Panitumumab: A Review of Clinical Pharmacokinetic and Pharmacology Properties After Over a Decade of Experience in Patients with Solid Tumors
Johannes Kast . Sandeep Dutta . Vijay V. Upreti

Received: March 23, 2021 / Accepted: May 26, 2021 / Published online: June 18, 2021
© The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature 2021

ABSTRACT
Panitumumab is a fully human monoclonal antibody that binds to the epidermal growth factor receptor (EGFR), thereby inhibiting the growth and survival of tumors expressing EGFR. Panitumumab received approval in the USA in 2006 for the treatment of wild-type RAS (defined as wild-type in both KRAS and NRAS) metastatic colorectal cancer. Over the last 10 years, the pharmacokinetic and pharmacodynamic profile of panitumumab has been studied to further evaluate its safety, efficacy, and optimal dosing regimen. In this review, we summarize the key clinical pharmacokinetic and pharmacology data for panitumumab, and considerations for its use in special populations. Panitumumab has a nonlinear pharmacokinetic profile and its approved dosing regimen (6 mg/kg every 2 weeks) is based on body weight; dose
adjustments are not needed based on sex, age, or renal or hepatic impairment. Drug interactions do not occur when panitumumab is combined with chemotherapy drugs including irinotecan, paclitaxel, and carboplatin. The level of tumor EGFR expression was found to have no effect on panitumumab pharmacokinetics or efficacy. The incidence of anti-panitumumab antibodies is low; when anti-panitumumab antibodies are produced, they do not affect the efficacy, safety, or pharmacokinetics of panitumumab. In sum- mary, the pharmacokinetic and pharmacody- namic profile of panitumumab is well suited for standard dosing, and the approved body weight–based dosing regimen maintains efficacy and safety in the treatment of wild-type RAS metastatic colorectal cancer across a broad range of patients.

Keywords: Clinical pharmacology; Colorectal neoplasms; Dose–exposure relationship; Epidermal growth factor receptor antagonist; Panitumumab; Pharmacokinetics

·
J. Kast V. V. Upreti (&)
Clinical Pharmacology, Modeling and Simulation, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA
e-mail: [email protected]

S. Dutta
Clinical Pharmacology, Modeling and Simulation, Amgen Inc., Thousand Oaks, CA, USA

Key Summary Points
Panitumumab is a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR) that is indicated as first-line treatment of wild-type RAS metastatic colorectal cancer.
Panitumumab displays nonlinear pharmacokinetics at therapeutic doses; its pharmacokinetics are not affected by tumor EGFR expression level or renal or hepatic impairment.
Body weight–based dosing at 6 mg/kg every 2 weeks optimizes efficacy and safety of panitumumab and minimizes interpatient variability in panitumumab exposure.

DIGITAL FEATURES
This article is published with digital features, including a summary slide, to facilitate under- standing of the article. To view digital features for this article go to https://doi.org/10.6084/ m9.figshare.14673549.

INTRODUCTION
Panitumumab is an epidermal growth factor receptor (EGFR) antagonist first approved in the USA in 2006 for the treatment of wild-type RAS (defined as wild-type in both KRAS and NRAS) metastatic colorectal cancer (mCRC) [1]. In the USA, panitumumab is currently indicated as first-line treatment for mCRC in combination with the cytotoxic doublet 5-fluorouracil with folinic acid plus oxaliplatin (FOLFOX). Panitu- mumab is also indicated as monotherapy in patients with disease progression after fluo- ropyrimidine-, oxaliplatin-, and irinotecan- containing chemotherapy. Panitumumab is approved in Europe for similar indications, and
in combination with 5-fluorouracil with folinic acid plus irinotecan (FOLFIRI) in patients pro- gressing after treatment with fluoropyrimidine [2].
Clinical experience supports the benefit of panitumumab in the management of RAS wild- type mCRC [3]. On the basis of the product label in both the USA and Europe, panitu- mumab should be administered at a dose of 6 mg/kg every 2 weeks (Q2W) as an intravenous infusion over 60 min (doses up to 1000 mg diluted in 100 mL of normal saline) or 90 min (doses above 1000 mg diluted in 150 mL normal saline) [1, 2]. Recently, the need for body weight–based dosing for monoclonal antibodies (mAbs) in general including panitumumab has been questioned by some [4, 5] but not all researchers [6]; this has led to potential confu- sion for clinicians. The goal of this article is to review and summarize the key clinical phar- macokinetic and pharmacology data for pani- tumumab with a special emphasis on ensuring clinicians understand the approach taken to determine the optimal dose of panitumumab. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

