Generic placeholder image

Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Systematic Review Article

Review of the Clinical Pharmacokinetics, Efficacy and Safety of Pembrolizumab

Author(s): Ana Homšek, Davorin Radosavljević, Nebojša Miletić, Jelena Spasić, Marija Jovanović, Branislava Miljković, Tatjana Stanojković and Katarina Vučićević*

Volume 23, Issue 6, 2022

Published on: 22 June, 2022

Page: [460 - 472] Pages: 13

DOI: 10.2174/1389200223666220609125013

Price: $65

Abstract

Background: Treatment of various types of cancer has been improved significantly with the discovery of biological drugs that act as immune checkpoint inhibitors (ICIs). Pembrolizumab is a humanized monoclonal anti- PD-1 antibody currently approved for the treatment of a wide range of tumors, with more indications still being investigated in ongoing clinical trials.

Objective: The aim of this paper is to present all currently available data regarding pembrolizumab pharmacokinetic and pharmacodynamic characteristics. Also, the possibility of using predictive biomarkers to monitor patients during cancer treatment is discussed.

Methods: Database research was carried out (PubMed, ScienceDirect). Information was gathered from original articles, the European Medicines Agency datasheets and results from clinical trials.

Results: This review summarizes present-day knowledge about the pharmacokinetics, different modeling approaches and dosage regimens, efficacy and safety of pembrolizumab and therapeutic monitoring of disease progression.

Conclusion: This review points out consistent pharmacokinetic characteristics of pembrolizumab in various cancer patients, the lack of pharmacokinetic-pharmacodynamic/outcome relationships, and the need for adequate biomarkers to predict treatment success. Hence, there is a clear necessity for more data and experience in order to optimize pembrolizumab treatment for each individual patient.

Keywords: Pembrolizumab, immune checkpoint inhibitors, monoclonal antibody, Target Mediated Drug Disposition (TMDD), pharmacokinetics, PKPD.

