                       0.86 (3.7, 5.5)                     (3.6, 5.5)               (0.70, 1.05)
OS                          11.8                           11.1                       0.91 (10.4, 13.1)                   (10.2, 12.4)              (0.76, 1.10) 
The efficacy of Vectibix in first-line in combination with FOLFIRI was evaluated in a single-arm study of 154 patients with the primary endpoint of objective response rate (ORR). Other key endpoints included the PFS, time to response, TTP, and duration of response.

A predefined retrospective subset analysis of 143 patients of the 154 patients with wild-type KRAS (exon 2) mCRC was performed, where tumor samples from these patients were tested for additional RAS mutations. The incidence of these additional RAS mutations (KRAS exons 3, 4 and NRAS exons 2, 3, 4) in the wild-type KRAS (exon 2) population was approximately 10%.

Results in patients with wild-type RAS mCRC and mutant RAS mCRC from the primary analysis are presented in the table below.

Panitumumab + FOLFIRI
Wild-type RAS (n = 69)    Mutant RAS (n = 74)
ORR (%)                                                59                       41 (95% CI)                                            (46, 71)                 (30, 53) Median PFS (months)                                   11.2                     7.3 (95% CI)                                           (7.6, 14.8)              (5.8, 7.5) Median duration of response (months)                  13.0                     5.8 (95% CI)                                           (9.3, 15.7)              (3.9, 7.8) Median TTP (months)                                   13.2                     7.3 (95% CI)                                           (7.8, 17.0)              (6.1, 7.6) 
First-line combination with bevacizumab and oxaliplatin or irinotecan-based chemotherapy 
In a randomized, open-label, controlled clinical trial, chemotherapy (oxaliplatin or irinotecan) and bevacizumab were given with and without panitumumab in the first-line treatment of patients with metastatic colorectal cancer (n = 1,053 [n = 823 oxaliplatin cohort, n = 230 irinotecan cohort]).
Panitumumab treatment was discontinued due to a statistically significant reduction in PFS in patients receiving panitumumab observed in an interim analysis.

The major study objective was comparison of PFS in the oxaliplatin cohort. In the final analysis, the hazard ratio for PFS was 1.27 (95% CI: 1.06, 1.52). Median PFS was 10.0 (95% CI: 8.9, 11.0) and 11.4 (95% CI: 10.5, 11.9) months in the panitumumab and the non-panitumumab arm, respectively.
There was an increase in mortality in the panitumumab arm. The hazard ratio for overall survival was 1.43 (95% CI: 1.11, 1.83). Median overall survival was 19.4 (95% CI: 18.4, 20.8) and 24.5 (95% CI: 20.4, 24.5) in the panitumumab arm and the non-panitumumab arm.

An additional analysis of efficacy data by KRAS (exon 2) status did not identify a subset of patients who benefited from panitumumab in combination with oxaliplatin- or irinotecan-based chemotherapy and bevacizumab. For the wild-type KRAS subset of the oxaliplatin cohort, the hazard ratio for PFS was 1.36 with 95% CI: 1.04-1.77. For the mutant KRAS subset, the hazard ratio for PFS was 1.25 with 95% CI: 0.91-1.71. A trend for OS favouring the control arm was observed in the wild-type KRAS subset of the oxaliplatin cohort (hazard ratio = 1.89; 95% CI: 1.30, 2.75). A trend towards worse survival was also observed with panitumumab in the irinotecan cohort regardless of KRAS mutational status. Overall, panitumumab treatment combined with chemotherapy and bevacizumab is associated with an unfavourable benefit-to-risk profile irrespective of tumor KRAS mutational status.

Pediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Vectibix in all subsets of the pediatric population in colorectal cancer (see section 4.2 for information on pediatric use).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Vectibix administered as a single agent or in combination with chemotherapy exhibits nonlinear pharmacokinetics.

Following a single-dose administration of panitumumab as a 1-hour infusion, 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 increases 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 (± Standard Deviation [SD]) peak and trough concentrations of 213 ± 59 and 39 ± 14 mcg/mL, respectively. The mean (± SD) AUC0-tau and CL were 1,306 ± 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), gender, race, hepatic function, renal function, chemotherapeutic agents, and EGFR membrane staining intensity (1+, 2+, 3+) in tumor cells had no apparent impact on the pharmacokinetics of panitumumab.

No clinical studies have been conducted to examine the pharmacokinetics of panitumumab in patients with renal or hepatic impairment.