IN VITRO PHARMACOLOGY
Overview of EGFR

EGFR is a transmembrane glycoprotein that is constitutively expressed in epithelial tissues, and is overexpressed in certain cancers. EGFR binds the extracellular protein ligand members of the epidermal growth family; upon binding, EGFR transforms from its inactive monomeric state to an active homo- or heterodimer [7]. Dimerization induces autophosphorylation of tyrosine residues, followed by an intracellular signaling cascade. EGFR activation modulates three major pathways: the RAS/RAF/MAPK pathway, the JAK/STAT pathway, and the PI3K/ AKT pathway [8, 9]. Activation of these path- ways promotes cell migration, survival, and proliferation through the blockade of apoptosis.

Fig. 1 Mechanism of action of panitumumab. EGF epidermal growth factor, EGFR epidermal growth factor receptor, TGF-a transforming growth factor alpha

Structure and Chemical Properties of Panitumumab

Panitumumab is a recombinant, fully human immunoglobulin (Ig) G2 subtype mAb directed against the EGFR, with a binding affinity of
0.05 nM [10]. Panitumumab has an approxi- mate molecular weight of 147 kDa [1]. By binding to the ligand binding domain of the EGFR, panitumumab prevents ligand-induced receptor autophosphorylation and activation of receptor-associated kinases (Fig. 1) [11]. Panitu- mumab localizes to the W386, E388, R390, and T391 residues on EGFR [12]. Binding of pani- tumumab to EGFR results in internalization of the receptor, induction of apoptosis, inhibition of cell growth, and decreased interleukin-8 and vascular endothelial growth factor production [1, 13]. In vitro assays and in vivo animal studies have shown that panitumumab inhibits the growth and survival of tumor cells lines expressing EGFR [13]. In vitro, panitumumab inhibited growth of EGFR-expressing tumor cell lines from breast and epidermal origin in a dose-
dependent manner [10]. EGF-induced phos- phorylation was inhibited by panitumumab in human non-small cell lung carcinoma cells expressing wild-type or mutant EGFR [14] and in epidermoid carcinoma cells [15]. Addition- ally, panitumumab has been shown to mediate antibody-dependent cellular cytotoxicity in vitro by polymorphonuclear cells [16] and peripheral blood mononuclear cells [17]. In vivo, panitumumab inhibited EGFR- expressing tumors of breast (MDA-MB-468), epidermal (A431), renal (SK-RC-29), pancreatic (BxPC-3 and HS766T), prostate (PC-3), and ovarian (IGROVI) origin in xenograft models in the absence of concomitant chemotherapy [10, 11]. Nude mice with A431 tumor xenografts treated with panitumumab showed reduced staining for markers of proliferation and MAPK signaling, suggesting that panitumumab decreases cellular proliferation and downstream MAPK signaling [15]. Furthermore, the antitu- mor effects of panitumumab on mutant EGFR-expressing non-small cell lung carcinoma xenografts were increased with chemotherapy

Table 1 Overview of studies involved in the pharmacokinetic-related program

Study phase Clinical trial identifier Cancer type(s)a Dose (mg/ kg) Number of doses/duration Concomitant therapy
Phase 1 – CRC, other 0.1–9.0 Four doses None
NCT00091806 CRC, other 6.0, 9.0 Unlimited None
– CRC, other 2.5–9.0 Unlimited None
– CRC, other 0.01–9.0 6 months None
Phase 2 NCT00111761 CRC 2.5 B 48 weeks Irinotecan, 5-fluorouracil,
leucovorin
NCT00111774 CRC 2.5 Unlimited None
NCT00083616 CRC 6.0 24 months None
NCT00089635 CRC 6.0 24 months None
NCT00101920 Lung 2.5 B 48 weeks None
– Prostate 2.5 B 48 weeks None
NCT00425035 Renal 2.5 10 months None
NCT00034346 Lung 1.0–2.5 36 weeks Paclitaxel, carboplatin
Phase 3 NCT00113763 CRC 6.0 Unlimited None
CRC colorectal cancer
a Other includes various other solid tumor cancer types

and/or targeted therapeutic agents compared with chemotherapy or targeted agents alone [14].

