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Published on 13 July 2009

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Panitumumab in the individualised treatment of metastatic colorectal cancer

teaser

Panitumumab is the first fully human monoclonal antibody that targets EGFR1. Can the drug be an option in patients with intolerance to cetuximab? Can supportive management of dermatologic reactions be optimised?

Hans-Peter Lipp
PhD

Chief Pharmacist
Department of Pharmacy
University Hospital of
Tubingen
Germany

Prespecified analysis of the pivotal phase III study of panitumumab and retrospective analyses of several cetuximab trials have shown that only patients with KRAS wild-type expressing tumours benefit from treatment with anti-EGFR therapy, which highlights the potential for greater individualisation of tumour therapy. The use of cetuximab, a chimeric monoclonal antibody (MAB) directed against the epidermal growth factor receptor (EGFR), has been associated with infusion reactions. However, the incidence of panitumumab-related infusion reactions is low, which is likely related to the fully human structure of this MAB. Skin toxicity is a common adverse event associated with EGFR inhibitors, but recent phase II data suggest that a prophylactic approach rather than intensive reactive skin treatment is a viable approach for further investigation.

Colorectal cancer belongs to the most frequently observed solid tumours in industrial countries. About 20% can be estimated to be metastatic (mCRC) at the time of diagnosis. Oral fluoropyridines, oxaliplatin and irinotecan alongside the antivascular epithelial growth factor inhibitor bevacizumab (Avastin®) are rapidly becoming established as the new standards of care in the treatment of mCRC. However, targeted therapy directed against the EGFR has become of increasing importance within the last few years based on overexpression of EGFR in mCRC tumour tissue, encouraging clinical study results and the identification of KRAS as the first important predictive marker of efficacy.[1] This article reviews the pharmacologic properties of MABs directed against the EGFR with a particular focus on panitumumab (Vectibix®), the most recently approved drug in this class.

Cetuximab
Cetuximab (Erbitux®) was the first MAB to be approved for the treatment of mCRC as combination therapy with irinotecan in irinotecan-refractory patients. Recently the use of cetuximab in mCRC has been restricted to patients with KRAS wild-type mCRC (either in combination with chemotherapy or as monotherapy in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan). As a chimeric MAB with a human IgG1 backbone, it remains unclear whether its structure, which can potentially provoke antibody-dependent cell-mediated cytotoxicity (ADCC), is linked to any particular clinical benefits (Table 1). Cetuximab is administered following premedication as an initial intravenous (IV) loading dose of 400 mg/m², followed by a weekly maintenance dose of 250 mg/m². Clinical pharmacokinetic data are summarised in Table 2.[2,3]

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Panitumumab
Panitumumab is the first fully human MAB directed against EGFR to be approved for clinical use as monotherapy treatment of patients with nonmutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin- and irinotecan- containing chemotherapy (Table 1). The clinical development of panitumumab is based on a xenomouse model via immunisation of genetically engineered mice with the human cervix carcinoma cell line A431.[4] Panitumumab has been shown to exert a higher binding affinity to the EGFR as well as a longer elimination half-life than cetuximab (Table 2).[5,6] This allows panitumumab to be administered as a more convenient dosing regimen of 6 mg/kg every two weeks.

Physicochemical considerations
Cetuximab and panitumumab represent monoclonal IgG antibodies that have to be handled carefully during preparation. Both drugs must be stored between 2°C and 8°C (36-46°F). If panitumumab is diluted with 0.9% sodium chloride, the use of PVC or polyolefin bags does not affect drug stability at 2-25°C. Generally, the final concentration of diluted panitumumab solutions must not exceed 10 mg/ml, which indicates that common doses of about 400 mg (absolute) can be diluted in, for example, 250 ml NaCl 0.9%, resulting in a final concentration of about 1.3 mg/ml. The ready-to-use solution has to be infused via a low protein, particlebinding 0.22micrometre inline filter. The physiochemical stability of this solution beyond 24 hours has not yet been elucidated (personnel communication, Amgen).