Graphical Abstract

[1]
Topalian, S.L.; Taube, J.M.; Anders, R.A.; Pardoll, D.M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer, 2016, 16(5), 275-287.
[http://dx.doi.org/10.1038/nrc.2016.36] [PMID: 27079802]
[2]
Kyi, C.; Postow, M.A. Checkpoint blocking antibodies in cancer immunotherapy. FEBS Lett., 2014, 588(2), 368-376.
[http://dx.doi.org/10.1016/j.febslet.2013.10.015] [PMID: 24161671]
[3]
Hodi, F.S.; O’Day, S.J.; McDermott, D.F.; Weber, R.W.; Sosman, J.A.; Haanen, J.B.; Gonzalez, R.; Robert, C.; Schadendorf, D.; Hassel, J.C.; Akerley, W.; van den Eertwegh, A.J.M.; Lutzky, J.; Lorigan, P.; Vaubel, J.M.; Linette, G.P.; Hogg, D.; Ottensmeier, C.H.; Lebbé, C.; Peschel, C.; Quirt, I.; Clark, J.I.; Wolchok, J.D.; Weber, J.S.; Tian, J.; Yellin, M.J.; Nichol, G.M.; Hoos, A.; Urba, W.J. Improved survival with ipili-mumab in patients with metastatic melanoma. N. Engl. J. Med., 2010, 363(8), 711-723.
[http://dx.doi.org/10.1056/NEJMoa1003466] [PMID: 20525992]
[4]
Robert, C.; Thomas, L.; Bondarenko, I.; O’Day, S.; Weber, J.; Garbe, C.; Lebbe, C.; Baurain, J-F.; Testori, A.; Grob, J-J.; Davidson, N.; Rich-ards, J.; Maio, M.; Hauschild, A.; Miller, W.H., Jr; Gascon, P.; Lotem, M.; Harmankaya, K.; Ibrahim, R.; Francis, S.; Chen, T-T.; Humphrey, R.; Hoos, A.; Wolchok, J.D. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med., 2011, 364(26), 2517-2526.
[http://dx.doi.org/10.1056/NEJMoa1104621] [PMID: 21639810]
[5]
McDermott, D.F.; Atkins, M.B. PD-1 as a potential target in cancer therapy. Cancer Med., 2013, 2(5), 662-673.
[http://dx.doi.org/10.1002/cam4.106] [PMID: 24403232]
[6]
Ishida, Y.; Agata, Y.; Shibahara, K.; Honjo, T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J., 1992, 11(11), 3887-3895.
[http://dx.doi.org/10.1002/j.1460-2075.1992.tb05481.x] [PMID: 1396582]
[7]
Nishimura, H.; Nose, M.; Hiai, H.; Minato, N.; Honjo, T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity, 1999, 11(2), 141-151.
[http://dx.doi.org/10.1016/S1074-7613(00)80089-8] [PMID: 10485649]
[8]
Carter, L.; Fouser, L.A.; Jussif, J.; Fitz, L.; Deng, B.; Wood, C.R.; Collins, M.; Honjo, T.; Freeman, G.J.; Carreno, B.M. PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur. J. Immunol., 2002, 32(3), 634-643.
[http://dx.doi.org/10.1002/1521-4141(200203)32:3<634:AID-IMMU634>3.0.CO;2-9] [PMID: 11857337]
[9]
Freeman, G.J.; Long, A.J.; Iwai, Y.; Bourque, K.; Chernova, T.; Nishimura, H.; Fitz, L.J.; Malenkovich, N.; Okazaki, T.; Byrne, M.C.; Horton, H.F.; Fouser, L.; Carter, L.; Ling, V.; Bowman, M.R.; Carreno, B.M.; Collins, M.; Wood, C.R.; Honjo, T. Engagement of the PD-1 im-munoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med., 2000, 192(7), 1027-1034.
[http://dx.doi.org/10.1084/jem.192.7.1027] [PMID: 11015443]
[10]
Latchman, Y.; Wood, C.R.; Chernova, T.; Chaudhary, D.; Borde, M.; Chernova, I.; Iwai, Y.; Long, A.J.; Brown, J.A.; Nunes, R.; Greenfield, E.A.; Bourque, K.; Boussiotis, V.A.; Carter, L.L.; Carreno, B.M.; Malenkovich, N.; Nishimura, H.; Okazaki, T.; Honjo, T.; Sharpe, A.H.; Freeman, G.J. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol., 2001, 2(3), 261-268.
[http://dx.doi.org/10.1038/85330] [PMID: 11224527]
[11]
Merck. Keytruda (Pembrolizumab) Prescribing Information Available from: http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf Accessed on Jun 6, 2021).
[12]
Patnaik, A.; Kang, S.P.; Rasco, D.; Papadopoulos, K.P.; Elassaiss-Schaap, J.; Beeram, M.; Drengler, R.; Chen, C.; Smith, L.; Espino, G.; Ger-gich, K.; Delgado, L.; Daud, A.; Lindia, J.A.; Li, X.N.; Pierce, R.H.; Yearley, J.H.; Wu, D.; Laterza, O.; Lehnert, M.; Iannone, R.; Tolcher, A.W.; Phase, I. Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin. Cancer Res., 2015, 21(19), 4286-4293.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-2607] [PMID: 25977344]
[13]
Ahamadi, M.; Freshwater, T.; Prohn, M.; Li, C.H.; de Alwis, D.P.; de Greef, R.; Elassaiss-Schaap, J.; Kondic, A.; Stone, J.A. Model-based characterization of the pharmacokinetics of pembrolizumab: A humanized anti-PD-1 monoclonal antibody in advanced solid tumors. CPT Pharm. Syst. Pharmacol., 2017, 6(1), 49-57.
[http://dx.doi.org/10.1002/psp4.12139] [PMID: 27863186]
[14]
Larkin, J.; Minor, D.; D’Angelo, S.; Neyns, B.; Smylie, M.; Miller, W.H., Jr; Gutzmer, R.; Linette, G.; Chmielowski, B.; Lao, C.D.; Lorigan, P.; Grossmann, K.; Hassel, J.C.; Sznol, M.; Daud, A.; Sosman, J.; Khushalani, N.; Schadendorf, D.; Hoeller, C.; Walker, D.; Kong, G.; Horak, C.; Weber, J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator’s choice chemotherapy in checkmate 037: A randomized, controlled, open-label phase III trial. J. Clin. Oncol., 2018, 36(4), 383-390.