CLINICAL PHARMACOKINETICS
Overview of Pharmacokinetic Profile

The pharmacokinetic profile of panitumumab was determined from phase 1 to phase 3 studies in patients with various solid tumors (Table 1) [18]. The pharmacokinetics of panitumumab are best described using a two-compartment model with linear and nonlinear clearance (Fig. 2) [18, 19]. At doses of 2 mg/kg or below, concentrations of panitumumab increase non- linearly, likely as a result of progressive satura- tion of the fixed EGFR binding sites (known as the EGFR sink) [19]. At clinically relevant doses (above 2 mg/kg) the area under the concentra- tion time curve (AUC) increases dose propor- tionally, suggesting that the EGFR sink is fully

Fig. 2 Schematic of two-compartment model with linear and nonlinear clearance. C concentration, CL linear clearance, Km Michaelis–Menten constant, Q inter- compartmental clearance, Vmax maximum elimination rate, V1 central compartment volume of distribution, V2 peripheral compartment volume of distribution
saturated [13]. After administration, the central volume of distribution (V1) is estimated at 3.66 (SD, 0.390) L [18], representative of the plasma

Table 2 Overview of pharmacokinetics parameters from phase 1 studies and from pharmacokinetic modeling
Dose (mg/kg)/frequency Pharmacokinetic parameters, median (range)

AUC0–tau (lg·day/mL) Cmax (lg/mL) CL (mL/kg/day) t1/2 (days)
After panitumumab first dose 0.75a
25 (10–28) 14 (9–20) 30.6 (26.3–73.0) 0.8 (0.2–2.0)
58 (34–83) 28 (24–31) 17.7 (11.9–29.3) 0.8 (0.7–0.9)
60 (51–88) 34 (26–40) 24 (17–27) 1.1 (0.8–2.3)
147 (122–176) 50 (40–53) 12.0 (9.6–14.9) 2.3 (2.1–2.6)
194 (133–265) 63 (50–86) 11.9 (8.4–17.6) 2.8 (0.7–3.7)
468 (339–570) 116 (78–132) NC 4.8 (3.3–5.8)

1a
1.5a
2a 2.5a
5a

6 931 (554–1092) 148 (109–183) 6.8 (4.5–10.4) 5.6 (3.4–7.3)
9 1622 (1038–2068) 211 (158–320) 4.8 (4.0–7.9) 6.5 (4.9–13.6)
After panitumumab third dose
2.5/QW 246 (197–384) 69 (53–89) NC 4.2 (3.4–5.8)
6/Q2W 1292 (823–1911) 207 (122–324) 4.6 (3.1–7.3) 7.0 (3.6–10.9)
9/Q3W 2220 (1528–2639) 256 (169–282) 4.1 (3.4–5.9) 8.3 (6.8–10.6)
Panitumumab parameter estimates from population pharmacokinetic model (estimate [SD]) [18]
Linear CL (L/day) V1 (L) V2 (L) Vmax (mg/day) Km (lg/mL)
0.269 (0.422) 3.66 (0.390) 2.58 (0.434) 10.6 (0.341) 0.401 (0.726)
AUC0–tau area under the concentration curve from time 0–tau, CL clearance, Cmax maximum serum concentration, Km Michaelis–Menten constant, NC not calculated, QW once weekly, Q2W every 2 weeks, Q3W every 3 weeks, SD standard deviation, t1/2 half-life, Vmax maximum elimination rate, V1 volume of distribution of the central compartment, V2 volume of distribution of the peripheral compartment
a Panitumumab manufactured from hybridoma expression system

volume. Panitumumab is subject to inter- compartmental clearance (Q = 0.389 L/day) between the central and peripheral compart- ment (estimated [SD] volume of distribution of the peripheral compartment [V2], 2.58 [0.434] L; Table 2). Distribution into the peripheral com- partment is limited because of the large molec- ular size of panitumumab [13]. Total body clearance (CL) from the central compartment (estimate (SD), 0.269 (0.422) L/day) occurs by reticuloendothelial system and EGFR-mediated internalization. Over the dose range 0.75–9.0 mg/kg, CL decreases approximately sixfold, and the estimated (SD) maximum elim- ination rate (Vmax) is 10.6 (0.341) mg/day
[13, 18]. The CL of panitumumab appears to be similar in patients with mCRC and those with renal cancer. The inter-individual variability is approximately 53% for CL and 25% for V1 [13]. Actual body weight has been identified as the covariate which has the most impact on inter- individual variability [18]. A body weight–based dosing regimen results in less variability in pan- itumumab exposure than a fixed dose [6].