Phase III trial
Van Cutsem et al randomised a total of 463 chemotherapy-refractory mCRC patients with disease progression during or within six months of last administered cytotoxic chemotherapy to receive either panitumumab (6 mg/kg every two weeks) plus best supportive care (BSC; n = 231) or BSC alone (n = 232). The primary endpoint of the study was progression-free survival; objective response rates and overall survival were two of the secondary endpoints. A crossover study allowed patients in the BSC arm to switch to receive the panitumumab regimen at time of disease progression. The primary analysis showed the panitumumab plus BSC regimen is significantly superior to BSC alone: patients who received panitumumab had a 46% decrease in rate of progression or death (p < 0.0001). In contrast with the BSC arm with no observable response rate (0%) after a 12-month minimum follow-up, response rate for patients treated with panitumumab was 10%. No difference was observed between the investigational arm and the BSC arm in terms of overall survival, which was likely confounded by the similar activity of panitumumab after the crossover design of the trial allowed 76% of BSC patients to receive panitumumab after progression.[7]

KRAS as predictive factor for anti-EGFR therapy
In a prespecified retrospective analysis of the phase III trial, KRAS status was determined in tumour tissue samples from 92% (427 of 463) of patients. Constitutive activation of KRAS driven by an oncogenic mutation is an important negative predictive marker for response to treatment with anti-EGFR therapy. In the KRAS wildtype group 51% of mCRC patients had disease control (partial response [17%] plus stable disease [34%]). In contrast, none of the patients with mutated KRAS had a response to treatment with panitumumab, and only 12% had stable disease (Table 3).[8] On this basis, the approval of panitumumab monotherapy in the treatment of advanced mCRC was limited to patients with KRAS wild-type expressing tumours. The same conclusions have since been drawn from retrospective analyses of cetuximab monotherapy and combination studies, and subsequently the label has been updated to restrict its use to KRAS wild-type patients.[9,10]

[[HPE.34]]

The identification of this important predictive biomarker has brought anti-EGFR treatment to the forefront of targeted therapy. In the phase III pantiumumab study 43% of patients were found to have mutated KRAS expressing tumours. Adoption of KRAS testing permits personalised medicine with efficient and cost-effective allocation of healthcare resources.

Anti-EGFR treatment-related adverse events
Skin toxicity
Skin toxicity is a common treatment-related adverse event induced by EGFR inhibitors. In the phase III monotherapy trial, 14% of patients treated with panitumumab developed grade less than 3 dermatologic toxicity, including symptomatic generalised skin rash, skin exfoliation, erythema, pruritus, paronychia and skin fissures (Table 4). Besides topical and systemic intervention (eg, doxycycline 100 mg b.i.d.), dose modification or interruption of treatment may be necessary.[11] A broad spectrum of supportive measures have been discussed in the literature (eg, topical use of nadifloxacin, prednicarbate, adapalen and even vitamin K1). Recently presented data suggest that future management strategies may employ prophylactic rash treatment. Data from the STEPP trial showed that patients who received prophylactic treatment with supportive agents (eg, skin moisturising creams, sun blockers SPF less than 15, hydrocortisone cream 1% and doxycyclin 100 mg b.i.d.) developed a lower severity of dermatologic toxicity compared with those who received reactive supportive therapy (Table 5). In addition, prophylactic use of supportive agents in this small phase II trial was associated with fewer interruptions and delays of treatment, which may lead to better tumour management. Although these results are promising this strategy still has to be validated in a larger patient set before any firm conclusions can be drawn.[12]

Infusion reactions
Nearly all systemic anticancer therapies are associated with infusion or hypersensitivity reactions.[13] Severity of reactions (ranging from mild flushing and chills to febrile reactions, bronchospasms and anaphylaxis)[14] and the frequency of their occurrence vary between therapies. Incidence of severe infusion reactions to the chimeric MAB (cetuximab) in a phase III monotherapy trial was 4%.[15] To reduce the risk of infusion reactions, prior to first infusion patients must be given an H1-antihistamine and a corticosteroid. This premedication is recommended prior to all subsequent infusions.[16]

Unlike cetuximab, treatment with the fully human MAB panitumumab is rarely associated with severe infusion reactions (<1%) and thus does not require premedication.[17] Furthermore, recently published case reports suggest that panitumumab can be safely administered in patients who have previously experienced a severe infusion reaction to cetuximab (Table 6).[18-20] These data suggest that panitumumab may have a more acceptable safety profile than cetuximab, which may be attributed to its fully human structure. However, a head-to-head comparison between these agents would be needed to draw any firm conclusions.