[http://dx.doi.org/10.1200/JCO.2016.71.8023] [PMID: 28671856]
[15]
Sul, J.; Blumenthal, G.M.; Jiang, X.; He, K.; Keegan, P.; Pazdur, R. FDA approval summary: Pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1. Oncologist, 2016, 21(5), 643-650.
[http://dx.doi.org/10.1634/theoncologist.2015-0498] [PMID: 27026676]
[16]
Shu, C.A.; Rizvi, N.A. Into the clinic with nivolumab and pembrolizumab. Oncologist, 2016, 21(5), 527-528.
[http://dx.doi.org/10.1634/theoncologist.2016-0099] [PMID: 27026678]
[17]
Zheng, J.; Mehl, J.; Zhu, Y.; Xin, B.; Olah, T. Application and challenges in using LC-MS assays for absolute quantitative analysis of thera-peutic proteins in drug discovery. Bioanalysis, 2014, 6(6), 859-879.
[http://dx.doi.org/10.4155/bio.14.36] [PMID: 24702115]
[18]
Hoofnagle, A.N.; Wener, M.H. The fundamental flaws of immunoassays and potential solutions using tandem mass spectrometry. J. Immunol. Methods, 2009, 347(1-2), 3-11.
[http://dx.doi.org/10.1016/j.jim.2009.06.003] [PMID: 19538965]
[19]
Ouyang, Z.; Furlong, M.T.; Wu, S.; Sleczka, B.; Tamura, J.; Wang, H.; Suchard, S.; Suri, A.; Olah, T.; Tymiak, A.; Jemal, M. Pellet digestion: A simple and efficient sample preparation technique for LC-MS/MS quantification of large therapeutic proteins in plasma. Bioanalysis, 2012, 4(1), 17-28.
[http://dx.doi.org/10.4155/bio.11.286] [PMID: 22191591]
[20]
Wild, D.; John, R.; Sheehan, C. The Immunoassay Handbook, Fourth Edi; Wild, D., Ed.; Elsevier, 2013.
[21]
Pandya, K.; Ray, C.A.; Brunner, L.; Wang, J.; Lee, J.W.; DeSilva, B. Strategies to minimize variability and bias associated with manual pipet-ting in ligand binding assays to assure data quality of protein therapeutic quantification. J. Pharm. Biomed. Anal., 2010, 53(3), 623-630.
[http://dx.doi.org/10.1016/j.jpba.2010.04.025] [PMID: 20483557]
[22]
Lee, J.W.; Kelley, M. Quality assessment of bioanalytical quantification of monoclonal antibody drugs. Ther. Deliv., 2011, 2(3), 383-396.
[http://dx.doi.org/10.4155/tde.10.99] [PMID: 22834008]
[23]
Ray, C.A.; Zhou, L.; Tsoi, J.; Uy, L.; Gu, J.; Malella, J.; Desimone, D.; Gunn, H.; Ma, M.; Lee, J.; DeSilva, B. A strategy for improving com-parability across sites for ligand binding assays measuring therapeutic proteins. J. Pharm. Biomed. Anal., 2010, 53(3), 729-734.
[http://dx.doi.org/10.1016/j.jpba.2010.04.022] [PMID: 20457502]
[24]
Yohrling, J. Ligand-binding assays: Risk of using a platform supported by a single vendor. Bioanalysis, 2009, 1(3), 629-636.
[http://dx.doi.org/10.4155/bio.09.46] [PMID: 21083158]
[25]
Basak, E.A.; Wijkhuijs, A.J.M.; Mathijssen, R.H.J.; Koolen, S.L.W.; Schreurs, M.W.J. Development of an enzyme-linked immune sorbent assay to measure nivolumab and pembrolizumab serum concentrations. Ther. Drug Monit., 2018, 40(5), 596-601.
[http://dx.doi.org/10.1097/FTD.0000000000000534] [PMID: 29847460]
[26]
Pluim, D.; Ros, W.; van Bussel, M.T.J.; Brandsma, D.; Beijnen, J.H.; Schellens, J.H.M. Enzyme linked immunosorbent assay for the quantifi-cation of nivolumab and pembrolizumab in human serum and cerebrospinal fluid. J. Pharm. Biomed. Anal., 2019, 164, 128-134.
[http://dx.doi.org/10.1016/j.jpba.2018.10.025] [PMID: 30368118]
[27]
Yuan, L.; Arnold, M.E.; Aubry, A.F.; Ji, Q.C. Simple and efficient digestion of a monoclonal antibody in serum using pellet digestion: Com-parison with traditional digestion methods in LC-MS/MS bioanalysis. Bioanalysis, 2012, 4(24), 2887-2896.
[http://dx.doi.org/10.4155/bio.12.284] [PMID: 23244280]
[28]
Bronsema, K.J.; Bischoff, R.; van de Merbel, N.C. Internal standards in the quantitative determination of protein biopharmaceuticals using liquid chromatography coupled to mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2012, 893-894, 1-14.
[http://dx.doi.org/10.1016/j.jchromb.2012.02.021] [PMID: 22426285]
[29]
Pan, S.; Aebersold, R.; Chen, R.; Rush, J.; Goodlett, D.R.; McIntosh, M.W.; Zhang, J.; Brentnall, T.A. Mass spectrometry based targeted pro-tein quantification: Methods and applications. J. Proteome Res., 2009, 8(2), 787-797.
[http://dx.doi.org/10.1021/pr800538n] [PMID: 19105742]
[30]
van den Broek, I.; Niessen, W.M.A.; van Dongen, W.D. Bioanalytical LC-MS/MS of protein-based biopharmaceuticals. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2013, 929, 161-179.
[http://dx.doi.org/10.1016/j.jchromb.2013.04.030] [PMID: 23685427]
[31]
Chiu, H.H.; Liao, H.W.; Shao, Y.Y.; Lu, Y.S.; Lin, C.H.; Tsai, I.L.; Kuo, C.H. Development of a general method for quantifying IgG-based therapeutic monoclonal antibodies in human plasma using protein G purification coupled with a two internal standard calibration strategy us-ing LC-MS/MS. Anal. Chim. Acta, 2018, 1019, 93-102.
