Immunogenicity of panitumumab in combination chemotherapy clinical trials

Dohan Weeraratne, Alin Chen, Jason J Pennucci, Chi-Yuan Wu, Kathy Zhang, Jacqueline Wright, Juan José Pérez-Ruixo, Bing-Bing Yang, Arunan Kaliyaperumal, Shalini Gupta, Steven J Swanson, Narendra Chirmule, Marta Starcevic, Dohan Weeraratne, Alin Chen, Jason J Pennucci, Chi-Yuan Wu, Kathy Zhang, Jacqueline Wright, Juan José Pérez-Ruixo, Bing-Bing Yang, Arunan Kaliyaperumal, Shalini Gupta, Steven J Swanson, Narendra Chirmule, Marta Starcevic

Abstract

Background: Panitumumab is a fully human antibody against the epidermal growth factor receptor that is indicated for the treatment of metastatic colorectal cancer (mCRC) after disease progression on standard chemotherapy. The purpose of this analysis was to examine the immunogenicity of panitumumab and to evaluate the effect of anti-panitumumab antibodies on pharmacokinetic and safety profiles in patients with mCRC receiving panitumumab in combination with oxaliplatin- or irinotecan-based chemotherapies.

Methods: Three validated assays (two screening immunoassays and a neutralizing antibody bioassay) were used to detect the presence of anti-panitumumab antibodies in serum samples collected from patients enrolled in four panitumumab combination chemotherapy clinical trials. The impact of anti-panitumumab antibodies on pharmacokinetic and safety profiles was analyzed using population pharmacokinetic analysis and descriptive statistics, respectively.

Results: Of 1124 patients treated with panitumumab in combination with oxaliplatin- or irinotecan-based chemotherapy with postbaseline samples available for testing, 20 (1.8%) patients developed binding antibodies and 2 (0.2%) developed neutralizing antibodies. The incidence of anti-panitumumab antibodies was similar in patients with tumors expressing wild-type or mutant KRAS and in patients receiving oxaliplatin- or irinotecan-based chemotherapies. No evidence of an altered pharmacokinetic or safety profile was found in patients who tested positive for anti-panitumumab antibodies.

Conclusions: The immunogenicity of panitumumab in the combination chemotherapy setting was infrequent and similar to the immunogenicity observed in the monotherapy setting. Panitumumab immunogenicity did not appear to alter pharmacokinetic or safety profiles. This low rate of immunogenicity may be attributed to the fully human nature of panitumumab.

Trial registration: ClinicalTrials.gov NCT00332163 NCT00339183 NCT00364013 NCT00411450.

Figures

Figure 1
Figure 1
Panitumumab immunogenicity testing strategy. Three validated assays were used to detect the presence of anti-panitumumab antibodies. All clinical study samples were tested in two screening immunoassays (an acid-dissociation ELISA and a Biacore-based biosensor assay) to detect antibodies capable of binding to panitumumab. Samples that tested above the assay threshold and demonstrated reduction in response in the drug-competition specificity assay were reported as positive for binding antibodies and tested further in a cell-based neutralizing antibody bioassay. Assay thresholds were based on the upper bound of a one-sided 95% reference interval for the distribution of signals generated by serum samples from healthy subjects or cancer patients. S/N, signal-to-noise ratio.
Figure 2
Figure 2
Sensitivity analysis. The sensitivity analysis estimated the minimum difference in panitumumab concentration between antibody-positive and antibody-negative samples that could be statistically significant (P < 0.05) with respect to the model prediction. Results show that the current observed sample size for pharmacokinetic testing (n = 38) from antibody-positive patients was only adequate to detect a difference of > 55%. Approximately 200 and 650 samples from antibody-positive patients would be required to detect differences of 38% and 20%, respectively.