Single-Dose and Multiple-Dose Pharmacokinetics

After single-dose administration of panitu- mumab ranging from 0.75 to 9 mg/kg,

Fig. 3 Indicative serum concentrations of panitumumab across different drug regimens

panitumumab displayed a nonlinear pharma- cokinetic profile [1, 2]. With increasing dose, clearance decreased and half-life increased [13]. At panitumumab doses below 2 mg/kg, AUC increased in a greater than dose-proportional manner; however, AUC increased dose-proportionally at doses above 2 mg/kg.
Pharmacokinetic parameters change over time with multiple-dose administration of panitumumab 6 mg/kg Q2W. Clearance decreased and half-life increased after the third dose compared with the first dose (Table 2). Steady state was achieved after the third dose [18]. Pharmacokinetic simulations showed that 6 mg/kg Q2W or 9 mg/kg every 3 weeks (Q3W) resulted in a similar trough serum concentra- tion (Ctrough; Fig. 3) [20]. The elimination half- life of panitumumab was 7.5 and 8.4 days, respectively, for these dose regimens [21].

Special Populations

The pharmacokinetic profile of panitumumab appears to be largely unaffected by race,
ethnicity, or renal or hepatic impairment. No meaningful differences in AUC values were observed among White, Black, Hispanic, Asian, and other subgroups (Table 3) [13]. The mean AUC for Asian patients was approximately 12% lower than for White patients; however, this difference was attributed to lower body weight in Asian patients (62 kg vs 83 kg, respectively). Japanese patients appear to have the same maximal serum concentration (Cmax) and min- imum serum concentration (Cmin) as White patients of the same body weight [18]. After matching demographic and baseline character- istics, a comparison of pharmacokinetic models for Japanese and non-Japanese patients showed that panitumumab exposure was similar between groups [18].
The pharmacokinetics of panitumumab in patients with severe renal or hepatic impair- ment have not been specifically studied. How- ever, in a patient with chronic kidney disease (estimated creatinine clearance 11 mL/min), the pharmacokinetic profile was similar to that observed in patients without chronic kidney

Table 3 Overview of pharmacokinetic parameters of panitumumab at 6 mg/kg Q2W in various patient subgroups

Subgroup Ctrough (lg/mL), mean (%CV) Cmax (lg/mL), mean (%CV) Simulated AUC (lg·day/mL), mean (SD)
Sex
Female 33 (51) 172 (37) –
Male 29 (57) 168 (36) –
Race
White 31 (53) 171 (37) 1250 (445)
Black – – 1228 (436)
Hispanic – – 1214 (448)
Asian – – 1097 (329)
Other – – 1326
Renal function
Mildly impaired 32 (42) 183 (28) –
Moderately impaired 38 (54) 183 (30) –
Normal 29 (62) 161 (41) –
Hepatic function
Impaired 34 (51) 177 (37) –
Normal 30 (55) 169 (36) –
AUC area under the concentration time curve, Cmax maximum serum concentration, Ctrough trough serum concentration,
CV coefficient of variation, Q2W every 2 weeks, SD standard deviation

disease [22]. Similarly, in a patient with severe hepatic impairment, the pharmacokinetic pro- file of panitumumab was similar to that in patients with normal liver function [23]. In patients with mild-to-moderate renal or hepatic impairment, no clinically meaningful differ- ences were observed in Cmax and Ctrough com- pared to patients with normal organ function (Table 3) [13]. Together, these data indicate that the pharmacokinetics of panitumumab are not affected by renal or hepatic impairment.
Small differences have been observed in the pharmacokinetics of panitumumab based on age and sex, but these differences do not appear to be clinically meaningful. Mean panitu- mumab concentration was approximately 10% higher in patients over 75 years of age com- pared with patients 75 years of age or younger.
With respect to sex, mean peak panitumumab concentration values and ranges were similar between male and female patients, although Ctrough was 15% higher in female patients compared to male patients [13]. In a population pharmacokinetic model of panitumumab, sex and age had small yet significant contributions to the total model variance (2.4% and 0.7%, respectively) [18]; a pooled analysis of Cmax and Cmin values further found that sex and age had no meaningful effect on the pharmacokinetics of panitumumab, and that dose modifications based on sex or age were not necessary [21].

Drug–Drug Interactions

Therapeutic mAbs do not undergo hepatic metabolism by cytochrome P450 or

P-glycoprotein transporters, and therefore interactions between mAbs and coadministered therapeutic agents are not likely [24]. Consis- tent with other mAbs, panitumumab is degra- ded into amino acids and therefore no interactions with coadministered therapeutic agents are expected.
Panitumumab is approved for use in combi- nation regimens [1, 2], and potential interac- tions with chemotherapy agents have been studied. In patients with mCRC, panitumumab had no effect on the pharmacokinetics of irinotecan [25, 26]. In a phase 2 study of patients with non-small cell lung cancer (NSCLC), panitumumab was administered in combination with paclitaxel and carboplatin [27]. Because these studies did not include a panitumumab only arm, Yang et al. [21] com- pared the pharmacokinetic profiles from these studies with a simulated pharmacokinetic pro- file of panitumumab from a phase 2 study of panitumumab as monotherapy [28]. Panitu- mumab concentrations from mCRC and NSCLC studies were comparable to the simulated pan- itumumab-only curve, suggesting that pacli- taxel, carboplatin, and irinotecan have no effect on the pharmacokinetics of panitumumab [21]. To date, no interactions between panitumumab and other drugs have been reported [29].

Pharmacokinetics of Fixed vs Body Weight–Based Dosing

The approved panitumumab dosing regimen is based on body weight and is 6 mg/kg Q2W [1, 2]. When dosed according to actual body weight, exposures of panitumumab were greater in heavier patients compared with lighter patients [6, 21]. AUC increased with increasing body weight with a weight-based regimen [13]. Conversely, AUC decreased with increasing body weight with a fixed-dose regimen. Popu- lation pharmacokinetic analyses of panitu- mumab identified body weight as a significant covariate influencing panitumumab exposure [18, 21]. Over a wide range of patient body weights, the variability in simulated AUC was lower for body weight–based dosing compared with fixed dosing [6]. Although it has recently
been suggested that fixed dosing is appropriate for therapeutic mAbs such as panitumumab [4, 30], body weight–based dosing of panitu- mumab results in less variability in exposure compared with a fixed dose over a range of body weights [6, 31].

Effect of EGFR Expression Level on Pharmacokinetics

Studies have demonstrated that the level of EGFR expression (medium/low vs high) has minimal effect on the pharmacokinetics of panitumumab. In a phase 2 study of panitu- mumab administered 2.5 mg/kg once weekly in patients with mCRC, no differences in phar- macokinetics were observed between high (at least 10%) and low (less than 10%) EGFR expression groups [28]. Similarly, in phase 2 and
3 studies of patients with mCRC receiving panitumumab 6 mg/kg Q2W, EGFR expression level had no impact on the serum concentra- tions of panitumumab [18]. A population pharmacokinetic model of panitumumab demonstrated that baseline EGFR expression did not significantly correlate with CL, V1, and Vmax [18].

EXPOSURE–RESPONSE RELATIONSHIP
Effect of EGFR Expression Level on Response

Because panitumumab targets EGFR, preclinical and clinical studies have investigated the rela- tionship between the level of EGFR expression and panitumumab efficacy. In an in vitro study, expression levels of EGFR in human tumor xenograft did not predict response to panitu- mumab [32]. A multicenter phase 2 study of patients with EGFR-expressing mCRC divided patients into high or low tumor EGFR expres- sion groups as determined by immunohisto- chemistry (IHC) [28]. After 8 weeks of treatment with panitumumab 2.5 mg/kg once weekly, response rates between EGFR expression groups were not significantly different. Another

phase 2 study of patients with mCRC examined response rates in patients with low (1–9%) or no (less than 1%) EGFR expression (determined by IHC) after 16 weeks of treatment with panitu- mumab 6 mg/kg Q2W [33]. Interestingly, response rates in patients with no EGFR expression were similar to patients with low expression. Similarly, in phase 2 and phase 3 studies of patients with mCRC receiving pani- tumumab 6 mg/kg Q2W, EGFR expression levels of 1% or higher had no effect on response rate [34, 35]. EGFR expression was not associ- ated with efficacy outcomes in patients with advanced NSCLC receiving panitumumab in combination with carboplatin and paclitaxel [36]. Given these data, patients should not be excluded from treatment with panitumumab solely on the basis of tumor EGFR expression level [37]. Nonetheless, further studies are required to establish whether there is any asso- ciation between EGFR expression level in tumors at more granular cutoff levels and the clinical response to panitumumab.