[http://dx.doi.org/10.1016/j.aca.2018.02.040] [PMID: 29625688]
[32]
Iwamoto, N.; Hamada, A.; Shimada, T. Antibody drug quantitation in coexistence with anti-drug antibodies on nSMOL bioanalysis. Anal. Biochem., 2018, 540-541, 30-37.
[http://dx.doi.org/10.1016/j.ab.2017.11.002] [PMID: 29128290]
[33]
Rudek, M.A.; Chau, C.H.; Figg, W.D. Handbook of anticancer pharmacokinetics and pharmacodynamics. In: Rudek, M.A.; Chau, C.H.; Figg, W.D.; McLeod, H.L., Eds. Cancer Drug Discovery and Development; Springer New York: New York, NY, 2014.
[34]
Shimizu, T.; Seto, T.; Hirai, F.; Takenoyama, M.; Nosaki, K.; Tsurutani, J.; Kaneda, H.; Iwasa, T.; Kawakami, H.; Noguchi, K.; Shimamoto, T.; Nakagawa, K. Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced solid tu-mors. Invest. New Drugs, 2016, 34(3), 347-354.
[http://dx.doi.org/10.1007/s10637-016-0347-6] [PMID: 27000274]
[35]
Ma, Y.; Fang, W.; Zhang, Y.; Yang, Y.; Hong, S.; Zhao, Y.; Xie, S.; Ge, J.; Zhou, H.; Zhao, H.; Zhang, L. KEYNOTE-032: A randomized phase I study of pembrolizumab in chinese patients with advanced non-small cell lung cancer. Oncologist, 2020, 25(8), 650-e1145.
[http://dx.doi.org/10.1634/theoncologist.2020-0067] [PMID: 32134163]
[36]
van Vugt, M.J.H.; Stone, J.A.; De Greef, R.H.J.M.M.; Snyder, E.S.; Lipka, L.; Turner, D.C.; Chain, A.; Lala, M.; Li, M.; Robey, S.H.; Kondic, A.G.; De Alwis, D.; Mayawala, K.; Jain, L.; Freshwater, T. Immunogenicity of pembrolizumab in patients with advanced tumors. J. Immunother. Cancer, 2019, 7(1), 212.
[http://dx.doi.org/10.1186/s40425-019-0663-4] [PMID: 31395089]
[37]
Elassaiss-Schaap, J.; Rossenu, S.; Lindauer, A.; Kang, S.P.; de Greef, R.; Sachs, J.R.; de Alwis, D.P. Using model-based “learn and confirm” to reveal the pharmacokinetics-pharmacodynamics relationship of pembrolizumab in the KEYNOTE-001 trial. CPT Pharmacometrics Syst. Pharmacol., 2017, 6(1), 21-28.
[http://dx.doi.org/10.1002/psp4.12132] [PMID: 27863143]
[38]
Li, H.; Yu, J.; Liu, C.; Liu, J.; Subramaniam, S.; Zhao, H.; Blumenthal, G.M.; Turner, D.C.; Li, C.; Ahamadi, M.; de Greef, R.; Chatterjee, M.; Kondic, A.G.; Stone, J.A.; Booth, B.P.; Keegan, P.; Rahman, A.; Wang, Y. Time dependent pharmacokinetics of pembrolizumab in patients with solid tumor and its correlation with best overall response. J. Pharmacokinet. Pharmacodyn., 2017, 44(5), 403-414.
[http://dx.doi.org/10.1007/s10928-017-9528-y] [PMID: 28573468]
[39]
Li, H.; Sun, Y.; Yu, J.; Liu, C.; Liu, J.; Wang, Y. Semimechanistically based modeling of pembrolizumab time-varying clearance using 4 lon-gitudinal covariates in patients with non-small cell lung cancer. J. Pharm. Sci., 2019, 108(1), 692-700.
[http://dx.doi.org/10.1016/j.xphs.2018.10.064] [PMID: 30423341]
[40]
Chatterjee, M.S.; Elassaiss-Schaap, J.; Lindauer, A.; Turner, D.C.; Sostelly, A.; Freshwater, T.; Mayawala, K.; Ahamadi, M.; Stone, J.A.; de Greef, R.; Kondic, A.G.; de Alwis, D.P. Population pharmacokinetic/pharmacodynamic modeling of tumor size dynamics in pembrolizumab-treated advanced melanoma. CPT Pharma. Syst. Pharmacol., 2017, 6(1), 29-39.
[http://dx.doi.org/10.1002/psp4.12140] [PMID: 27896938]
[41]
Hamid, O.; Robert, C.; Daud, A.; Hodi, F.S.; Hwu, W-J.; Kefford, R.; Wolchok, J.D.; Hersey, P.; Joseph, R.W.; Weber, J.S.; Dronca, R.; Gan-gadhar, T.C.; Patnaik, A.; Zarour, H.; Joshua, A.M.; Gergich, K.; Elassaiss-Schaap, J.; Algazi, A.; Mateus, C.; Boasberg, P.; Tumeh, P.C.; Chmielowski, B.; Ebbinghaus, S.W.; Li, X.N.; Kang, S.P.; Ribas, A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melano-ma. N. Engl. J. Med., 2013, 369(2), 134-144.
[http://dx.doi.org/10.1056/NEJMoa1305133] [PMID: 23724846]
[42]
Robert, C.; Ribas, A.; Wolchok, J.D.; Hodi, F.S.; Hamid, O.; Kefford, R.; Weber, J.S.; Joshua, A.M.; Hwu, W.J.; Gangadhar, T.C.; Patnaik, A.; Dronca, R.; Zarour, H.; Joseph, R.W.; Boasberg, P.; Chmielowski, B.; Mateus, C.; Postow, M.A.; Gergich, K.; Elassaiss-Schaap, J.; Li, X.N.; Iannone, R.; Ebbinghaus, S.W.; Kang, S.P.; Daud, A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial. Lancet, 2014, 384(9948), 1109-1117.
[http://dx.doi.org/10.1016/S0140-6736(14)60958-2] [PMID: 25034862]
[43]
Ribas, A.; Puzanov, I.; Dummer, R.; Schadendorf, D.; Hamid, O.; Robert, C.; Hodi, F.S.; Schachter, J.; Pavlick, A.C.; Lewis, K.D.; Cranmer, L.D.; Blank, C.U.; O’Day, S.J.; Ascierto, P.A.; Salama, A.K.S.; Margolin, K.A.; Loquai, C.; Eigentler, T.K.; Gangadhar, T.C.; Carlino, M.S.; Agarwala, S.S.; Moschos, S.J.; Sosman, J.A.; Goldinger, S.M.; Shapira-Frommer, R.; Gonzalez, R.; Kirkwood, J.M.; Wolchok, J.D.; Egger-mont, A.; Li, X.N.; Zhou, W.; Zernhelt, A.M.; Lis, J.; Ebbinghaus, S.; Kang, S.P.; Daud, A. Pembrolizumab versus investigator-choice chemo-therapy for ipilimumab-refractory melanoma (KEYNOTE-002): A randomised, controlled, phase 2 trial. Lancet Oncol., 2015, 16(8), 908-918.