References

    1. Vectibix® (panitumumab) prescribing information. Amgen Inc, Thousand Oaks, CA; 2011.
    1. EPARs for authorised medicinal products for human use.
    1. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J. et al.Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28(31):4697–4705. doi: 10.1200/JCO.2009.27.4860.
    1. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, Andre T, Chan E, Lordick F, Punt CJ. et al.Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28(31):4706–4713. doi: 10.1200/JCO.2009.27.6055.
    1. Shankar G, Pendley C, Stein KE. A risk-based bioanalytical strategy for the assessment of antibody immune responses against biological drugs. Nat Biotechnol. 2007;25(5):555–561. doi: 10.1038/nbt1303.
    1. Nelson AL, Dhimolea E, Reichert JM. Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov. 2010;9(10):767–774. doi: 10.1038/nrd3229.
    1. Hwang WY, Foote J. Immunogenicity of engineered antibodies. Methods. 2005;36(1):3–10. doi: 10.1016/j.ymeth.2005.01.001.
    1. Bartelds GM, Wijbrandts CA, Nurmohamed MT, Stapel S, Lems WF, Aarden L, Dijkmans BA, Tak PP, Wolbink GJ. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis. 2007;66(7):921–926. doi: 10.1136/ard.2006.065615.
    1. Bender NK, Heilig CE, Droll B, Wohlgemuth J, Armbruster FP, Heilig B. Immunogenicity, efficacy and adverse events of adalimumab in RA patients. Rheumatol Int. 2007;27(3):269–274.
    1. Khazaeli M, LoBuglio A, Falcey J, Paulter V, Fetzer M, Waksal H. Low immunogenicity of a chimeric monoclonal antibody (MoAb), IM-C225, used to treat epidermal growth factor receptor-positive tumor [abstract] Proc Am Soc Clin Oncol. 2000;19:Abst 808.
    1. Fracasso PM, Burris H, Arquette MA, Govindan R, Gao F, Wright LP, Goodner SA, Greco FA, Jones SF, Willcut N. et al.A phase 1 escalating single-dose and weekly fixed-dose study of cetuximab: pharmacokinetic and pharmacodynamic rationale for dosing. Clin Cancer Res. 2007;13(3):986–993. doi: 10.1158/1078-0432.CCR-06-1542.
    1. O'Neil BH, Allen R, Spigel DR, Stinchcombe TE, Moore DT, Berlin JD, Goldberg RM. High incidence of cetuximab-related infusion reactions in Tennessee and North Carolina and the association with atopic history. J Clin Oncol. 2007;25(24):3644–3648. doi: 10.1200/JCO.2007.11.7812.
    1. Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, Murphy BA, Satinover SM, Hosen J, Mauro D. et al.Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358(11):1109–1117. doi: 10.1056/NEJMoa074943.
    1. Ghaderi D, Taylor RE, Padler-Karavani V, Diaz S, Varki A. Implications of the presence of N-glycolylneuraminic acid in recombinant therapeutic glycoproteins. Nat Biotechnol. 2010;28(8):863–867. doi: 10.1038/nbt.1651.
    1. Weiner LM. Fully human therapeutic monoclonal antibodies. J Immunother. 2006;29(1):1–9. doi: 10.1097/01.cji.0000192105.24583.83.
    1. Lofgren JA, Dhandapani S, Pennucci JJ, Abbott CM, Mytych DT, Kaliyaperumal A, Swanson SJ, Mullenix MC. Comparing ELISA and surface plasmon resonance for assessing clinical immunogenicity of panitumumab. J Immunol. 2007;178(11):7467–7472.
    1. Lacouture ME, Mitchell EP, Piperdi B, Pillai MV, Shearer H, Iannotti N, Xu F, Yassine M. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28(8):1351–1357. doi: 10.1200/JCO.2008.21.7828.
    1. Cohn AL, Shumaker GC, Khandelwal P, Smith DA, Neubauer MA, Mehta N, Richards D, Watkins DL, Zhang K, Yassine MR. An open-label, single-arm, phase 2 trial of panitumumab plus FOLFIRI as second-line therapy in patients with metastatic colorectal cancer. Clin Colorectal Cancer. 2011;10(3):171–177. doi: 10.1016/j.clcc.2011.03.022.
    1. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R. et al.Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626–1634. doi: 10.1200/JCO.2007.14.7116.
    1. Barger TE, Zhou L, Hale M, Moxness M, Swanson SJ, Chirmule N. Comparing exponentially weighted moving average and run rules in process control of semiquantitative immunogenicity immunoassays. AAPS J. 2010;12(1):79–86. doi: 10.1208/s12248-009-9166-4.
    1. Ma P, Yang BB, Wang YM, Peterson M, Narayanan A, Sutjandra L, Rodriguez R, Chow A. Population pharmacokinetic analysis of panitumumab in patients with advanced solid tumors. J Clin Pharmacol. 2009;49(10):1142–1156. doi: 10.1177/0091270009344989.
    1. Yang BB, Lum P, Chen A, Arends R, Roskos L, Smith B, Perez Ruixo JJ. Pharmacokinetic and pharmacodynamic perspectives on the clinical drug development of panitumumab. Clin Pharmacokinet. 2010;49(11):729–740. doi: 10.2165/11535970-000000000-00000.
    1. Yano Y, Beal SL, Sheiner LB. Evaluating pharmacokinetic/pharmacodynamic models using the posterior predictive check. J Pharmacokinet Pharmacodyn. 2001;28(2):171–192. doi: 10.1023/A:1011555016423.
    1. Eloxatin® (oxaliplatin) prescribing information. sanofi aventis, Bridgewater, NJ; 2009.
    1. Camptosar® (irinotecan hydrochloride) prescribing information. Pharmacia & Upjohn Co. Division of Pfizer Inc., New York, NY; 2010.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe