Utilization of pharmacokinetics in the dosing of pembrolizumab in non-small cell lung cancer

Introduction

The recent incorporation of immunotherapy into the treatment of non-small cell lung cancer (NSCLC) has revolutionized patient expectations of potential survival. Neoplastic cells with high immunogenicity may develop the ability to evade the host’s immune system through the expression of programmed death-ligand 1 (PD-L1) on their surface. The consequential binding of PD-L1 to programmed cell death-1 (PD-1), which is expressed on the surface of effector T cells, provides an inhibitory signal that prevents immune-mediated cytotoxicity. The use of PD-1/PD-L1 antibodies prevents this interaction, thereby augmenting the host’s anti-tumor immune response. PD-L1 expression on tumors is classified into three separate groups: PD-L1 positive (≥50%), PD-L1 low positive (1–49%), and PD-L1 negative (<1% of expressed tumor cells). The percentage of PD-L1 predicts the likelihood of response to checkpoint inhibitor immunotherapy (1).

Pembrolizumab, a PD-1 inhibitor, is approved for use in the treatment of several solid-organ cancers. The earlier trials involving the role of pembrolizumab in the treatment of NSCLC primarily utilized weight-based dosing. A PIONEER study, the KEYNOTE-001 trial, demonstrated dramatic responses in many patients leading to initial approval in NSCLC, but interestingly showed similar efficacy in patients receiving 2 mg/kg dosing versus 10 mg/kg dosing in 2015 (2). The findings of the KEYNOTE-024 trial the following year ultimately led to the approval of pembrolizumab as a first-line therapy by demonstrating that, in patients with stage IV NSCLC and PD-L1 expression of at least 50%, treatment with pembrolizumab was associated with longer overall survival and progression-free period than was platinum-based chemotherapy. However, this trial used a fixed (rather than weight-based) dose of 200 mg every 3 weeks, which became the new standard of care (3). A study demonstrated similar efficacy in comparison of both the fixed dose and weight-based dosing, but are limited to pharmacokinetic measurements rather than therapeutic outcomes (4). Pharmacokinetic studies have remained ongoing to investigate variations to this schedule that allows for continued efficacy while attempting to optimize patient convenience and tolerability. For example, in 2020, based on a study employing pharmacokinetic modeling, the Food and Drug Administration (FDA) approved the administration of pembrolizumab at an interval of 6 weeks with a dosing of 400 mg (5), the longest of any checkpoint inhibitor.

The decision to continue administering pembrolizumab as a fixed dose versus as a weight-based dose has treatment and cost implications. The wide therapeutic range of pembrolizumab makes the utilization of a fixed dose appealing. However, the financial implications of using a fixed dose are significant: in the USA, using weight-based dosing would save more than $800 million—24% of the annual total cost of pembrolizumab (6).

Furthermore, the plateaued exposure-response curve of PD-1 and PD-L1 inhibitors and recent data demonstrating variation in drug clearance, specifically a decreased clearance in responders, may propose a role for individualized timing of doses, which would allow for even more judicious utilization of pembrolizumab (7,8). The protective binding of monoclonal antibodies (mAbs) to the receptor protein, neonatal Fc receptor (FcRn), has been shown to prevent the degradation of mAbs in the lysosome (9,10). Studies have shown that variation to the variable number of tandem repeats (VNTR) in the promoter region of the FcRn promoter can affect this binding ability (11,12).

The article titled “Clinical efficacy and safety of individualized pembrolizumab administration based on pharmacokinetic in advanced non-small cell lung cancer: A prospective exploratory clinical trial”, the focus of this commentary, offers a way to utilize pharmacokinetics as a means of personalizing the scheduled regimen of pembrolizumab (13).

Summarization of prospective clinical trial

The present study was a prospective exploratory clinical trial investigating the efficacy of the utilization of pharmacokinetic-guided pembrolizumab interval dosing schedules in advanced NSCLC. The control group was collected retrospectively from patients who had received the standard fixed dose (200 mg) and frequency (every 3 weeks) administration of pembrolizumab. The experimental group was chosen prospectively from patients who had completed 4 cycles of the standard fixed dose and scheduled (200 mg every 3 weeks) of pembrolizumab and had no evidence of progression upon completion. The experimental group’s steady state plasma-concentration (Css) was then detected through utilizing high performance liquid chromatography coupled to mass spectrometry. As active PD-1 inhibits the release of IL-2, measuring the ex-vivo lymphocyte IL-2 stimulation response served as a surrogate for gauging the efficacy of PD-1 blockade. As data has shown that the plasma concentration of 10 µg/mL achieved 95% inhibition, this study used a minimum value of 15 µg/mL to guide dosage timing. The formula T = (Css × 21)/(15 µg/mL) days was utilized to calculate a new dosage interval in days. The primary outcome measured in this study was progression-free survival (PFS), defined as the time from the initiation of pembrolizumab to progressive disease or death, as determined by the Immunotherapy Response Evaluation Criteria In Solid Tumors (iRECIST). Secondary outcomes include disease control rate (DCR), percentage of patients with complete response, partial response, or stable disease, objective response rate (ORR), percentage of patients with partial or complete response, and immune-related adverse events (IRAEs) (13).