[http://dx.doi.org/10.1016/S1470-2045(15)00083-2] [PMID: 26115796]
[44]
Robert, C.; Schachter, J.; Long, G.V.; Arance, A.; Grob, J.J.; Mortier, L.; Daud, A.; Carlino, M.S.; McNeil, C.; Lotem, M.; Larkin, J.; Lorigan, P.; Neyns, B.; Blank, C.U.; Hamid, O.; Mateus, C.; Shapira-Frommer, R.; Kosh, M.; Zhou, H.; Ibrahim, N.; Ebbinghaus, S.; Ribas, A. Pem-brolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med., 2015, 372(26), 2521-2532.
[http://dx.doi.org/10.1056/NEJMoa1503093] [PMID: 25891173]
[45]
Turner, D.C.; Kondic, A.G.; Anderson, K.M.; Robinson, A.G.; Garon, E.B.; Riess, J.W.; Jain, L.; Mayawala, K.; Kang, J.; Ebbinghaus, S.W.; Sinha, V.; de Alwis, D.P.; Stone, J.A. Pembrolizumab exposure-response assessments challenged by association of cancer cachexia and cata-bolic clearance. Clin. Cancer Res., 2018, 24(23), 5841-5849.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-0415] [PMID: 29891725]
[46]
Bins, S.; Koolen, S.L.W.; Mathijssen, R.H.J. Pembrolizumab exposure-response assessments challenged by association of cancer cachexia and catabolic clearance-letter. Clin. Cancer Res., 2019, 25(10), 3192.
[http://dx.doi.org/10.1158/1078-0432.CCR-19-0164] [PMID: 31092616]
[47]
Garon, E.B.; Rizvi, N.A.; Hui, R.; Leighl, N.; Balmanoukian, A.S.; Eder, J.P.; Patnaik, A.; Aggarwal, C.; Gubens, M.; Horn, L.; Carcereny, E.; Ahn, M-J.; Felip, E.; Lee, J-S.; Hellmann, M.D.; Hamid, O.; Goldman, J.W.; Soria, J-C.; Dolled-Filhart, M.; Rutledge, R.Z.; Zhang, J.; Lunce-ford, J.K.; Rangwala, R.; Lubiniecki, G.M.; Roach, C.; Emancipator, K.; Gandhi, L. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med., 2015, 372(21), 2018-2028.
[http://dx.doi.org/10.1056/NEJMoa1501824] [PMID: 25891174]
[48]
Chatterjee, M.; Turner, D.C.; Felip, E.; Lena, H.; Cappuzzo, F.; Horn, L.; Garon, E.B.; Hui, R.; Arkenau, H.T.; Gubens, M.A.; Hellmann, M.D.; Dong, D.; Li, C.; Mayawala, K.; Freshwater, T.; Ahamadi, M.; Stone, J.; Lubiniecki, G.M.; Zhang, J. Im, E.; De Alwis, D.P.; Kondic, A.G.; Fløtten, Ø. Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer. Ann. Oncol., 2016, 27(7), 1291-1298.
[http://dx.doi.org/10.1093/annonc/mdw174] [PMID: 27117531]
[49]
Lisberg, A.; Cummings, A.; Goldman, J.W.; Bornazyan, K.; Reese, N.; Wang, T.; Coluzzi, P.; Ledezma, B.; Mendenhall, M.; Hunt, J.; Wolf, B.; Jones, B.; Madrigal, J.; Horton, J.; Spiegel, M.; Carroll, J.; Gukasyan, J.; Williams, T.; Sauer, L.; Wells, C.; Hardy, A.; Linares, P.; Lim, C.; Ma, L.; Adame, C.; Garon, E.B. A phase II study of pembrolizumab in EGFR-Mutant, PD-L1+, tyrosine kinase inhibitor naïve patients with advanced NSCLC. J. Thorac. Oncol., 2018, 13(8), 1138-1145.
[http://dx.doi.org/10.1016/j.jtho.2018.03.035] [PMID: 29874546]
[50]
Reck, M.; Rodríguez-Abreu, D.; Robinson, A.G.; Hui, R.; Csőszi, T.; Fülöp, A.; Gottfried, M.; Peled, N.; Tafreshi, A.; Cuffe, S.; O’Brien, M.; Rao, S.; Hotta, K.; Leiby, M.A.; Lubiniecki, G.M.; Shentu, Y.; Rangwala, R.; Brahmer, J.R. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med., 2016, 375(19), 1823-1833.
[http://dx.doi.org/10.1056/NEJMoa1606774] [PMID: 27718847]
[51]
Gadgeel, S.M.; Stevenson, J.P.; Langer, C.J.; Gandhi, L.; Borghaei, H.; Patnaik, A.; Villaruz, L.C.; Gubens, M.; Hauke, R.; Yang, J.C.H.; Sequist, L.V.; Bachman, R.; Saraf, S.; Raftopoulos, H.; Papadimitrakopoulou, V. Pembrolizumab and platinum-based chemotherapy as first-line therapy for advanced non-small-cell lung cancer: Phase 1 cohorts from the KEYNOTE-021 study. Lung Cancer, 2018, 125, 273-281.
[http://dx.doi.org/10.1016/j.lungcan.2018.08.019] [PMID: 30429032]
[52]
Rizvi, N.A.; Hellmann, M.D.; Snyder, A.; Kvistborg, P.; Makarov, V.; Havel, J.J.; Lee, W.; Yuan, J.; Wong, P.; Ho, T.S.; Miller, M.L.; Rekhtman, N.; Moreira, A.L.; Ibrahim, F.; Bruggeman, C.; Gasmi, B.; Zappasodi, R.; Maeda, Y.; Sander, C.; Garon, E.B.; Merghoub, T.; Wolchok, J.D.; Schumacher, T.N.; Chan, T.A. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science, 2015, 348(6230), 124-128.
[53]
Shin, S.H.; Park, H.Y.; Im, Y.; Jung, H.A.; Sun, J.M.; Ahn, J.S.; Ahn, M.J.; Park, K.; Lee, H.Y.; Lee, S.H. Improved treatment outcome of pembrolizumab in patients with nonsmall cell lung cancer and chronic obstructive pulmonary disease. Int. J. Cancer, 2019, 145(9), 2433-2439.
