Pembrolizumab weight based dosing – A call for policy change

Introduction

Immuno-oncology (IO) drugs are now approved for use in metastatic, adjuvant, and/or neoadjuvant setting for a growing list of cancers including non-small cell lung cancer, small cell lung cancer, melanoma, urothelial cancer, renal cell carcinoma, head and neck squamous cell carcinoma, esophageal cancer, gastric cancer, cervical cancer, endometrial cancer, hepatocellular cancer, Merkel cell carcinoma, microsatellite instability-high or mismatch repair deficient colorectal cancer and other cancers, tumor mutational burden-high cancer, cutaneous squamous cell carcinoma, triple-negative breast cancer, classical Hodgkin lymphoma, and primary mediastinal large B cell lymphoma. This list continues to expand at an impressive speed. The benefits in improving progression-free survival (PFS) and overall survival are a welcome advance beyond the plateau that we seem to have reached with conventional chemotherapy treatment. The biggest challenge is to identify biomarkers that would help select the 20 to 40% patients who respond to immunotherapy drugs, thereby limiting treatment to those most likely to benefit, avoiding toxicity among the patients unlikely to respond. This has very important pharmacoeconomic implications, especially because immunotherapy drugs are very expensive.

The important question is whether we can do something substantial to address unnecessary wastage of expensive medicines. The answer is yes. It is based on a long established principle of using dose according to the individual's weight/surface area. It is based on avoiding “flat” dosing—a flawed strategy that leads to unnecessary wastage of expensive medicines and subjects our patients to avoidable toxicity. There is a strong rationale to integrate the concepts of pharmacoeconomics.[1] We present here our policy brief on rational use of pembrolizumab that optimizes patient benefit as well as utilization of resources.