The mean Css of pembrolizumab in the treatment group (n=33) was 27.95 µg/mL. The treatment duration was then subsequently extended to 22–80 days in 30 patients and shortened to 15–20 days in 3 patients.

The study group demonstrated global improvement in the primary outcome and several secondary outcomes. The median PFS was 15.1 months with ORR 56.7%, DCR 100%; whereas the history-controlled group demonstrated a median PFS of 7.7 months with ORR 48.2% and DCR 100%. A similar trend was observed upon dividing the study group and historical patients who were treatment-naïve, patients who were receiving pembrolizumab as second and later line therapy, patients who were receiving a combination of pembrolizumab and chemotherapy, and patients who received pembrolizumab as a monotherapy (13).

The study and historical group demonstrated similar incident rates of IRAEs. The experimental group had a total incidence rate of IRAEs of 15% and the control group had an IRAE rate of 17.9%.

Polymorphism testing of the FcRn gene was also completed in 38 patients, 92% were homozygous for VNTR3/VNTR3 and 8% were heterozygotes for VNTR2/VNTR3. The homozygotes demonstrated significantly higher steady state plasma concentration than the heterozygous patients (13).

How do we incorporate into clinical practice?

This publication serves as an outline for further utilization of pharmacokinetics in the titration of both the dosage and scheduling interval of pembrolizumab. The proposition of utilizing pharmacokinetics to adjust the treatment interval of pembrolizumab shows promise for reducing the cost of immunotherapy likely without compromising efficacy. This could be particularly useful in resource constrained environments. For example, a country could develop a central laboratory to measure pembrolizumab levels, and clinicians could send a blood sample just before the cycle 5 dose. Based on the formula, many patients could be offered reduced dosing frequency intervals. This would also save on the cost of care for visits. Similarly, this also offers a promising way of decreasing the risk of pembrolizumab’s adverse effects by minimizing potentially unnecessary drug exposure. This offers great promise, as adverse events are associated with a great deal of both patient morbidity and termination of continued treatment with immunotherapy. Additionally, this manuscript offers a potential means of utilizing the VNTR gene polymorphisms as a means of predicting patients’ Css levels, thereby allowing for a potential preliminary prediction of the necessary dosing intervals before the pembrolizumab drug level result returns.

One question not addressed by this study is the use of weight-based dosing of pembrolizumab. To further reduce utilization, given that subsequent pharmacokinetic studies demonstrated that the average patient with cancer weighs 75 kg, only approximately 150 mg would be required to maintain clinical efficacy compared with the fixed dose of 200 mg. Weight-based dosing is still preferred in many other countries, such as Canada, as a mechanism to decrease payment expenditure (14). However, there are several logistical barriers that make using weight-based dosing in clinical practice more challenging. For example, previously there were both 100 and 50 mg vials, however, the 50 mg were recently removed from the United States (14). Thus, the simplicity of administering two 100 mg vials is very appealing and minimizes the risk of wasting leftover product. Despite these logistical concerns, it would be interesting to do a pharmacokinetic analysis of pembrolizumab at steady state of 10 mg/kg and then try to adjust dosing amount—rather than interval—to target the minimum pembrolizumab threshold. Despite the inconvenience of vial sizes, this would likely allow the greatest reduction in usage of drug and also maintain a convenient dosing interval of every 3 weeks.

This study poses some limitations that should be considered when discerning its generalizability to patient care. As the study acknowledges, the role of selection bias must be considered, specifically in the setting of juxtaposing a prospective experimental group with a retrospective historical control group. The manuscript draws on this limitation when describing the role selection bias may play in physician’s increased likelihood to pursue combination chemotherapy in some patients based on their characteristics. Similarly, while numerically better, the PFS in the study group should not be interpreted as “better” than the historical controls, because of the potential for selection bias and confounders due to a small sample size. Interestingly, 81.6% of the patients considered for the historical control analysis were excluded from the study due to irregularities in dose and treatment interval. Furthermore, the PD-L1 tumor status was known in less than half of the study group due to insufficient sample. The small scale of the study also limits its external validity given the sample size and its isolation to a single institution. Thus, as the authors acknowledge, a multicentric large-scale non-inferiority trial would be required to validate the efficacy of alternative dosing strategies proposed by this study but could be a significant addition to inform the use of pembrolizumab.

This manuscript poses an innovative way to utilize pharmacokinetics to combine the convenience of a fixed dose with the cost saving measure of weight-based dosing by continuing to utilize the set dose of 200 mg while allowing pharmacokinetics to adjust the dosage schedule. Overall, this study serves as a springboard towards further research targeting the incorporation of pharmacokinetics in the administration of pembrolizumab, which would need larger cohorts.