[http://dx.doi.org/10.1002/ijc.32235] [PMID: 30807641]
[54]
Green, M.R.; Monti, S.; Rodig, S.J.; Juszczynski, P.; Currie, T.; O’Donnell, E.; Chapuy, B.; Takeyama, K.; Neuberg, D.; Golub, T.R.; Kutok, J.L.; Shipp, M.A. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood, 2010, 116(17), 3268-3277.
[http://dx.doi.org/10.1182/blood-2010-05-282780] [PMID: 20628145]
[55]
Armand, P.; Shipp, M.A.; Ribrag, V.; Michot, J.M.; Zinzani, P.L.; Kuruvilla, J.; Snyder, E.S.; Ricart, A.D.; Balakumaran, A.; Rose, S.; Mos-kowitz, C.H. Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J. Clin. Oncol., 2016, 34(31), 3733-3739.
[http://dx.doi.org/10.1200/JCO.2016.67.3467] [PMID: 27354476]
[56]
Chen, R.; Zinzani, P.L.; Fanale, M.A.; Armand, P.; Johnson, N.A.; Brice, P.; Radford, J.; Ribrag, V.; Molin, D.; Vassilakopoulos, T.P.; To-mita, A.; von Tresckow, B.; Shipp, M.A.; Zhang, Y.; Ricart, A.D.; Balakumaran, A.; Moskowitz, C.H. Phase II study of the efficacy and safe-ty of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J. Clin. Oncol., 2017, 35(19), 2125-2132.
[http://dx.doi.org/10.1200/JCO.2016.72.1316] [PMID: 28441111]
[57]
Zinzani, P.L.; Ribrag, V.; Moskowitz, C.H.; Michot, J.M.; Kuruvilla, J.; Balakumaran, A.; Zhang, Y.; Chlosta, S.; Shipp, M.A.; Armand, P. Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood, 2017, 130(3), 267-270.
[http://dx.doi.org/10.1182/blood-2016-12-758383] [PMID: 28490569]
[58]
Plimack, E.R.; Bellmunt, J.; Gupta, S.; Berger, R.; Chow, L.Q.M.; Juco, J.; Lunceford, J.; Saraf, S.; Perini, R.F.; O’Donnell, P.H. Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): A non-randomised, open-label, phase 1b study. Lancet Oncol., 2017, 18(2), 212-220.
[http://dx.doi.org/10.1016/S1470-2045(17)30007-4] [PMID: 28081914]
[59]
Bellmunt, J.; de Wit, R.; Vaughn, D.J.; Fradet, Y.; Lee, J-L.; Fong, L.; Vogelzang, N.J.; Climent, M.A.; Petrylak, D.P.; Choueiri, T.K.; Necchi, A.; Gerritsen, W.; Gurney, H.; Quinn, D.I.; Culine, S.; Sternberg, C.N.; Mai, Y.; Poehlein, C.H.; Perini, R.F.; Bajorin, D.F. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N. Engl. J. Med., 2017, 376(11), 1015-1026.
[http://dx.doi.org/10.1056/NEJMoa1613683] [PMID: 28212060]
[60]
McDermott, D.F.; Lee, J.L.; Bjarnason, G.A.; Larkin, J.M.G.; Gafanov, R.A.; Kochenderfer, M.D.; Jensen, N.V.; Donskov, F.; Malik, J.; Poprach, A.; Tykodi, S.S.; Alonso-Gordoa, T.; Cho, D.C.; Geertsen, P.F.; Climent Duran, M.A.; DiSimone, C.; Silverman, R.K.; Perini, R.F.; Schloss, C.; Atkins, M.B. Open-label, single-arm phase II study of pembrolizumab monotherapy as first-line therapy in patients with ad-vanced clear cell renal cell carcinoma. J. Clin. Oncol., 2021, 39(9), 1020-1028.
[http://dx.doi.org/10.1200/JCO.20.02363] [PMID: 33529051]
[61]
McDermott, D.F.; Lee, J-L.; Ziobro, M.; Suarez, C.; Langiewicz, P.; Matveev, V.B.; Wiechno, P.; Gafanov, R.A.; Tomczak, P.; Pouliot, F.; Donskov, F.; Alekseev, B.Y.; Shin, S.J.; Bjarnason, G.A.; Castellano, D.; Silverman, R.K.; Perini, R.F.; Schloss, C.; Atkins, M.B. Open-label, single-arm, phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced non-clear cell renal cell carcinoma. J. Clin. Oncol., 2021, 39(9), 1029-1039.
[http://dx.doi.org/10.1200/JCO.20.02365] [PMID: 33529058]
[62]
Seiwert, T.Y.; Burtness, B.; Mehra, R.; Weiss, J.; Berger, R.; Eder, J.P.; Heath, K.; McClanahan, T.; Lunceford, J.; Gause, C.; Cheng, J.D.; Chow, L.Q. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): An open-label, multicentre, phase 1b trial. Lancet Oncol., 2016, 17(7), 956-965.
[http://dx.doi.org/10.1016/S1470-2045(16)30066-3] [PMID: 27247226]
[63]
Chow, L.Q.M.; Haddad, R.; Gupta, S.; Mahipal, A.; Mehra, R.; Tahara, M.; Berger, R.; Eder, J.P.; Burtness, B.; Lee, S.H.; Keam, B.; Kang, H.; Muro, K.; Weiss, J.; Geva, R.; Lin, C.C.; Chung, H.C.; Meister, A.; Dolled-Filhart, M.; Pathiraja, K.; Cheng, J.D.; Seiwert, T.Y. Antitumor ac-tivity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: Results from the phase Ib KEYNOTE-012 expansion cohort. J. Clin. Oncol., 2016, 34(32), 3838-3845.
[http://dx.doi.org/10.1200/JCO.2016.68.1478] [PMID: 27646946]
[64]
