Influence of age on the efficacy of immune checkpoint inhibitors in advanced cancers: a systematic review and meta-analysis

Abstract

Background: Immune checkpoint inhibitors (ICIs) represent a paradigm shift in the development of cancer treatment. However, it remains to be clarified whether the benefits that they confer differ according to patient age. We conducted a systematic review and meta-analysis to assess age differences in the benefits of ICI treatment. Methods: We systematically searched the PubMed database for randomised controlled trials of ICIs, including PD-1, PD-L1 and CTLA-4 inhibitors across multiple cancer types, such as melanoma, lung cancer and gastric cancer. We extracted trials including hazard ratios (HRs) for death stratified by patient age (cut-off age, 65 years). The primary objective of this study was to assess the difference in ICI efficacy between younger and older patients. We calculated pooled HRs and 95% confidence intervals (CIs) for younger and older cancer patients, and assessed data heterogeneity. Results: We identified 3999 studies in our search. Of these, 24 eligible randomised trials, including a total of 8157 (57%) younger and 6104 (43%) older cancer patients, fulfilled the criteria for our study and were thus further analysed. The pooled HRs of the younger and older patients were 0.76 (95% CI: 0.69-0.84) and 0.80 (95% CI: 0.71-0.86), respectively; the difference in ICI efficacy between younger and older cancer patients was not significant (p ¼ .82). Regarding the PD-1 and PD-L1 inhibitors, the survival benefit was similar in both age groups (HR: 0.74; p ¼ .96), whereas for the CTLA-4 inhibitors, there tended to be less survival benefit for older versus younger patients (HR: 0.90 and 0.77, respectively; p ¼ .26). Conclusions: The survival benefit conferred by ICI was not age-dependent, amongst patients aged 65 years or younger. However, age-dependent benefits may vary amongst different types of ICIs.

Impact of Age on the Efficacy of Immune Checkpoint Inhibitor-Based Combination Therapy for Non-small-Cell Lung Cancer: A Systematic Review and Meta-Analysis

“…Age affects host immunity and therefore could affect the effectiveness of ICI treatment. Although some meta-analyses have found that the therapeutic effect of ICI was independent of age ( 21 , 22 , 43 – 45 ), these meta-analyses mainly focused on ICI monotherapy or total cancer treatment and did not specifically study the influence of age on ICI combined with other treatments in the context of NSCLC. To the best of our knowledge, this is the first meta-analysis to investigate the impact of age on the efficacy of ICI-based combination therapy vs. non-ICI therapy in NSCLC patients.…”

“…Based on the preclinical data mentioned above, it is speculated that older patients obtain limited benefits from ICI treatment compared to younger patients. However, some studies have reported that the benefit of ICI treatment is independent of age (21)(22)(23).…”

Mikronährstoffe, Immunüberwachung und Immunseneszenz

“…Zwar liegt z. B. eine größere Metaanalyse zur Wirkung von Checkpoint-Inhibitoren bei verschiedenen Tumoren und die potenzielle Beeinflussung des Effekts durch das Alter vor, bei denen für Anti-PD-1-und Anti-PD-L1-Therapie eine ähnliche Wirkung bei jüngeren wie älteren Patienten und eine allerdings nicht signifikante schwächere Wirkung bei Älteren für CTLA-4-Inhibitoren gezeigt wurde [12], die Rolle von Mikronährstoffen war dabei aber nicht berücksichtigt worden. Außerdem waren Patienten über 65 Jahren in den zugrundeliegenden Studien ausgeschlossen, die Hauptzielgruppe ist also gar nicht abgebildet worden.…”

Understanding Checkpoint Inhibitors in Cancer Therapy, Mechanisms of Action, Resistance and Future Challenges

“…PD-L1 (Atezolizumab) inhibitors had comparable efficacy in adults with metastatic cancer in people older than 65 years of age [36]. Furthermore, two large meta-analysis investing the impact of age on the efficacy of ICIs used for treatment of multiple metastatic cancer types showed no difference between young and older patients (cut off = 65 years) [40,41]. In addition, a systematic review of 23 randomized controlled trials involving 9322 men (67.9%) and 4399 women (32.1%) with advanced cancer receiving ICIs showed no statistically significant impact of patients' gender on the efficacy of ICIs measuring overall survival as the primary outcome [42].…”