Publikationsverlauf

Artikel online veröffentlicht:
21. Februar 2022

• References

• 1 Tannock IF, Patel A. Pharmacoeconomics. Ind J Med Paediatr Oncol 2021; 42: 218-220
• 2 Centanni M, Moes DJAR, Trocóniz IF, Ciccolini J, van Hasselt JGC. Clinical pharmacokinetics and pharmacodynamics of immune checkpoint inhibitors. Clin Pharmacokinet 2019; 58 (07) 835-857
• 3 Canadian Agency for Drugs and Technologies in Health. CADTH technology review: optimal use 360 report: dosing and timing of immuno-oncology drugs. Published online November 2019. Accessed May 19, 2020 at: https://www.cadth.ca/sites/default/files/ou-tr/ho0008-dosing-timing-immuno-oncology-drugs.pdf
• 4 Health Canada. Guidance Document: Conduct and Analysis of Comparative Bioavailability Studies [Internet], 2012. Accessed August 29, 2021 at: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/bioavailability-bioequivalence/conduct-analysis-comparative.html
• 5 Patnaik A, Kang SP, Rasco D. 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 (19) 4286-4293
• 6 Chatterjee M, Turner DC, Felip E. et al. Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer. Ann Oncol 2016; 27 (07) 1291-1298
• 7 Chatterjee MS, Elassaiss-Schaap J, Lindauer A. et al. Population pharmacokinetic/pharmacodynamic modeling of tumor size dynamics in pembrolizumab-treated advanced melanoma. CPT Pharmacometrics Syst Pharmacol 2017; 6 (01) 29-39
• 8 Garon EB, Rizvi NA, Hui R. et al; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372 (21) 2018-2028
• 9 Herbst RS, Baas P, Kim D-W. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016; 387 (10027): 1540-1550
• 10 Ribas A, Puzanov I, Dummer R. et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 2015; 16 (08) 908-918
• 11 Turner DC, Kondic AG, Anderson KM. et al. Pembrolizumab exposure-response assessments challenged by association of cancer cachexia and catabolic clearance. Clin Cancer Res 2018; 24 (23) 5841-5849
• 12 Reck M, Rodríguez-Abreu D, Robinson AG. et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016; 375 (19) 1823-1833
• 13 Freshwater T, Kondic A, Ahamadi M. et al. Evaluation of dosing strategy for pembrolizumab for oncology indications. J Immunother Cancer 2017; 5: 43
• 14 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
• 15 Keytruda prescribing information (package insert is based on worldwide physician circular S-CCDS-MK3475- IV-112017). 2017
• 16 National Comprehensive Cancer Network guidelines on cutaneous melanoma. Accessed October 10, 2021 at: https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf
• 17 Patail NK, Sher AF, Wu S. Improving tolerability of pembrolizumab with weight based dosing: a meta-analysis. Journal of Clinical Oncology 2021; 39 (15) 2639-2639
• 18 Mukherjee S, Ibrahimi S, Machiorlatti M. et al. Personalized dosing versus fixed dosing of immune checkpoint inhibitors: a cost analysis study. Am J Ther 2018; 25 (06) e767-e768
• 19 Low JL, Huang Y, Sooi K. et al. Low-dose pembrolizumab in the treatment of advanced non-small cell lung cancer. Int J Cancer 2021; 149 (01) 169-176
• 20 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;109(11).
• 21 Goldstein DA, Ratain MJ, Saltz LB. Weight-based dosing of pembrolizumab every 6 weeks in the time of COVID-19. JAMA Oncol 2020; 6 (11) 1694-1695
• 22 23rd Expert Committee on Selection and Use of Essential Medicines [Internet]. Accessed September 26, 2021 at: https://www.who.int/news-room/events/detail/2021/06/21/default-calendar/23rd-expert-committee-on-selection-and-use-of-essential-medicines
• 23 Noronha V, Abraham G, Patil V. et al. A real-world data of immune checkpoint inhibitors in solid tumors from India. Cancer Med 2021; 10 (05) 1525-1534
• 24 Singh N, Aggarwal AN, Gupta D, Behera D. Prevalence of low body mass index among newly diagnosed lung cancer patients in North India and its association with smoking status. Thorac Cancer 2011; 2 (01) 27-31
• 25 Kaur H, Sehgal IS, Bal A. et al. Evolving epidemiology of lung cancer in India: reducing non-small cell lung cancer-not otherwise specified and quantifying tobacco smoke exposure are the key. Indian J Cancer 2017; 54 (01) 285-290
• 26 Average height of men and women worldwide [Internet]. Worlddata.info. Accessed November 23, 2021 at: https://www.worlddata.info/average-bodyheight.php
• 27 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 (04) 582-590
• 28 National dose banding table for pembrolizumab, NHS England. Accessed January 1, 2022 at: https://www.england.nhs.uk/publication/national-dose-banding-table-pembrolizumab-25-mgml/
• 29 National dose banding table for nivolumab, NHS England. Accessed January 1, 2022 at: https://www.england.nhs.uk/publication/national-dose-banding-table-nivolumab-10mgml/
• 30 Piccoli M, Selmin F, Mangoni G. et al. 3PC-044 In use physicochemical stability of pembrolizumab under the dilution condition required for use in a day hospital. European Journal of Hospital Pharmacy 2020; 27 (Suppl. 01) A42-A42
• 31 Sundaramurthi P, Chadwick S, Narasimhan C. Physicochemical stability of pembrolizumab admixture solution in normal saline intravenous infusion bag. J Oncol Pharm Pract 2020; 26 (03) 641-646
• 32 Le Guyader G, Vieillard V, Mouraud S, Do B, Marabelle A, Paul M. Stability of nivolumab in its original vials after opening and handing in normal saline bag for intravenous infusion. Eur J Cancer 2020; 135: 192-202
• 33 Geoerger B, Kang HJ, Yalon-Oren M. et al. Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial. Lancet Oncol 2020; 21 (01) 121-133
• 34 Highlights of prescribing information. Accessed January 1, 2022 at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s066lbl.pdf