Cohen, E.E.W.; Soulières, D.; Le Tourneau, C.; Dinis, J.; Licitra, L.; Ahn, M-J.; Soria, A.; Machiels, J-P.; Mach, N.; Mehra, R.; Burtness, B.; Zhang, P.; Cheng, J.; Swaby, R.F.; Harrington, K.J.; Acosta-Rivera, M.; Adkins, D.R.; Aghmesheh, M.; Ahn, M-J.; Airoldi, M.; Aleknavicius, E.; Al-Farhat, Y.; Algazi, A.P.; Almokadem, S.; Alyasova, A.; Bauman, J.R.; Benasso, M.; Berrocal, A.; Bray, V.; Burtness, B.A.; Caponigro, F.; Castro, A.; Cescon, T.P.; Chan, K.; Chaudhry, A.; Chauffert, B.; Cohen, E.; Csoszi, T.; De Boer, J.P.; Delord, J-P.; Dietz, A.; Dinis, J.; Dupuis, C.; Digue, L.; Erfan, J.; Escobar Alvarez, Y.; Evans, M.; Fidler, M.J.; Forster, M.D.; Friesland, S.; Ganti, A.K.; Geoffrois, L.; Grant, C.; Gruenwald, V.; Harrington, K.; Hoffmann, T.; Horvai, G.; Inciura, A.; Jang, R.; Jankowska, P.; Jimeno, A.; Joseph, M.; Juarez Ramiro, A.; Karaszewska, B.; Kawecki, A.; Keilholz, U.; Keller, U.; Kim, S-B.; Kocsis, J.; Kotecki, N.; Kozloff, M.F.; Lambea, J.; Landherr, L.; Lantsu-khay, Y.; Lazarev, S.A.; Lee, L.W.; Le Tourneau, C.; Licitra, L.; Lifirenko, I.D.; Mach, N.; Martincic, D.; Matorin, O.V.; McGrath, M.; Ma-chiels, J-P.; Mehra, R.; Misiukiewicz, K.; Morris, J.C.; Mufazalov, F.F.; Niu, J.; Pamoorthy Srinivasan, D.; Perez Segura, P.; Rauch, D.; Ribei-ro, M.L.; Rodriguez, C.; Rolland, F.; Russo, A.; Ruzsa, A.; Sanches, F.; Shin, S-W.; Shtiveland, M.; Soulieres, D.; Soria, A.; Specenier, P.; Szekanecz, E.; Szota, J.; van Herpen, C.M.L.; Velez-Cortes, H.A.; Walsh, W.V.; Wilop, S.; Winterhalder, R.; Wojtukiewicz, M.; Wong, D.; Zandberg, D. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carci-noma (KEYNOTE-040): A randomised, open-label, phase 3 study. Lancet, 2019, 393(10167), 156-167.
[http://dx.doi.org/10.1016/S0140-6736(18)31999-8] [PMID: 30509740]
[65]
Ho, W.J.; Mehra, R. Pembrolizumab for the treatment of head and neck squamous cell cancer. Expert Opin. Biol. Ther., 2019, 19(9), 879-885.
[http://dx.doi.org/10.1080/14712598.2019.1644315] [PMID: 31317798]
[66]
Imamura, C.K. Therapeutic drug monitoring of monoclonal antibodies: Applicability based on their pharmacokinetic properties. Drug Metab. Pharmacokinet., 2019, 34(1), 14-18.
[http://dx.doi.org/10.1016/j.dmpk.2018.11.003] [PMID: 30606646]
[67]
Lindauer, A.; Valiathan, C.R.; Mehta, K.; Sriram, V.; de Greef, R.; Elassaiss-Schaap, J.; de Alwis, D.P. Translational pharmacokinet-ic/pharmacodynamic modeling of tumor growth inhibition supports dose-range selection of the anti-PD-1 antibody pembrolizumab. CPT Pharmacometrics Syst. Pharmacol., 2017, 6(1), 11-20.
[http://dx.doi.org/10.1002/psp4.12130] [PMID: 27863176]
[68]
Li, N.; Hou, X.; Huang, S.; Tai, R.; Lei, L.; Li, S.; Abuliz, A.; Wang, G.; Yang, S. Biomarkers related to immune checkpoint inhibitors thera-py. Biomed. Pharmacother., 2022, 147, 112470.
[http://dx.doi.org/10.1016/j.biopha.2021.112470] [PMID: 35074251]
[69]
Capalbo, C.; Scafetta, G.; Filetti, M.; Marchetti, P.; Bartolazzi, A. Predictive biomarkers for checkpoint inhibitor-based immunotherapy: The galectin-3 signature in NSCLCs. Int. J. Mol. Sci., 2019, 20(7), 1607.
[http://dx.doi.org/10.3390/ijms20071607] [PMID: 30935099]
[70]
Tumeh, P.C.; Harview, C.L.; Yearley, J.H.; Shintaku, I.P.; Taylor, E.J.M.; Robert, L.; Chmielowski, B.; Spasic, M.; Henry, G.; Ciobanu, V.; West, A.N.; Carmona, M.; Kivork, C.; Seja, E.; Cherry, G.; Gutierrez, A.J.; Grogan, T.R.; Mateus, C.; Tomasic, G.; Glaspy, J.A.; Emerson, R.O.; Robins, H.; Pierce, R.H.; Elashoff, D.A.; Robert, C.; Ribas, A. PD-1 blockade induces responses by inhibiting adaptive immune re-sistance. Nature, 2014, 515(7528), 568-571.
[http://dx.doi.org/10.1038/nature13954] [PMID: 25428505]
[71]
Rooney, M.S.; Shukla, S.A.; Wu, C.J.; Getz, G.; Hacohen, N. Molecular and genetic properties of tumors associated with local immune cyto-lytic activity. Cell, 2015, 160(1-2), 48-61.
[http://dx.doi.org/10.1016/j.cell.2014.12.033] [PMID: 25594174]
[72]
Yarchoan, M.; Hopkins, A.; Jaffee, E.M. Tumor mutational burden and response rate to PD-1 inhibition. N. Engl. J. Med., 2017, 377(25), 2500-2501.
[http://dx.doi.org/10.1056/NEJMc1713444] [PMID: 29262275]
[73]
McGranahan, N.; Furness, A.J.S.; Rosenthal, R.; Ramskov, S.; Lyngaa, R.; Saini, S.K.; Jamal-Hanjani, M.; Wilson, G.A.; Birkbak, N.J.; Hiley, C.T.; Watkins, T.B.K.; Shafi, S.; Murugaesu, N.; Mitter, R.; Akarca, A.U.; Linares, J.; Marafioti, T.; Henry, J.Y.; Van Allen, E.M.; Miao, D.; Schilling, B.; Schadendorf, D.; Garraway, L.A.; Makarov, V.; Rizvi, N.A.; Snyder, A.; Hellmann, M.D.; Merghoub, T.; Wolchok, J.D.; Shukla, S.A.; Wu, C.J.; Peggs, K.S.; Chan, T.A.; Hadrup, S.R.; Quezada, S.A.; Swanton, C. Clonal neoantigens elicit T cell immuno-reactivity and sensitivity to immune checkpoint blockade. Science, 2016, 351(6280), 1463-1469.
[74]
Gibney, G.T.; Weiner, L.M.; Atkins, M.B. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol., 2016, 17(12), e542-e551.
[http://dx.doi.org/10.1016/S1470-2045(16)30406-5] [PMID: 27924752]
[75]
Graves, M. CelliMarchett, G.; van Zyl, B.; Tang, D.; Vilain, R.E.; van der Westhuizen, A.; Bowden, N.A. Monitoring patient response to pembrolizumab with peripheral blood exhaustion marker profiles. Front. Med., 2019, 6, 113.