However, there can be scientific shortcomings of single parameter pharmacokinetics as means of personalizing treatments. For example, dosing changes may change the efficacy of drugs, and lead to immune exhaustion vs. activation. Additionally, pharmacokinetic changes may have differential effects on other immune cells in the tumor microenvironment that response may be dependent upon (15). However, as it stands, this study could serve as a roadmap to conserve the precious resource of anti-cancer immunotherapy in an economically-limited patient population.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-36/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-36/coif). J.W.N. reports research funding from Genentech/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Nektar Therapeutics, Takeda Pharmaceuticals, Adaptimmune, GSK, Janssen, AbbVie, and Novocure; and personal fees for consulting and advisory from AstraZeneca, Genentech/Roche, Exelixis, Takeda Pharmaceuticals, Eli Lilly and Company, Amgen, Iovance Biotherapeutics, Blueprint Pharmaceuticals, Regeneron Pharmaceuticals, Natera, Sanofi/Regeneron, D2G Oncology, Surface Oncology, Turning Point Therapeutics, Mirati Therapeutics, Gilead Sciences, AbbVie, Summit Therapeutics, Novartis, Novocure, Janssen Oncology and Anheart Therapeutics. He also reports honoraria from CME Matters, Clinical Care Options CME, Research to Practice CME, Medscape CME, Biomedical Learning Institute CME, MLI Peerview CME, Prime Oncology CME, Projects in Knowledge CME, Rockpointe CME, MJH Life Sciences CME, Medical Educator Consortium, and HMP Education. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Mithoowani H, Febbraro M. Non-Small-Cell Lung Cancer in 2022: A Review for General Practitioners in Oncology. Curr Oncol 2022;29:1828-39. [Crossref] [PubMed]
2. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372:2018-28. [Crossref] [PubMed]
3. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33. [Crossref] [PubMed]
4. Freshwater T, Kondic A, Ahamadi M, et al. Evaluation of dosing strategy for pembrolizumab for oncology indications. J Immunother Cancer 2017;5:43. [Crossref] [PubMed]
5. Lala M, Li TR, de Alwis DP, 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. [Crossref] [PubMed]
6. Goldstein DA, Gordon N, Davidescu M, et al. A Phamacoeconomic Analysis of Personalized Dosing vs Fixed Dosing of Pembrolizumab in Firstline PD-L1-Positive Non-Small Cell Lung Cancer. J Natl Cancer Inst 2017; [Crossref] [PubMed]
7. Chatelut E, Le Louedec F, Milano G. Setting the Dose of Checkpoint Inhibitors: The Role of Clinical Pharmacology. Clin Pharmacokinet 2020;59:287-96. [Crossref] [PubMed]
8. Maritaz C, Broutin S, Chaput N, et al. Immune checkpoint-targeted antibodies: a room for dose and schedule optimization? J Hematol Oncol 2022;15:6. [Crossref] [PubMed]
9. Andersen JT, Sandlie I. The versatile MHC class I-related FcRn protects IgG and albumin from degradation: implications for development of new diagnostics and therapeutics. Drug Metab Pharmacokinet 2009;24:318-32. [Crossref] [PubMed]
10. Paci A, Desnoyer A, Delahousse J, et al. Pharmacokinetic/pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 1, monoclonal antibodies, antibody-drug conjugates and bispecific T-cell engagers. Eur J Cancer 2020;128:107-18. [Crossref] [PubMed]
11. Sachs UJ, Socher I, Braeunlich CG, et al. A variable number of tandem repeats polymorphism influences the transcriptional activity of the neonatal Fc receptor alpha-chain promoter. Immunology 2006;119:83-9. [Crossref] [PubMed]
12. Ishii-Watabe A, Saito Y, Suzuki T, et al. Genetic polymorphisms of FCGRT encoding FcRn in a Japanese population and their functional analysis. Drug Metab Pharmacokinet 2010;25:578-87. [Crossref] [PubMed]
13. Wang N, Zheng L, Li M, et al. Clinical efficacy and safety of individualized pembrolizumab administration based on pharmacokinetic in advanced non-small cell lung cancer: A prospective exploratory clinical trial. Lung Cancer 2023;178:183-90. [Crossref] [PubMed]
14. Goldstein DA, Ratain MJ, Saltz LB. Weight-Based Dosing of Pembrolizumab Every 6 Weeks in the Time of COVID-19. JAMA Oncol 2020;6:1694-5. [Crossref] [PubMed]
15. Chyuan IT, Chu CL, Hsu PN. Targeting the Tumor Microenvironment for Improving Therapeutic Effectiveness in Cancer Immunotherapy: Focusing on Immune Checkpoint Inhibitors and Combination Therapies. Cancers (Basel) 2021;13:1188. [Crossref] [PubMed]