A 2022 review explored the dosing and schedule optimization of immune checkpoint-targeted antibodies, particularly anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) and anti-programmed cell death protein/ligand 1 (anti-PD-1/PD-L1) monoclonal antibodies, which have become pivotal in cancer immunotherapy. These therapeutic antibodies, including ipilimumab, nivolumab, pembrolizumab, atezolizumab, and others, were developed with dosing regimens largely guided by conventional models from chemotherapy, emphasizing fixed intervals or weight-based calculations. Development trials identified no dose-limiting toxicities for most PD-1/PD-L1 inhibitors, allowing fixed dosing options to evolve from weight-based regimens, despite notable economic and clinical implications. Fixed-dose regimens, such as pembrolizumab at 200 mg every three weeks or nivolumab at 480 mg every four weeks, were standardized based on average patient weights during trials, often leading to overexposure in lower-weight patients; however, due to exceeding the minimum effective dose, the effect of increased plasma concentration on treatment may be clinically negligible. Prospective evaluations of therapeutic drug monitoring could ensure dose customization, optimizing patient outcomes while mitigating the substantial financial burden of these therapies. [1]
A 2022 commentary article highlights the clinical and pharmacoeconomic rationale for adopting weight-based dosing of pembrolizumab (2 mg/kg every 3 weeks or 4 mg/kg every 6 weeks) instead of the currently favored flat dose of 200 mg. The authors argue that weight-based dosing achieves similar efficacy and safety outcomes, supported by pharmacokinetic, pharmacodynamic, and clinical trial data, while substantially reducing drug wastage and cost, especially in lower-weight populations. The commentary outlines that flat dosing was adopted primarily for logistical convenience and manufacturer-driven modeling studies, despite evidence that higher doses do not improve clinical outcomes. Real-world studies and pharmacokinetic models show that a 2 mg/kg dose achieves comparable drug exposure to the 200 mg flat dose, with some meta-analyses suggesting better tolerability and lower discontinuation rates. International agencies, such as the such as the Canadian Agency for Drugs and Technologies in Health (CADTH) and the World Health Organization (WHO), also support weight-based dosing due to its cost-effectiveness. The authors recommend implementing dose banding and vial sharing strategies to optimize pembrolizumab use and advocate for the reintroduction of the 50 mg vial to improve dosing flexibility and reduce waste, especially in pediatric settings. Ultimately, the authors call on policymakers and regulatory agencies to support weight-based dosing of pembrolizumab as a rational, cost-saving approach without compromising patient outcomes. [2]
A 2021 meta-analysis abstract presented at the American Society of Clinical Oncology (ASCO) Annual Meeting evaluated the tolerability of pembrolizumab across 20 prospective clinical trials involving 6,380 patients with various malignancies. The analysis included both weight-based and fixed dosing regimens. The overall discontinuation rate due to adverse events was 8.2% (95% confidence interval [CI] 6.4 to 10.4%). Notably, the rate was 6.5% (95% CI 4.8 to 8.8%) with weight-based dosing and 9.2% (95% CI 6.9 to 12%) with fixed dosing. Additionally, weight-based dosing was associated with a significantly lower risk of discontinuation compared to controls (RR 0.62; 95% CI 0.47 to 0.81; p<0.0001), whereas fixed dosing did not show a statistically significant difference (RR 1.03; 95% CI 0.89 to 1.20; p= 0.67). [3]
A 2024 retrospective cohort analysis (see Table3 ) was conducted to compare the outcomes of weight-based dosing versus fixed dosing of pembrolizumab in patients with non-small cell lung cancer (NSCLC). The study utilized data from 1413 adult patients who were members of Kaiser Permanente in Northern and Southern California, spanning treatments initiated between January 2015 and December 2020. The patients, all weighing under 100 kg, were stratified into two cohorts based on their dosing regimen: those who received a weight-based dose of 2 mg/kg every three weeks or 4 mg/kg every six weeks, and those who received a fixed dose of 200 mg every three weeks or 400 mg every six weeks. The primary effectiveness outcome assessed was overall survival (OS), while safety outcomes focused on all-cause emergency room visits, hospitalizations, and the incidence of immune-related adverse events (irAEs). These outcomes were analyzed through non-inferiority (NI) analysis, with OS compared using a lower margin of 10% and safety outcomes using an upper margin of 10%. The analysis revealed that the OS rate in the fixed dose group was 36.6%, while the weight-based dose group exhibited a 37.7% survival rate, with a rate difference of 1% and a 90% confidence interval ranging from −6% to 8%. The NI analysis demonstrated a significant result with p-values <0.01. Furthermore, non-inferiority was supported in all safety outcomes, with the rates of all-cause emergency room visits and hospitalizations showing minimal differences between the two dosing regimens. The proportion of patients experiencing irAEs was slightly higher in the weight-based group but still met the non-inferiority criteria, with NI p-values under 0.01. Overall, these findings suggest that weight-based dosing of pembrolizumab offers comparable effectiveness and safety to fixed dosing, providing flexibility in treatment without compromising patient outcomes. [4]