[76]
Soyano, A.E.; Dholaria, B.; Marin-Acevedo, J.A.; Diehl, N.; Hodge, D.; Luo, Y.; Manochakian, R.; Chumsri, S.; Adjei, A.; Knutson, K.L.; Lou, Y. Peripheral blood biomarkers correlate with outcomes in advanced non-small cell lung Cancer patients treated with anti-PD-1 antibod-ies. J. Immunother. Cancer, 2018, 6(1), 129.
[http://dx.doi.org/10.1186/s40425-018-0447-2] [PMID: 30470260]
[77]
Costantini, A.; Takam Kamga, P.; Julie, C.; Corjon, A.; Dumenil, C.; Dumoulin, J.; Ouaknine, J.; Giraud, V.; Chinet, T.; Rottman, M.; Emile, J.F.; Giroux Leprieur, E. Plasma biomarkers screening by multiplex ELISA assay in patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors. Cancers (Basel), 2020, 13(1), 1-12.
[http://dx.doi.org/10.3390/cancers13010097] [PMID: 33396187]
[78]
Awada, G.; Jansen, Y.; Schwarze, J.K.; Tijtgat, J.; Hellinckx, L.; Gondry, O.; Vermeulen, S.; Warren, S.; Schats, K.; van Dam, P.J.; Kockx, M.; Keyaerts, M.; Everaert, H.; Seremet, T.; Rogiers, A.; Neyns, B. A comprehensive analysis of baseline clinical characteristics and bi-omarkers associated with outcome in advanced melanoma patients treated with pembrolizumab. Cancers (Basel), 2021, 13(2), 1-18.
[http://dx.doi.org/10.3390/cancers13020168] [PMID: 33418936]
[79]
Ribas, A.; Robert, C.; Hodi, F.S.; Wolchok, J.D.; Joshua, A.M.; Hwu, W-J.; Weber, J.S.; Zarour, H.M.; Kefford, R.; Loboda, A.; Albright, A.; Kang, S.P.; Ebbinghaus, S.; Yearley, J.; Murphy, E.; Nebozhyn, M.; Lunceford, J.K.; McClanahan, T.; Ayers, M.; Daud, A. Association of response to Programmed Death receptor 1 (PD-1) blockade with pembrolizumab (MK-3475) with an Interferon-inflammatory immune gene signature. J. Clin. Oncol., 2015, 33(15)(Suppl.), 3001-3001.
[http://dx.doi.org/10.1200/jco.2015.33.15_suppl.3001]
[80]
Freshwater, T.; Kondic, A.; Ahamadi, M.; Li, C.H.; de Greef, R.; de Alwis, D.; Stone, J.A. Evaluation of dosing strategy for pembrolizumab for oncology indications. J. Immunother. Cancer, 2017, 5(1), 43.
[http://dx.doi.org/10.1186/s40425-017-0242-5] [PMID: 28515943]
[81]
Ogungbenro, K.; Patel, A.; Duncombe, R.; Nuttall, R.; Clark, J.; Lorigan, P. Dose rationalization of pembrolizumab and nivolumab using pharmacokinetic modeling and simulation and cost analysis. Clin. Pharmacol. Ther., 2018, 103(4), 582-590.
[http://dx.doi.org/10.1002/cpt.875] [PMID: 28913853]
[82]
Lala, M.; Li, T.R.; de Alwis, D.P.; Sinha, V.; Mayawala, K.; Yamamoto, N.; Siu, L.L.; Chartash, E.; Aboshady, H.; Jain, L. A six-weekly dos-ing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur. J. Cancer, 2020, 131, 68-75.
[http://dx.doi.org/10.1016/j.ejca.2020.02.016] [PMID: 32305010]
[83]
Georgieva, M.; da Silveira Nogueira Lima, J.P.; Aguiar, P., Jr; de Lima Lopes, G., Jr; Haaland, B. Cost-effectiveness of pembrolizumab as first-line therapy for advanced non-small cell lung cancer. Lung Cancer, 2018, 124, 248-254.
[http://dx.doi.org/10.1016/j.lungcan.2018.08.018] [PMID: 30268469]
[84]
Hu, X.; Hay, J.W. First-line pembrolizumab in PD-L1 positive non-small-cell lung cancer: A cost-effectiveness analysis from the UK health care perspective. Lung Cancer, 2018, 123, 166-171.
[http://dx.doi.org/10.1016/j.lungcan.2018.07.012] [PMID: 30089590]
[85]
Huang, M.; Lou, Y.; Pellissier, J.; Burke, T.; Liu, F.X.; Xu, R.; Velcheti, V. Cost effectiveness of pembrolizumab vs. standard-of-care chemo-therapy as first-line treatment for metastatic NSCLC that expresses high levels of PD-L1 in the United States. PharmacoEconomics, 2017, 35(8), 831-844.
[http://dx.doi.org/10.1007/s40273-017-0527-z] [PMID: 28620848]
[86]
Neumann, P.J.; Cohen, J.T.; Weinstein, M.C. Updating cost-effectiveness-the curious resilience of the $50,000-per-QALY threshold. N. Engl. J. Med., 2014, 371(9), 796-797.
[http://dx.doi.org/10.1056/NEJMp1405158] [PMID: 25162885]
[87]
Chouaid, C.; Bensimon, L.; Clay, E.; Millier, A.; Levy-Bachelot, L.; Huang, M.; Levy, P. Cost-effectiveness analysis of pembrolizumab ver-sus standard-of-care chemotherapy for first-line treatment of PD-L1 positive (>50%) metastatic squamous and non-squamous non-small cell lung cancer in France. Lung Cancer, 2019, 127, 44-52.
[http://dx.doi.org/10.1016/j.lungcan.2018.11.008] [PMID: 30642550]
[88]
Peer, C.J.; Goldstein, D.A.; Goodell, J.C.; Nguyen, R.; Figg, W.D.; Ratain, M.J. Opportunities for using in silico-based extended dosing regi-mens for monoclonal antibody immune checkpoint inhibitors. Br. J. Clin. Pharmacol., 2020, 86(9), 1769-1777.
[http://dx.doi.org/10.1111/bcp.14369] [PMID: 32424951]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy