Dosing of Immune Checkpoint Inhibitors

Key Messages

What Is the Issue?

• Immune checkpoint inhibitors (ICIs) are cancer therapies that boost the immune system’s ability to fight cancer cells.
• ICIs differ in their dosing regimens (e.g., in terms of the use of fixed versus weight-based dosing and the length of dosing intervals). The dosing approach may influence patient outcomes.
• This report assessed clinical outcomes for the following ICIs: atezolizumab, avelumab, cemiplimab, dostarlimab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and tremelimumab.

What Did We Do?

• We reviewed and summarized the best available evidence comparing different dosing regimens for eligible ICIs.
• We summarized the clinical safety, efficacy, and effectiveness outcomes, and the pharmacokinetic and pharmacodynamic outcomes.
• We employed a narrative (descriptive) approach, rather than a quantitative synthesis (meta-analysis), because of the large variation in design, populations, and outcomes across the studies.

What Did We Find?

• Most comparative evidence in our data relates to pembrolizumab and nivolumab, with less evidence available for the other ICIs and comparators.
• Across studies evaluating fixed dosing versus weight-based dosing, survival and progression outcomes were often similar, and toxicity rates were usually comparable.
• Evidence for pharmacokinetic and pharmacodynamic outcomes suggests that fixed-dose regimens may result in average drug exposure similar to that achieved with weight-based dosing, whereas extended-interval regimens may produce higher peak concentrations and lower trough concentrations.

What Does It Mean?

• For several ICIs, particularly pembrolizumab and nivolumab, different dosing regimens (fixed versus weight-based) may result in similar overall outcomes. However, our confidence in these findings is limited due to the limited availability of evidence from large randomized controlled trials and the considerable amount of evidence from inconclusive nonrandomized studies.
• Across multiple ICIs (e.g., avelumab, cemiplimab, durvalumab, pembrolizumab, nivolumab), the available evidence generally suggests no consistent or clinically meaningful differences in safety or efficacy between fixed and weight-based dosing, although this conclusion is limited by risk of bias.
• Pharmacokinetic and pharmacodynamic evidence indicates that differences in average drug exposure between fixed dosing and weight-based dosing are mainly peak and trough concentration differences that are unlikely to be clinically meaningful.
• For some ICIs (e.g., atezolizumab, dostarlimab, tremelimumab), evidence remains sparse or insufficient, and no firm conclusions can be drawn regarding comparative efficacy or safety between dosing strategies.