A 2017 pharmacokinetic study assessed whether a fixed-dose approach could be used in place of traditional weight-based dosing for pembrolizumab. Historically, monoclonal antibodies have been dosed based on body weight due to the assumption that body size influences pharmacokinetic variability. Early pembrolizumab trials followed this model, but later population pharmacokinetic (popPK) and exposure-response data prompted a re-evaluation. Using an established popPK model and exposure-response analyses from patients with advanced melanoma and NSCLC, the authors explored whether a fixed 200 mg dose administered every 3 weeks could maintain drug exposures within the therapeutic window established in prior trials of 2 mg/kg and 10 mg/kg every 3 weeks. To support their findings, they examined pharmacokinetic exposures in additional tumor types, including head and neck cancer, NSCLC, microsatellite instability-high (MSI-H) colorectal cancer, and urothelial cancer, where fixed dosing had been implemented. Results showed that clearance of pembrolizumab depended on body weight, but the relationship followed a power function with an exponent of 0.578. This indicated that both fixed and weight-based dosing would similarly control variability in drug exposure. The 6-week steady-state area under the curve (AUCss) was 1.87 mg·day/mL (coefficient of variation [CV] 37%, n= 830) for 200 mg every 3 weeks, 1.38 mg·day/mL (CV 38%, n= 760) for 2 mg/kg every 3 weeks, and 7.63 mg·day/mL (CV 35%, n= 1405) for 10 mg/kg every 3 weeks. Although high-weight patients (>90 kg) had lower exposures on the 200 mg fixed dose, these remained within the clinically effective exposure range established in early studies. The authors concluded that fixed-dose and weight-based pembrolizumab regimens produce comparable exposure profiles and pharmacokinetic variability. Both strategies were deemed appropriate for clinical use, offering flexibility in dosing approaches depending on institutional preferences or logistical considerations. [5]
Abstracts of two recent retrospective studies evaluated the use of weight-based versus fixed dosing of pembrolizumab. In the first single-center study, 46 patients with NSCLC and a CPS score of <50% received pembrolizumab in combination with pemetrexed and platinum. Twenty-six patients received weight-based dosing (2 mg/kg every three weeks), while the remainder received a fixed 200 mg dose. The overall response rate (complete/partial response) was 60%in the weight-based group and 50% in the fixed-dose group. Progression-free survival averaged 13.24 months (95% CI 10 to 16.5) in the weight-based group and 13.7 months (95% CI 8.1 to 19.1) in the fixed-dose group. OS was 18.15 months and 18.16 months, respectively, with no statistically significant differences found. The weight-based group received a lower average dose (148 ± 27 mg), resulting in a 34% cost reduction compared to fixed dosing. In the second study, adverse drug reactions (ADRs) were analyzed among 391 patients treated with pembrolizumab across various cancer types. Patients were stratified by weight (<80 kg vs. ≥80 kg), and ADRs were observed in 34.8% of those under 80 kg and 26% of those over 80 kg. While there was no statistically significant difference in ADR rates, the study concluded that weight-based dosing may be preferable in patients under 80 kg due to potentially lower toxicity and estimated cost savings of 26% compared to fixed dosing. Overall, both studies suggest that weight-based pembrolizumab may offer comparable clinical outcomes to fixed dosing while providing potential advantages in cost savings and, in certain populations, reduced toxicity. [6], [7]
Lastly, in a 2024 poster abstract, a retrospective study evaluating the outcomes of weight-based and flat dosing for immune checkpoint inhibitors (ICIs; e.g. pembrolizumab, nivolumab and/or ipilimumab) in underweight patients (<50 kg) was conducted. A total of 313 patients (median age, 66 years; 81.5% female) were included, with a median weight of 47 kg; of the included patients, 252 (80.5%) received flat-dosing, while 61 (19.5%) received weight-based dosing. In total, 120 (59%) received pembrolizumab. Although there were trends towards lower toxicity, less hospitalization, and less need for treatment for immune-related adverse events with weight-based dosing, these findings were non-significant. Similarly, there was no difference in mortality or requirements for hospice care between groups. As the full study and utilized dosages are unavailable for scrutiny, these findings should be considered with caution. [8]
In a detailed 2023 abstract, researchers analyzed the pharmacology and dosing strategies of immune checkpoint inhibitors, focusing on anti-PD-1 therapies, nivolumab and pembrolizumab. The paper presents a comprehensive overview of existing data on these therapies, emphasizing the necessity for cost-effective dosing strategies due to the financial strain on global health-care budgets. It is underscored that immune checkpoint inhibitors are often administered at doses exceeding those required for optimal anti-tumor efficacy, potentially leading to unnecessary financial burdens. The authors provide specific recommendations aimed at guiding health-care professionals through the process of prescribing, rounding, preparing, and administering these medications in a practical and economically prudent manner. By highlighting novel dosing strategies, the paper advocates for an approach that maximizes therapeutic outcomes while minimizing costs. The authors argue that by adopting these strategies, there is a significant potential for cost savings, which could preserve patient access to these transformative cancer therapies. Overall, the detailed analysis calls for a reassessment of current practices to ensure both clinical efficacy and financial sustainability. [9]