Electrolyte disorders
Electrolyte disorders, particularly hypomagnesaemia (Table 4), are associated with use of anti-EGFR therapy, with an average time of onset of six weeks after initiation of treatment. The underlying pathophysiology may be based on a high density of EGFR within the renal tubular system, particularly in the location of constitutive magnesium reabsorption. Consequently, constitutive function may be impaired by cetuximab or panitumumab.[21] Aside from the need for magnesium substitution in the individual patient, an early and marked fall of magnesium levels in plasma has been suggested to be a predictor for clinical response to treatment.[22]

[[HPE.35]]

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Other points of note
In contrast to the above-mentioned side-effects, drug-related pulmonary fibrosis rarely occurs during treatment with panitumumab or cetuximab. Early unspecific symptoms such as cough may pre-empt incidence; however, predisposed patients should not be treated with anti-EGFR regimens as a precautionary measure.[23]

[[HPE.36]]

Conclusions
Targeted treatment of mCRC has been clearly improved by the introduction of the anti-EGFR MABs for the specific treatment of patients with KRAS wildtype expressing tumours. We note that additional molecular biomarkers such as extent of intratumoral EGFR overexpression, PTEN deficiency, chromosome-7 polysomy and BRAF may also play a role in determining treatment benefit. The extent of the role that they play is being further evaluated in ongoing clinical trials (Table 7), highlighting the future important role of theranostics in treatment decision-making.[24]

There appear to be no obvious differences in extent and frequency of dermatologic side-effects and electrolyte disorders (eg, hypomagnesaemia) between cetuximab and panitumumab based on comparable phase III monotherapy data for both agents. According to the preliminary data from the phase II STEPP trial, a prophylactic and supportive strategy towards management of skin toxicities may be favourable; however, data from a larger clinical trial are required for validation.

[[HPE.366]]

Treatment with panitumumab is rarely associated with severe infusion reactions and thus does not require premedication. This is likely attributed to its fully human structure. However, administration of the chimeric MAB cetuximab is more frequently associated with incidence of severe infusion reactions, which may be a result of its ability to elicit human antichimeric antibodies.

In conclusion, clinical experience with cetuximab and panitumumab has clearly improved targeted therapy against EGFR under clinical pharmacological, ethical and pharmacoeconomic consideration in patients withmCRC. One may expect that other targeted therapies, such as anti-VEGF agents, may also need more intensified theranostics to improve clinical outcome in the near future. The fully human MAB panitumumab offers advantages in comparison with cetuximab regarding the extent of drug-related infusion reactions. Whether a prophylactic use of defined supportive agents is able to reduce the severity of drug-related dermatologic toxicity has to be elucidated in further trials.

References
1. Adams VR. Am J Health-Syst Pharm 2006;63 Suppl 2:S4-S11.
2. Jean GW, et al. Pharmacotherapy 2008;28:742-54.
3. Saadeh CE, et al. Ann Pharmacother 2007;41:606-13.
4. Rivera F. Anti-Cancer Drugs 2008;19:99-113.
5. Cohenuram M, et al. Anti-Cancer Drugs 2007;18:7-15.
6. Jakobovits A, et al. Nat Biotechnol 2007;25: 1134-43.
7. Van Cutsem E, et al. J Clin Oncol 2007;25:1658-64.
8. Amado RG et al. J Clin Oncol 2008;26:1626-34.
9. Jonker DJ, et al. N Engl J Med 2007;357:2040-8.
10. Bokemeyer C, et al. J Clin Oncol 2008;26 Suppl:178s (abstract 4000).
11. Segaert S, et al. Ann Oncol 2005;16:1425-33.
12. Mitchell EP, et al. Ann Oncol 2008;19 Suppl 6: vi14 (abstract O-021).
13. Zanotti KM, et al. Drug Saf 2001;24: 767-79.
14. Owera R, et al. J Clin Oncol 2008;26 Suppl:744s (abstract 20747).
15. Karapetis C, et al. N Engl J Med 2008;359: 1757-65.
16. Available at: http://www.emea.europa.eu/humandocs/ PDFs/EPAR/erbitux/H-558-PI-en.pdf
17. Available at http://www.emea.europa.eu/
humandocs/PDFs/EPAR/vectibix/H-741-PI-en.pdf
18. Saif MW, et al. Cancer Chemother Pharmacol 2009;63: 1017-22.
19. Helbing D et al. Ann Oncol 2007;18:963-4.
20. Heun J, et al. Clin Colorectal Cancer 2007;6:529-31.
21. Schrag D, et al. J Natl Cancer Inst 2005;97:1221-4.
22. Vincenzi B, et al. J Clin Oncol 2008;26 Suppl:204S (abstract 4106).
23. Giusti RM, et al. Clin Cancer Res 2008;14:1296-302.
24. Frattini M, et al. Br J Cancer 2007;97:1139-45.



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