Effect of Dose on Efficacy and Safety

On the basis of dose-escalation studies and their safety findings, 2.5 mg/kg was selected as an optimal weekly panitumumab dose. Pharma- cokinetic modeling of this dose regimen indi- cated that almost all patients would have Cmin values ninefold higher than the Km for EGFR- mediated clearance, thus the EGFR sink was saturated at this dose [18, 21]. In three studies examining efficacy, no significant correlation was identified between panitumumab Ctrough or Cmax and tumor response after 7 weeks of treatment [13]. However, approximately 27% (112/408) of patients discontinued before week 7 and conclusions regarding panitu- mumab concentration and clinical response could not be drawn because of small sample sizes.
A maximum tolerated dose was not reached in a phase 1 dose-escalation study of panitu- mumab at doses up to 9 mg/kg Q3W [20]. The relationship between panitumumab dose and the incidence of skin and mucosal toxicity (i.e., skin, nail, hair, and eye-related toxicities
commonly reported with EGFR inhibitors) has been described using a three-parameter logistic regression model [19, 20]. This model indicated that the incidence of skin rash plateaued at a dose of 2.5 mg/kg weekly. However, the severity of skin-related toxicities increased with increasing dose, with more patients receiving the 9 mg/kg dose experiencing a severe degree of skin and mucosal toxicity. Therefore, the 6 mg/kg Q2W dose regimen was selected as the preferred regimen.

OTHER IMPORTANT FACTORS
Immunogenicity

Fully human therapeutic mAbs are expected to have low immunogenicity; however, some degree of immunogenicity to the complemen- tarity determining region is still possible [38]. Acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) and Biacore®
(surface plasmon resonance assay) have been used to screen for anti-panitumumab antibodies (Abs) on the basis of their ability to bind high- and low-affinity Abs, respectively [39]. The reported incidence of non-transient binding anti-panitumumab Abs is less than 1% by ELISA and ranges from 3.8% to 5.3% by Biacore assay [1, 2, 39]. The incidence of anti-panitumumab Abs determined by ELISA or Biacore assay in a population analysis of panitumumab was slightly higher in patients receiving the dose regimen 9 mg/kg Q3W compared with 6 mg/kg Q2W (2/26 [7.7%] vs 16/498 [3.2%], respec-
tively); however, the overall incidence of 18/530 patients (3.4%) was comparable to pre- vious reports [18]. The incidence of neutralizing Abs was less than 2% as determined by ELISA or Biacore assays [1, 2, 39]. When combined with oxaliplatin- or irinotecan-based chemotherapy, the incidence of anti-panitumumab Abs and neutralizing Abs remained low (1.8% and 0.2%, respectively) [40]. In the pivotal clinical trial of panitumumab [35], all responders were negative for anti-panitumumab Abs [13]. There was no relationship between the presence of anti-pan- itumumab antibodies and pharmacokinetics,

efficacy, or safety when used as monotherapy or in combination with chemotherapy [1, 2, 18].

CONCLUSIONS
Over the last 10 years, the pharmacokinetic profile and dose regimen of panitumumab have been further explored, including in combina- tion with chemotherapy drugs and in patients with hepatic and renal impairment. The approved dosing regimen of 6 mg/kg Q2W maintains a Cmin to achieve clinical efficacy, reduces inter-individual variability, has a man- ageable safety profile, and is administered on a schedule that is compatible with the chemotherapy regimens typically used with it in mCRC. Panitumumab has a favorable phar- macokinetic/pharmacodynamic profile which makes it well suited for standard dosing for the treatment of wild-type RAS mCRC across a broad range of patients.

ACKNOWLEDGEMENTS

Funding. Amgen Inc. funded this analysis and the journal’s Rapid Service fees.

Medical Writing/Editorial Assistance. The authors thank Lee Hohaia, PharmD, and Allison Gillies, PhD (ICON, North Wales, PA), whose work was funded by Amgen Inc., for medical writing assistance in the preparation of this manuscript.

Authorship. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Authors’ Contributions. All authors con- tributed equally to this manuscript’s concep- tion, design, material preparation, data collection and analysis, reviewed and edited the manuscript, and read and approved the final manuscript.
Prior Presentation. Although based on pre- viously conducted studies, the analyses in this article have not been presented or published previously.

Disclosures. Johannes Kast, Sandeep Dutta and Vijay V. Upreti are employees of and stockholders in Amgen Inc.

Compliance with Ethics Guidelines. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Data Availability. Qualified researchers may request data from Amgen clinical studies. Complete details are available at the following: http://www.amgen.com/datasharing.

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