Malmberg R, Zietse M, Dumoulin DW, Hendrikx J, Aerts J, van der Veldt AAM, et al. Alternative dosing strategies for immune checkpoint inhibitors to improve cost-effectiveness: a special focus on nivolumab and pembrolizumab. Lancet Oncol. 2022;23:e552–e61.
Google Scholar
Peer CJ, Heiss BL, Goldstein DA, Goodell JC, Figg WD, Ratain MJ. Pharmacokinetic simulation analysis of less frequent nivolumab and pembrolizumab dosing: pharmacoeconomic rationale for dose deescalation. J Clin Pharm. 2022;62:532–40.
Google Scholar
Puszkiel A, Bianconi G, Pasquiers B, Balakirouchenane D, Arrondeau J, Boudou-Rouquette P, et al. Extending the dosing intervals of nivolumab: model-based simulations in unselected cancer patients. Br J Cancer. 2024;130:1866–74.
Google Scholar
Chatterjee M, Turner DC, Felip E, Lena H, Cappuzzo F, Horn L, et al. Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer. Ann Oncol. 2016;27:1291–8.
Google Scholar
Tie Y, Yang H, Zhao R, Zheng H, Yang D, Zhao J, et al. Safety and efficacy of atezolizumab in the treatment of cancers: a systematic review and pooled-analysis. Drug Des Dev Ther. 2019;13:523–38.
Google Scholar
Agrawal S, Feng Y, Roy A, Kollia G, Lestini B. Nivolumab dose selection: challenges, opportunities, and lessons learned for cancer immunotherapy. J Immunother Cancer. 2016;4:72.
Google Scholar
Le Louedec F, Leenhardt F, Marin C, Chatelut É, Evrard A, Ciccolini J. Cancer Immunotherapy dosing: a pharmacokinetic/pharmacodynamic perspective. Vaccines. 2020;8.
Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, Beeram M, et al. Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res. 2015;21:4286–93.
Google Scholar
Fu J, Wang F, Dong LH, Xing MJ, Cheng X, Wei S, et al. Receptor occupancy measurement of anti-PD-1 antibody drugs in support of clinical trials. Bioanalysis. 2019;11:1347–58.
Google Scholar
Ratain MJ, Peer CJ, Figg WD, Goldstein DA. Dose optimization of pembrolizumab: less may be more. Clin Pharmacol Ther. 2022;111:993.
Google Scholar
Tachiki LM, Chevez HR, Morningstar C, Alam R, Remington A, Hippe DS, et al. 526 Pharmacokinetic and pharmacodynamic analyses of PD-1 blockade with nivolumab at varying doses and schedules supports administration at markedly reduced dose and frequency. J ImmunoTher Cancer. 2024;12 (Suppl 2).
Patil VM, Noronha V, Menon N, Rai R, Bhattacharjee A, Singh A, et al. Low-dose immunotherapy in head and neck cancer: a randomized study. J Clin Oncol. 2023;41:222–32.
Google Scholar
Huang Z, Zeng L, Ruan Z, Zeng Q, Yan H, Jiang W, et al. Time-of-day immunochemotherapy in non-small cell lung cancer: a randomized phase 3 trial. Nat Med. 2026.
Karaboué A, Innominato PF, Wreglesworth NI, Duchemann B, Adam R, Lévi FA. Why does circadian timing of administration matter for immune checkpoint inhibitors’ efficacy? Br J Cancer. 2024;131:783–96.
Google Scholar
Verdonk JDJ, Piet B, Ter Heine R, van den Heuvel MM, Smeets RL, Koenen H. Ex vivo pembrolizumab pharmacology for personalized PD-1 inhibitor therapy reveals a critical gap between receptor occupancy and T cell functionality. Int Immunopharmacol. 2025;157:114754.
Google Scholar
De Sousa Linhares A, Battin C, Jutz S, Leitner J, Hafner C, Tobias J, et al. Therapeutic PD-L1 antibodies are more effective than PD-1 antibodies in blocking PD-1/PD-L1 signaling. Sci Rep. 2019;9:11472.
Google Scholar
Thurber GM, Schmidt MM, Wittrup KD. Antibody tumor penetration: transport opposed by systemic and antigen-mediated clearance. Adv Drug Deliv Rev. 2008;60:1421–34.
Google Scholar
Verdonk JDJ, ter Heine R, Piet B, van Rijssen E, van den Heuvel MM, Koenen HJPM, et al. Pre-treatment T cell phospho-signalling identifies clinical pembrolizumab response in non-small cell lung cancer patients. Int Immunopharmacol. 2026;188:117189.
Lindauer A, Valiathan C, Mehta K, Sriram V, de Greef R, Elassaiss-Schaap J, et al. Translational pharmacokinetic/pharmacodynamic modeling of tumor growth inhibition supports dose-range selection of the Anti–PD-1 antibody pembrolizumab. CPT: Pharmacomet Syst Pharmacol. 2017;6:11–20.
Li H, Yu J, Liu C, Liu J, Subramaniam S, Zhao H, et al. Time dependent pharmacokinetics of pembrolizumab in patients with solid tumor and its correlation with best overall response. J Pharmacokinet Pharmacodyn. 2017;44:403–14.
Google Scholar
de Vries F, Otten LS, Piet B, Franssen EJF, Smit AAJ, van den Heuvel MM, et al. Early pembrolizumab clearance as prognostic biomarker for non-response in patients with advanced non-small cell lung cancer. Int J Cancer. 2025;157:2569–76.
Google Scholar
Malek TR. The biology of interleukin-2. Annu Rev Immunol. 2008;26:453–79.
Google Scholar
Wang C, Thudium KB, Han M, Wang XT, Huang H, Feingersh D, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res. 2014;2:846–56.
Google Scholar
Zwep LB, Guo T, Nagler T, Knibbe CAJ, Meulman JJ, van Hasselt JGC. Virtual patient simulation using copula modeling. Clin Pharm Ther. 2024;115:795–804.
Google Scholar
Freshwater T, Kondic A, Ahamadi M, Li CH, de Greef R, de Alwis D, et al. Evaluation of dosing strategy for pembrolizumab for oncology indications. J Immunother Cancer. 2017;5:43.
Google Scholar
Lala M, Li TR, de Alwis DP, Sinha V, Mayawala K, Yamamoto N, et al. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur J Cancer. 2020;131:68–75.
Google Scholar
Li TR, Chatterjee M, Lala M, Abraham AK, Freshwater T, Jain L, et al. Pivotal dose of pembrolizumab: a dose-finding strategy for immuno-oncology. Clin Pharm Ther. 2021;110:200–9.
Google Scholar
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.
Google Scholar
Yoo SH, Keam B, Kim M, Kim SH, Kim YJ, Kim TM, et al. Low-dose nivolumab can be effective in non-small cell lung cancer: alternative option for financial toxicity. ESMO Open. 2018;3:e000332.
Google Scholar
Hayashida K, Bartlett AH, Chen Y, Park PW. Molecular and cellular mechanisms of ectodomain shedding. Anat Rec. 2010;293:925–37.
Google Scholar
Ohkuma R, Ieguchi K, Watanabe M, Takayanagi D, Goshima T, Onoue R, et al. Increased plasma soluble PD-1 concentration correlates with disease progression in patients with cancer treated with anti-PD-1 antibodies. Biomedicines. 2021;9.
Himuro H, Nakahara Y, Igarashi Y, Kouro T, Higashijima N, Matsuo N, et al. Clinical roles of soluble PD-1 and PD-L1 in plasma of NSCLC patients treated with immune checkpoint inhibitors. Cancer Immunol Immunother. 2023;72:2829–40.
Google Scholar
Huang Z, Karaboué A, Zeng L, Lecoeuvre A, Zhang L, Li XM, et al. Overall survival according to time-of-day of combined immuno-chemotherapy for advanced non-small cell lung cancer: a bicentric bicontinental study. EBioMedicine. 2025;113:105607.
Google Scholar
Landré T, Karaboué A, Buchwald ZS, Innominato PF, Qian DC, Assié JB, et al. Effect of immunotherapy-infusion time of day on survival of patients with advanced cancers: a study-level meta-analysis. ESMO Open. 2024;9:102220.
Google Scholar
Catozzi S, Assaad S, Delrieu L, Favier B, Dumas E, Hamy AS, et al. Early morning immune checkpoint blockade and overall survival of patients with metastatic cancer: an In-depth chronotherapeutic study. Eur J Cancer. 2024;199:113571.
Google Scholar

