Efficacy and safety of standard versus extended interval dosing of PD-1/PD-L1 immune checkpoint inhibitors in solid tumors: A meta-analysis of 4,063 patients.

Abstract

e14586 Background: PD-1/PD-L1 immune checkpoint inhibitors (ICIs) are used as monotherapy or in combination for various late-stage solid tumors. There are conflicting results on the optimal dosing regimen. A meta-analysis is needed to evaluate the impact of different ICIs dosing regimens for solid tumors. Methods: Databases PubMed, EMBASE and Cochrane Central were searched for studies comparing standard interval dosing (SD; pembrolizumab 200 mg every 3 weeks; nivolumab 240 mg every 2 weeks; durvalumab 10 mg/kg every 2 weeks) and extended interval dosing (ED; pembrolizumab 400 mg every 6 weeks; nivolumab 480 mg every 4 weeks; durvalumab 1500 mg every 4 weeks) of PD-1/PD-L1 ICIs in solid tumors. The primary outcomes were Immune Related Adverse Events (irAEs) evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE), overall survival (OS) and progression-free survival (PFS). Data analysis was conducted using a random-effects model. The standardized mean difference (SMD) and hazard ratios (HR) was used for continuous outcomes, while risk ratios (RR) were employed for categorical outcomes. Heterogeneity was assessed using the I² statistic. Results: We included 19 studies, of which 17 were observational studies and 2 were conference abstracts. The analysis included 4,063 patients, of whom 1,258 received ED. The solid tumors evaluated were non-small cell lung cancer (NSCLC) and melanoma, representing 54% and 21% of cases, respectively. There was no difference in overall irAEs (RR 1.02; 95% CI 0.89- 1.17; p = 0.78; I 2 = 69%) or in severe irAEs (grade ≥3) across tumors (RR 0.97; 95% CI 0.79- 1.19; p = 0. 75; I 2 = 0%). Similarly, no difference was found in melanoma subgroup with grade ≥3 irAEs (RR 1.03; 95% CI 0.68- 1.56; p = 0.89; I 2 = 0%). Nevertheless, a significant reduction in grade ≥3 irAEs was observed in the NSCLC subgroup with ED (RR 0.79; 95% CI 0.64- 0.98; p = 0.03; I 2 = 0%). Compared to the SD group, ED was associated with higher OS in the NSCLC subgroup (SMD = 0.27; 95% CI 0.09- 0.45; p = 0.003; I 2 = 0%). However, there was no significant reduction in mortality (HR 0.77; 95% 0.53- 1.12; p = 0.17; I 2 = 0%) and PFS also showed no significant differences. Conclusions: PD-1/PD-L1 ICIs in ED were associated with improved survival compared to SD, decreasing irAEs in the NSCLC subgroup. These findings suggest that optimized dosing schedules may be beneficial in specific patient subgroups, such as those with NSCLC, offering valuable insights for the design of RCTs.